Incident Cardiovascular Disease Events Research Articles

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. To clarify associations of sex hormones with these outcomes. Systematic literature review to July 2019, with bridge searches to March 2024. Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Observational study design, heterogeneity among studies, and imputation of missing data. Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Associations of Relative Intensity of Physical Activity with Incident Cardiovascular Events and All-Cause Mortality.

The relative intensity of a physical activity (PA) can be estimated as the percent of one's maximal effort required. We compared associations of relative and absolute intensity PA with incident major cardiovascular disease (CVD) and all-cause mortality in 5,633 women from the Objective Physical Activity and Cardiovascular Health Study (mean age 78.5±6.7). Absolute intensity was measured by accelerometry. Relative intensity was estimated by dividing accelerometer-estimated metabolic equivalents (METs) by maximal MET capacity. Both were aggregated into mean daily hours of light intensity PA (LPA) and moderate-to-vigorous PA (MVPA). Cox proportional hazards models estimated hazard ratios (HRs) for one-hour higher amounts of PA on outcomes. During follow-up (median=7.4 years), there were 748 incident CVD events and 1,312 deaths. Greater LPA and MVPA, on either scale, was associated with reduced risk of both outcomes. HRs for a one-hour increment of absolute LPA were 0.88 (95% CI:0.83-0.93) and 0.88 (95% CI:0.84-0.92) for incident CVD and mortality, respectively. HRs for a one-hour increment of absolute MPVA were 0.73 (95% CI:0.61-0.87) and 0.55 (95% CI:0.48-0.64) for the same outcomes. HRs for a one-hour increment of relative LPA were 0.70 (95% CI:0.59-0.84) and 0.78 (95% CI:0.68-0.89) for incident CVD and mortality, respectively. HRs for a one-hour increment of relative MPVA were 0.89 (95% CI:0.83-0.96) and 0.82 (95% CI:0.77-0.87) for the same outcomes. On the relative scale, LPA was more strongly, inversely associated with both outcomes than relative MVPA. Absolute MVPA was more strongly inversely associated with the outcomes than relative MVPA. Findings support the continued shift in the PA intensity paradigm towards recommendation of more movement, regardless of intensity. Relative LPA--a modifiable, more easily achieved behavioral target, particularly among ambulatory older adults--was associated with reduced risk of incident major CVD and death.

Abstract PO1-11-05: Diet quality and cardiovascular disease risk among breast cancer survivors in the Pathways Study

Abstract Background: While studies have shown that breast cancer survivors with healthier diets have a lower risk of non-breast cancer-specific and all-cause mortality after a breast cancer diagnosis, the relationship between diet quality and cardiovascular disease (CVