Risk Of Incident Coronary Heart Disease Research Articles

Changes in Sleep Patterns, Genetic Susceptibility, and Incident Cardiovascular Disease in China

The associations of changes in sleep patterns with incident cardiovascular disease (CVD) are not fully elucidated, and whether these associations are modified by genetic susceptibility remains unknown. To investigate the associations of 5-year changes in sleep patterns with incident CVD and whether genetic susceptibility modifies these associations. This prospective cohort study of the Dongfeng-Tongji cohort was conducted from 2008 to 2018 in China. Eligible participants included those with complete sleep information at baseline survey (2008-2010) and the first follow-up survey (2013); participants who had no CVD or cancer in 2013 were prospectively assessed until 2018. Statistical analysis was performed in November 2023. Five-year changes in sleep patterns (determined by bedtime, sleep duration, sleep quality, and midday napping) between 2008 and 2013, and polygenic risk scores (PRS) for coronary heart disease (CHD) and stroke. Incident CVD, CHD, and stroke were identified from 2013 to 2018. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% CIs. Among 15 306 individuals (mean [SD] age, 65.8 [7.4] years; 8858 [57.9%] female and 6448 male [42.1%]), 5474 (35.78%) had persistent unfavorable sleep patterns and 3946 (25.8%) had persistent favorable sleep patterns. A total of 3669 incident CVD cases were documented, including 2986 CHD cases and 683 stroke cases, over a mean (SD) follow-up of 4.9 (1.5) years. Compared with those with persistent unfavorable sleep patterns, individuals with persistent favorable sleep patterns over 5 years had lower risks of incident CVD (HR, 0.80; 95% CI, 0.73-0.87), CHD (HR, 0.84; 95% CI, 0.76-0.92), and stroke (HR, 0.66; 95% CI, 0.54-0.82) in the subsequent 5-year period. No significant effect modification by PRS was observed for sleep pattern change and CHD or stroke risk. However, sleep pattern changes and PRS were jointly associated with the CHD and stroke risk in a dose-dependent manner, with the lowest risk being among those with persistent favorable sleep patterns combined with low PRS (HR for CHD, 0.65; 95% CI, 0.52-0.82 and HR for stroke, 0.48; 95% CI, 0.29-0.79). In this cohort study of middle-aged and older Chinese adults, individuals with persistent favorable sleep patterns had a lower CVD risk, even among those with higher genetic risk. These findings highlight the importance of maintaining favorable sleep patterns for CVD prevention.

Abstract P277: Adherence to Time-Restricted Eating, Plasma Metabolomic Signatures, and Risk of Coronary Heart Disease

Introduction: Early time-restricted eating (TRE) has been recently suggested as an effective dietary intervention strategy to improve risk factors of coronary heart disease (CHD), whereas late TRE may be related to poor cardiometabolic health. Metabolomic pathways linking the adherence to habitual TREs depending on the time of the day and CHD risk are unknown. Hypothesis: We tested whether adherence to early or late TRE was related to distinct metabolomic signatures (including those in pathways of energy/purine pyrimidine metabolism, lipids, carbohydrates, and acylcarnitines). We then tested whether TRE-related plasma metabolites were associated with the risk of incident CHD among women without prior CHD. Methods: This study included 674 women without cardiovascular disease who completed 7-day food records and measurements of untargeted plasma metabolomics in a sub-study of the Nurses’ Health Studies (NHS/NHSII). TRE was indicated by 4-12 hours of daily eating window. The adherence to TRE was assessed by summing up the TRE days in a week (0-7 days). We analyzed two TRE habits: early TRE (starting before 9 a.m./ending no later than 9 p.m.) and late TRE (beginning after 9 a.m.). Separately, plasma metabolites were measured in a prospective nested case-control of 762 incident cases of CHD and 762 matched controls identified over 10-14 years of follow-up in the NHS. A metabolomic risk score for predicting adherence to late TRE (MRS-TRE late ) was created based on metabolites selected through the elastic net procedure with a 10-fold cross-validation. Results: Adherence to late TRE was positively associated with greater adiposity, insulin/proinsulin, uric acid, and medium-chain fatty acids/acylcarnitines; the late TRE habit was inversely related to metabolites in the TCA cycle/pyruvate metabolism and specific PC species ( P FDR <0.05). On the other hand, metabolites in lipid pathways (including diglyceride DG 38:5) and glucose were inversely related to the adherence to early TRE. Individual levels of late-TRE-related metabolites in energy/phosphatidylcholine /acylcarnitine pathways were significantly associated with an increased risk of CHD. Every 1 SD increment of MRS-TRE late , based on 21 metabolites in various metabolic pathways, was associated with a relative risk (RR) of 1.24 (95% CI: 1.11, 1.38) for CHD in a model adjusted for matching factors, and a RR of 1.15 (1.02, 1.29) after adjusting for covariates, such as demographic factors, diet quality, alcohol, lifestyle factors, and BMI. Women in the top tertile of MRS-TRE late had a 1.44-fold (1.10, 1.89) increased risk of CHD as compared to those in the lowest tertile after adjusting for the covariates. Conclusions: TRE habit, depending on the timing, was related to distinct metabolomic pathways, and adherence to late TRE may be associated with metabolic reliance linked to the risk of incident CHD among women.

Abstract MP46: Recurrent Hypertensive Disorders of Pregnancy and Subsequent Maternal Coronary Heart Disease and Stroke

Introduction: Hypertensive disorders of pregnancy (HDP) complicate 5-10% of pregnancies and lead to maternal morbidity and mortality. Prior HDP increases HDP risk in subsequent pregnancies with little known about coronary heart disease (CHD) and stroke in recurrent HDP. We aimed to assess the relationship between recurrent HDP and subsequent CHD and stroke. Methods: This retrospective cohort study included women aged 12-49 with one or more singleton, live birth in South Carolina from 2004-2016. Deliveries were evaluated for HDP (preeclampsia, eclampsia, gestational hypertension) defined by birth certificate and/or hospitalization/emergency department (ED) visit data. Women were classified as having no, one, or two or more pregnancies with HDP. Hospitalization/ED visit and death certificate data defined incident CHD and stroke. Extended Cox models with time varying covariates were used to evaluate the association of recurrent HDP with CHD and stroke controlling for sociodemographic, behavioral, and clinical characteristics. Results: The 163,598 women (non-Hispanic White (NHW; 57.8%), non-Hispanic Black (NHB; 33.9%), and Hispanic (8.3%) had two or more (3.3%), one (12.0%), or no (84.7%) HDP pregnancies. Women with recurrent HDP were more likely to develop subsequent CHD or stroke after covariable adjustment (Table 1). Having one or two or more HDP pregnancies compared with no HDP pregnancies increased the subsequent risk of CHD (HR=2.25; 95% CI: 1.97-2.56 and HR=2.98; 95% CI: 2.43-3.67, respectively). Having one or two or more HDP pregnancies compared with no HDP pregnancies increased the subsequent risk of stroke (HR=2.05; 95% CI: 1.61-2.61 and HR=2.97; 95% CI: 2.04-4.32, respectively). Discussion: Women with recurrent HDP are at higher risk of subsequent CHD and stroke. Higher incident CHD and stroke risk appears to persist into the next pregnancy with accumulated HDP conferring higher risk.

Abstract MP73: The Association of Urinary Metals With Cardiovascular Disease Incidence and All-Cause Mortality in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Environmental exposure to metals is widespread yet preventable and has been associated with cardiovascular disease (CVD) endpoints, although evidence from prospective studies with racial and ethnic diversity is limited. Objective: We assessed the prospective association of urinary metals with incident coronary heart disease (CHD) and CVD and all-cause mortality in a diverse population of adults from the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: We included 6,638 MESA participants (mean (SD) age 62.1(10.2) years, 53% female, 39% non-Hispanic white, 27% non-Hispanic Black, 22% Hispanic/Latino, 12% Chinese). Urinary non-essential metals (cadmium, tungsten, and uranium), and essential metals (cobalt, copper, and zinc) were assessed at baseline (2000-2001). We used Cox proportional hazards regression to estimate adjusted (table footnote) hazard ratios (HR) for the association between urine metals with incident CHD, CVD, and all-cause mortality through 2019. Results: Over 17.7 years median follow up (IQR: 12.4, 18.5), 749 (11%) participants developed CHD, 1,162 (17%) developed CVD, and 1,844 (28%) died. In the models adjusted by sociodemographic and behavioral factors (Table 1, [Model 1]), one IQR increase in urinary cadmium, tungsten, cobalt, copper, and zinc at baseline was significantly associated with higher risk of incident CHD, incident CVD and all-cause mortality. Uranium levels were significantly associated with all-cause mortality and incident CVD, but not CHD. The magnitude of the association was attenuated when adjusting the models for clinical risk factors (Table 1, [Model 2]). A linear trend was identified for cadmium and copper and all endpoints. Conclusion: Our findings among a large and ethnically diverse US population support that metal exposure is associated with incident CVD and premature mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health.

Microvascular Disease, Cardiovascular Health, and Risk of Coronary Heart Disease in Type 2 Diabetes: A UK Biobank Study.

The interplay between cardiovascular health metrics (CVHMs) and microvascular disease (MVD) in relation to the risk of incident coronary heart disease (CHD) among individuals with type 2 diabetes mellitus (T2DM) remains to be evaluated. To investigate the role of MVD and CVHMs in the development of CHD among T2DM. We included 19,664 participants with T2DM from the UK Biobank who had data on CVH metrics (CVHMs) and were free of CHD during recruitment. CVHMs were defined based on five behavioral (body mass index, diet, sleep duration, smoking, and regular exercise) and three biological factors (glycemic control, hyperlipidemia, and hypertension). MVD was defined as the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. HR and 95% CI of CHD were estimated by multivariable Cox regression models. There were 3,252 incident cases of CHD recorded after a median follow-up of 12.3 years. After multivariable adjustment, each MVD was separately associated with risk of CHD, and those who had 1 or ≥2 MVD had a 27% and an 87% increased risk of developing CHD, respectively. Each of the unfavorable CVHMs was associated with a higher risk of CHD. As compared with MVD-free participants who had ideal CVHMs, those who had ≥2 MVD and had poor CVHMs were at particularly high risk of incident CHD (HR=4.58; 95% CI: 3.58, 5.86), similarly when considering behavioral CVH or biological CVH separately. On an additive scale, there was a positive statistically significant interaction between number of MVD and CVHMs. Coexistence of multiple MVDs was associated with a substantially higher risk of CHD among individuals with T2DM. Such an association may be amplified by unfavorable CVHMs.

Comparison of seven surrogate insulin resistance indexes for prediction of incident coronary heart disease risk: a 10-year prospective cohort study.

There were seven novel and easily accessed insulin resistance (IR) surrogates established, including the Chinese visceral adiposity index (CVAI), the visceral adiposity index (VAI), lipid accumulation product (LAP), triglyceride glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC) and TyG-waist to height ratio (TyG-WHtR). We aimed to explore the association between the seven IR surrogates and incident coronary heart disease (CHD), and to compare their predictive powers among Chinese population. This is a 10-year prospective cohort study conducted in China including 6393 participants without cardiovascular disease (CVD) at baseline. We developed Cox regression analyses to examine the association of IR surrogates with CHD (hazard ratio [HR], 95% confidence intervals [CI]). Moreover, the receiver operating characteristic (ROC) curve was performed to compare the predictive values of these indexes for incident CHD by the areas under the ROC curve (AUC). During a median follow-up period of 10.25 years, 246 individuals newly developed CHD. Significant associations of the IR surrogates (excepted for VAI) with incident CHD were found in our study after fully adjustment, and the fifth quintile HRs (95% CIs) for incident CHD were respectively 2.055(1.216-3.473), 1.446(0.948-2.205), 1.753(1.099-2.795), 2.013(1.214-3.339), 3.169(1.926-5.214), 2.275(1.391-3.719) and 2.309(1.419-3.759) for CVAI, VAI, LAP, TyG, TyG-BMI, TyG-WC and TyG-WHtR, compared with quintile 1. Furthermore, CVAI showed maximum predictive capacity for CHD among these seven IR surrogates with the largest AUC: 0.632(0.597,0.667). The seven IR surrogates (excepted for VAI) were independently associated with higher prevalence of CHD, among which CVAI is the most powerful predictor for CHD incidence in Chinese populations.

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

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. The objective of this study was to investigate these associations in a population with a high prevalence of dyslipidemia and CVD. 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. 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). 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.

Polygenic Risk, Rare Variants, and Family History: Independent and Additive Effects on Coronary Heart Disease

BackgroundGenetic factors are not included in prediction models for coronary heart disease (CHD). ObjectivesThe authors assessed the predictive utility of a polygenic risk score (PRS) for CHD (defined as myocardial infarction, coronary revascularization, or cardiovascular death) and whether the risks due to monogenic familial hypercholesterolemia (FH) and family history (FamHx) are independent of and additive to the PRS. MethodsIn UK-biobank participants, PRSCHD was calculated using metaGRS, and 10-year risk for incident CHD was estimated using the pooled cohort equations (PCE). The area under the curve (AUC) of the receiver operator curve and net reclassification improvement (NRI) were assessed. FH was defined as the presence of a pathogenic or likely pathogenic variant in LDLR, APOB, or PCSK9. FamHx was defined as a diagnosis of CHD in first-degree relatives. Independent and additive effects of PRSCHD, FH, and FamHx were evaluated in stratified analyses. ResultsIn 323,373 participants with genotype data, the addition of PRSCHD to PCE increased the AUC from 0.759 (95% CI: 0.755-0.763) to 0.773 (95% CI: 0.769-0.777). The AUC and NRIEvent for PRSCHD were higher before the age of 55 years. Of 199,997 participants with exome sequence data, 10,000 had a PRSCHD ≥95th percentile (PRSP95), 673 had FH, and 46,163 had FamHx. The CHD risk associated with PRSP95 was independent of FH and FamHx. The risks associated with combinations of PRSCHD, FH, and FamHx were additive and comprehensive estimates could be obtained by multiplying the risk from each genetic factor. ConclusionsIncorporating PRSCHD into the PCE improves risk prediction for CHD, especially at younger ages. The associations of PRSCHD, FH, and FamHx with CHD were independent and additive.

Association of retinal microvascular density and complexity with incident coronary heart disease

Background and aimsThe high mortality rate and huge disease burden of coronary heart disease (CHD) highlight the importance of its early detection and timely intervention. Given the non-invasive nature of fundus photography and recent development in the quantification of retinal microvascular parameters with deep learning techniques, our study aims to investigate the association between incident CHD and retinal microvascular parameters. MethodsUK Biobanks participants with gradable fundus images and without a history of diagnosed CHD at recruitment were included for analysis. A fully automated artificial intelligence system was used to extract quantitative measurements that represent the density and complexity of the retinal microvasculature, including fractal dimension (Df), number of vascular segments (NS), vascular skeleton density (VSD) and vascular area density (VAD). ResultsA total of 57,947 participants (mean age 55.6 ± 8.1 years; 56% female) without a history of diagnosed CHD were included. During a median follow-up of 11.0 (interquartile range, 10.88 to 11.19) years, 3211 incident CHD events occurred. In multivariable Cox proportional hazards models, we found decreasing Df (adjusted HR = 0.80, 95% CI, 0.65–0.98, p = 0.033), lower NS of arteries (adjusted HR = 0.69, 95% CI, 0.54–0.88, p = 0.002) and venules (adjusted HR = 0.77, 95% CI, 0.61–0.97, p = 0.024), and reduced arterial VSD (adjusted HR = 0.72, 95% CI, 0.57–0.91, p = 0.007) and venous VSD (adjusted HR = 0.78, 95% CI, 0.62–0.98, p = 0.034) were related to an increased risk of incident CHD. ConclusionsOur study revealed a significant association between retinal microvascular parameters and incident CHD. As the lower complexity and density of the retinal vascular network may indicate an increased risk of incident CHD, this may empower its prediction with the quantitative measurements of retinal structure.

Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events

Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.

Serum High-Sensitivity Cardiac Troponin T as an Independent Predictor for Incident Coronary Heart Disease in the Japanese General Population: The Circulatory Risk in Communities Study (CIRCS).

Epidemiological evidence is extremely limited about high-sensitivity cardiac troponin T (hs-cTnT) and future coronary heart disease (CHD) events for the general population in countries with low mortality from CHD. Therefore, we investigated the association between hs-cTnT levels and the risk of incident CHD using a nested case-control study in a large Japanese cohort study. The participants were residents of four Japanese communities in the Circulatory Risk in Communities Study (CIRCS). We obtained 120 cases (81 men and 39 women, aged 38-86 years at baseline) of first incident CHD and 240 controls matched by age, sex, communities, and blood sampling term. Serum hs-cTnT levels were measured using an electrochemiluminescence immunoassay with stored sera collected between 2001 and 2011. The median period between sampling at survey and CHD incidence was 2.0 (interquartile range, 0.9-3.7) years. After adjusting for conventional risk factors, the multivariable odds ratios (ORs) of CHD were calculated using conditional logistic regression analyses. hs-cTnT ranged from ≤ 3 (assay detection limit) to 155 ng/L. Compared with the lowest quartile of hs-cTnT, multivariable ORs (95% confidence intervals) of CHD for the second, third, and highest quartiles were 1.30 (0.57-2.95), 2.48 (1.09-5.64), and 3.01 (1.27-7.12), respectively. Similar associations were observed after adjusting for estimated glomerular filtration, or after excluding matched groups, including people with chronic kidney disease. Serum hs-cTnT could predict CHD in the Japanese general population. These findings implicate a benefit from monitoring hs-cTnT to predict CHD even among populations in countries with low mortality from CHD.

Abstract 16: Maternal Coronary Heart Disease and Mortality Within 5 Years of Delivery Among Women With Hypertensive Disorders of Pregnancy and/or Diabetes

Introduction: Pre-pregnancy hypertension (HTN), hypertensive disorders of pregnancy (HDP), and diabetes are linked to increased risk of post-pregnancy coronary heart disease (CHD) and all-cause mortality, but the cumulative impact of pre-pregnancy HTN, HDP, and diabetes has yet to be fully investigated. We aimed to examine associations between HDP and diabetes with CHD and mortality ≤5 years of delivery stratified by race/ethnicity. Methods: This retrospective cohort study included women aged 12-49 with ≥1 singleton, live birth in South Carolina (2004-2016). After exclusions, 431,839 women remained: non-Hispanic White [NHW; 58.8%], non-Hispanic Black [NHB; 31.7%], and Hispanic [9.5%]. Birth certificates defined pre-pregnancy HTN, HDP (preeclampsia, eclampsia, gestational hypertension), and diabetes (pre-pregnancy, gestational); hospitalization/ED visit data also defined pre-pregnancy HTN and HDP. Hospitalization/ED visit data and death certificates defined incident CHD and all-cause mortality. Cox proportional hazard models adjusted for covariates assessed associations by condition and race/ethnicity. Results: Incident CHD risk was increased ≤5 years of delivery for women with diabetes (HR=1.79, CI: 1.40-2.29), HDP (HR=2.91, CI: 1.98-2.65), diabetes and HDP (HR=3.95 CI:3.09-5.05), pre-pregnancy HTN and HDP (HR=3.94, CI: 3.11-5.00), and all three conditions (HR=5.78, CI: 4.41-8.06) compared to none. All-cause mortality risk was increased for HDP (HR=1.31, CI: 1.08-1.58), diabetes and HDP (HR=1.93, CI: 1.30-2.87), pre-pregnancy HTN and HDP (HR=2.20, CI: 1.54-3.15), and all three conditions (HR=2.88, CI: 1.61-5.16), but not with diabetes. The table shows overall and race/ethnic-specific event rates and model results. Discussion: Women with HDP (regardless of pre-pregnancy HTN) and/or diabetes experienced higher incident CHD and all-cause mortality risk ≤5 years of delivery. Event rates were highest for women with two or three conditions, with all event rates higher for NHB than NHW women.

Abstract 41: Comprehensive Plasma Metabolomic Risk Scores to Predict Incident Coronary Heart Disease Events

Introduction: Integrating multiple metabolomics signatures related to coronary heart disease (CHD) into a metabolomic risk score (MRS) may contribute to improving the risk prediction beyond traditional risk factors, although applications of the MRS remain underdetermined, especially in people at usual risk. Hypothesis: We analyzed associations of plasma metabolites with the risk of CHD to develop MRS for predicting risk of incident CHD by incorporating comprehensive metabolic pathways among women at usual risk from the Nurses’ Health Study (NHS). We also tested whether changes in CHD-related plasma metabolites were associated with significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk scores among participants in the POUNDS Lost trial. Methods: Untargeted metabolomics profiling was performed to measure plasma metabolites at baseline in a prospective nested case-control of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up time in NHS. An MRS of CHD risk was created based on metabolites that were selected through conditional logistic regression with the elastic net procedure. The POUNDS Lost trial included adults with overweight/obesity who consumed weight-loss diets with different macronutrient intakes. We measured untargeted plasma metabolomics signatures at baseline, 6 months, and 2 years to calculate changes in response to the dietary interventions. The primary outcome in the POUNDS Lost trial was the reduction of 10-year ASCVD risk scores calculated by the validated pooled cohort equations. Results: Various plasma metabolites (such as gut-microbiota-related and others in the pathways of ceramides, phospholipids, and polyamine metabolism) were associated with the risk of incident CHD ( P FDR &lt;0.05). We developed MRS for CHD combining 122 metabolites and found that the highest quartile (Q4) was associated with 11.3 times (95% CI: 6.88, 18.6) higher risk of CHD, as compared to the lowest quartile (Q1), even after adjusting for covariates including common CHD risk factors (such as a family history of MI, lifestyle factors, obesity, diabetes, hypertension, and dyslipidemia). Every 1 SD increment of MRS was associated with an adjusted RR of 3.23 (95% CI 2.62, 3.97) for CHD events. In the POUNDS Lost, diet-intervention-induced changes in CHD-related metabolites, particularly those in ceramide pathways, were significantly associated with reductions in the ASCVD risk score at 6 months and 2 years. Conclusions: Comprehensive metabolomic scores were strongly related to the risk of incident CHD among women without prior CHD. Dietary interventions may modify the unfavorable relations between CHD-risk-related metabolites and ASCVD risk. Further studies in other populations are warranted to validate the performance of MRS in predicting ASCVD events.

Abstract MP24: Atherogenic Gut Microbial Metabolite Scores and Risk of Coronary Heart Disease Among Women in the Nurses’ Health Study

Introduction: Recent evidence suggests that dietary proteins modulate the microbial composition and metabolite production to influence host physiology. Gut-microbiota-related metabolites, such as trimethylamine N-oxide (TMAO) and its precursors, phenylacetylglutamine (PAGln) and p-tolyl (cresol) sulfate, have been recently implicated as atherogenic metabolites derived from the microbial metabolism of protein foods (such as red meat) and amino acids. Hypothesis: We tested a hypothesis that combined effects of atherogenic gut microbiota-related metabolites may be strongly related to the risk of incident coronary heart disease (CHD) among women. Methods: We conducted a prospective nested case-control study of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up. Plasma metabolites (TMAO, N,N,N-trimethyllysine, PAGln, and p-tolyl (cresol) sulfate) were measured at baseline. We regressed the CHD outcome against metabolites using conditional logistic regression and then calculated an atherogenic microbial metabolite score (AMMS) of CHD by summing the β effects of metabolites. Results: Every 1 SD increment of AMMS was associated with a matching factor-adjusted RR of 1.28 (95% CI: 1.15, 1.44) and a multivariable-adjusted RR of 1.26 (1.12, 1.42) for CHD controlling for demographic, dietary, and lifestyle factors, postmenopausal hormone use, and body mass index. Dose-response analysis showed a linear relation between AMMS and the risk of CHD ( P &lt;0.001). In addition, there was a 1.20 (1.06, 1.36) times increased risk of CHD per 1 SD of AMMS after adjusting for common metabolic comorbidities (diabetes, hypertension, and dyslipidemia). The highest quintile (Q5) group had an adjusted RR of 1.60 (1.08, 2.37) for CHD, as compared to the lowest quintile (Q1) ( Fig ). Conclusions: Atherogenic gut microbiota-related metabolite scores were significantly associated with risk of incident CHD among women without prior CHD.

Abstract MP11: Ultra-Processed Food Consumption and Cardiovascular Disease in the European Prospective Investigation Into Cancer and Nutrition Study

Introduction: Diets containing many ultra-processed foods (UPF) are linked to unfavourable health. UPF are defined by the NOVA classification as industrial food and drinks made from substances not used in domestic culinary preparations, such as hydrogenated fats, modified starches, and other food additives. There is evidence suggesting a link between UPF consumption and cardiovascular disease (CVD) incidence, but this association has not been tested in a large European cohort. Using data from the pan-European Prospective Investigation into Cancer and nutrition (EPIC) study, we assessed the hypothesis that higher consumption of UPF is associated with an increased risk of incident fatal and non-fatal CHD and stroke in the EPIC-Heart cohort. Methods: Case-cohort design nested in the EPIC cohort including 36,415 adults from Denmark, Germany, Italy, the Netherlands, Spain, Sweden, and the UK. Socio-demographic, lifestyle factors and usual dietary intake were assessed at time of recruitment (1992 - 2000) using country-specific validated questionnaires. Consumption of UPF was expressed in percentage of grams per day. CVD cases ascertainment varied across EPIC centres and included hospital admissions, linkage to registers, self-report and mortality data. Proportion of missing values ranged from 0.95% for smoking status to 14.2% for history of diabetes. We performed multiple imputation on all covariates with missing values. Cox proportional hazard models with age as the underlying time variable stratified by sex, centre and age were used to test the longitudinal association between UPF consumption and coronary heart disease (CHD) and stroke incidence adjusted for confounders. We applied prentice weights to our cox proportional hazard models to account for the case-cohort design. Results: The mean contribution of UPF to the overall diet in grams was 14.2% in men and 12.8% in women. After a median follow-up time of 9.7 years, it was documented 11,973 non-fatal and 2,281 fatal CHD events, and 6,765 non-fatal and 899 fatal stroke events. In models adjusted for education, smoking, physical activity, body mass index, height, diabetes, high blood pressure, alcohol, energy, and sodium intake, and the Mediterranean diet score, each 10% increase in the consumption of grams from UPF was associated with an increased risk of non-fatal CHD (HR 1.13, 95%CI 1.02 - 1.26), fatal CHD (HR 1.33, 95%CI 1.09 - 1.62) and fatal stroke (HR 1.40, 95%CI 1.07 - 1.85), but not with non-fatal stroke (HR 1.11, 95%CI 0.98 - 1.24). Complete-case analysis showed similar results. Conclusion: In this large prospective cross-European study we found that higher proportion of UPF in the diet was associated with an increased risk of non-fatal CHD and fatal CHD and stroke. These findings corroborate other large-scale cohort studies indicating that the increasing consumption of ultra-processed intake may contribute to higher CVD incidence.

Abstract P449: Life’s Essential 8 and Risk of Coronary Heart Disease: A Prospective Study Among Racially and Geographically Diverse Populations

Introduction: Life’s Essential 8 (LE8) is a new guideline proposed by American Heart Association to improve cardiovascular health, including four health behaviors (i.e., eat better, be more active, quit tobacco, get healthy sleep) and four health factors (i.e., manage weight, control cholesterol, manage blood sugar, manage blood pressure). Hypothesis: Higher adherence to LE8 is associated with reduced risk of coronary heart disease (CHD) among racially and geographically diverse populations. Methods: The current analysis was based on CHD case-control studies nested within the Southern Community Cohort Study (baseline: 2002-2009), Shanghai Women’s Health Study (1996-2000), and Shanghai Men’s Health Study (2002-2006), including 900 incident CHD cases identified through 2018 and 900 age-/sex-/race-matched controls (300 pairs of White Americans, Black Americans, and Chinese adults, respectively). Within each cohort, we constructed the LE8 score (range: 0 to 100) based on DASH diet quality, moderate/vigorous physical activity, tobacco smoking, sleep hours, body mass index, total and non-HDL cholesterol, diabetes status/blood glucose, and hypertension status/blood pressure. We used conditional logistic regression to evaluate odds ratios (ORs) between the LE8 score and incident CHD, adjusting for sociodemographic factors and family history of CHD. Results: The mean ± standard deviation (SD) of LE8 score was 48.1±13.4 among White women, 48.5±14.4 among White men, 48.1±12.3 among Black women, 50.0±13.6 among Black men, 57.2±12.2 among Chinese women, and 50.7±12.5 among Chinese men. Higher LE8 score was associated with significantly reduced risk of CHD: OR for 1-SD increase was 0.58 (95% CI: 0.51-0.65) among all participants, 0.64 (95% CI: 0.53-0.78) among White Americans, 0.57 (95% CI: 0.46-0.69) among Black Americans, 0.52 (95% CI: 0.42-0.65) among Chinese, 0.49 (95% CI: 0.41-0.60) among women, and 0.65 (95% CI: 0.56-0.75) among men; all P &lt;0.001 ( P interaction &gt;0.05 for race and P interaction =0.01 for sex). Similar patterns of beneficial associations were also found in stratified analyses by age group, education level, and history of diabetes, hypertension, or dyslipidemia, with ORs ranging from 0.46 to 0.74. Conclusions: Higher adherence to LE8 is associated with ~35-50% reduced risk of incident CHD across racially and geographically diverse populations, supporting the importance of promoting healthy lifestyles and maintaining metabolic health.

Abstract MP23: Circulating Gut Microbiota-Related Metabolites and Risk of Coronary Heart Disease: A Prospective, Multiethnic, Metabolomic Study

Introduction: Despite the importance of gut microbiota in human cardiometabolic health, the associations between circulating levels of gut microbiota-related metabolites and incident coronary heart disease (CHD) remain largely unexplored. Hypothesis: Certain circulating microbial metabolites are associated with incident CHD. Methods: This is a multi-stage and multiethnic metabolomics study. We first conducted a global, semi-quantitative assay for discovery among 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively) selected from the Southern Community Cohort Study and Shanghai Men’s and Women’s Health Studies. We focused on 226 metabolites that were potentially related to gut microbiota and applied conditional logistic regression to estimate odds ratios (ORs) of CHD associated with a 1-SD increase of log-transformed metabolites adjusting for traditional CHD risk factors. Then, an in-silico validation was conducted using existing metabolites data of 9,264 participants from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study. Results: In the discovery stage, we identified 73 named microbial metabolites related to incident CHD risk with a false discovery rate&lt;0.10 or nominal p &lt;0.05 and a large effect size (ORs &gt;1.5 or &lt;0.5). These metabolites were from super pathways of amino acids (n=28), lipids (n=24), nucleotides (n=6), carbohydrates (n=4), energy (n=4), xenobiotics (n=4), and cofactors/vitamins (n=3). Of them, 61 metabolites were available for the in-silico validation, and 30 showed a significant association ( p &lt;0.05) with the same direction as the discovery results. After further adjustments for established CHD risk factors (e.g., glucose and LDL-cholesterol), 25 metabolites remained significant. A 14%-48% increased risk was observed for N-acetylglutamate (OR=1.48), sphingomyelin (1.42), imidazole propionate (1.37), hypoxanthine (1.29), guaiacol sulfate (1.28), glutamate (1.22), 2-hydroxyphenylacetate (1.20), 3-hydroxybutyrate (1.19), 3-hydroxy-2-ethylpropionate (1.17), 1-methyl-4-imidazoleacetate (1.16), urea (1.16), urate (1.16), 4-hydroxyphenylacetate (1.15), choline (1.15), isoleucine (1.14), and glycerol (1.14). Meanwhile, a significant inverse association was found for taurine (OR=0.64), asparagine (0.75), serotonin (0.78), histidine (0.79), threonine (0.81), glutamine (0.83), glycine (0.84), oxalate (0.85), and N-methylproline (0.89). Conclusions: Among ethnically and geographically diverse populations, we identified and validated some circulating gut microbiota-related metabolites as potential novel biomarkers for incident CHD. Targeted quantitative assays to confirm these results are ongoing, which are essential to inform potential clinical utility.

Abstract P406: Association Between Perceived Interpersonal Racism and Incident Coronary Heart Disease Among Black Women

Background: Racism is highly prevalent in our society and has disproportionate impact on Black individuals. However, little data exists about whether perceived interpersonal racism are associated with risk of coronary heart disease (CHD). Methods: We followed 48,297 participants in the Black Women’s Health Study from 1997, when they provided information on perceived interpersonal racism and were free of cardiovascular disease and cancer, until the end of 2019. We averaged participant’s responses to the five questions about perceived interpersonal racism in everyday activities, such as “people act as if they think you are dishonest.” We summed up the positive responses to the three questions for perceived racism in interactions that involved jobs, housing, and police; score ranged from 0 (No to all) to 3 (Yes to all). We used Cox proportional hazard models to assess the relation of perceived interpersonal racism with incident CHD, adjusting for major confounders. Results: During 22 years of follow-up, we identified 1,036 incident CHD cases. Women who were in the highest quartile of perceived interpersonal racism in daily life had a 21% increased risk of incident CHD (multivariable hazard ratios (HR)=1.21, 95% confidence interval (CI): 0.99-1.48, p trend=0.05), compared to women in the lowest quartile. Women who reported experience of racism in employment, housing, and the criminal justice system had a 29% increased risk (multivariable adjusted HR=1.29, 95%CI: 1.03-1.63, p trend=0.05) of CHD relative to those who reported no such perceived racism. Conclusion: Perceived experiences of racism in the context of employment, housing and the criminal justice system were associated with increased incidence of CHD among Black women. These findings support the hypothesis that experiences of racism may explain some of the disproportionately high incidence of CHD in the Black population.

Associations of genetic and infectious risk factors with coronary heart disease.

Coronary heart disease (CHD) is one of the most pressing health problems of our time and a major cause of preventable death. CHD results from complex interactions between genetic and environmental factors. Using multiplex serological testing for persistent or frequently recurring infections and genome-wide analysis in a prospective population study, we delineate the respective and combined influences of genetic variation, infections, and low-grade inflammation on the risk of incident CHD. Study participants are enrolled in the CoLaus|PsyCoLaus study, a longitudinal, population-based cohort with baseline assessments from 2003 through 2008 and follow-up visits every 5 years. We analyzed a subgroup of 3459 individuals with available genome-wide genotyping data and immunoglobulin G levels for 22 persistent or frequently recurring pathogens. All reported CHD events were evaluated by a panel of specialists. We identified independent associations with incident CHD using univariable and multivariable stepwise Cox proportional hazards regression analyses. Of the 3459 study participants, 210 (6.07%) had at least one CHD event during the 12 years of follow-up. Multivariable stepwise Cox regression analysis, adjusted for known cardiovascular risk factors, socioeconomic status, and statin intake, revealed that high polygenic risk (hazard ratio [HR] 1.31, 95% CI 1.10-1.56, p=2.64 × 10-3) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08-2.45, p=1.99 × 10-2) were independently associated with incident CHD. In a prospective, population-based cohort, high polygenic risk and infection with F. nucleatum have a small, yet independent impact on CHD risk.

Lifestyle Factors, Genetic Risk, and Cardiovascular Disease Risk among Breast Cancer Survivors: A Prospective Cohort Study in UK Biobank.

Evidence is limited regarding the association between lifestyles and cardiovascular disease (CVD), and the extent to which healthy lifestyles could offset the genetic risk of CVD in females with breast cancer (BC). Females diagnosed as BC, who were free of CVD at baseline, from UK Biobank were included. Five modifiable lifestyle factors were considered to calculate the healthy lifestyle score, namely body mass index (BMI), smoking, alcohol drinking, dietary habits, and physical activity. The polygenetic risk score (PRS) was derived for coronary heart disease (CHD), ischemic stroke (IS), and heart failure (HF). In 13,348 female BC survivors, there were 986 CVD events (736 CHD, 165 IS, and 353 HF) over a median of 8.01 years of follow-up. Participants with 4-5 healthy lifestyle components were associated with a decreased risk of incident CVD (HR: 0.50; 95%CI: 0.37, 0.66), CHD (HR: 0.49; 95%CI: 0.35, 0.69), IS (HR: 0.35; 95%CI: 0.19, 0.65), and HF (HR: 0.59; 95%CI: 0.36, 0.97), compared with those with 0-1 lifestyle components. Evidence for the genetic-lifestyle interaction was observed for CHD (p = 0.034) and HF (p = 0.044). Among participants at high genetic risk, a healthy lifestyle was associated with a lower risk of CHD (HR: 0.37; 95%CI: 0.24, 0.56), IS (HR: 0.37; 95%CI: 0.15, 0.93) and HF (HR: 0.39; 95%CI: 0.21, 0.73). Our findings suggest that BC survivors with a high genetic risk could benefit more from adherence to a healthy lifestyle in reducing CVD risk.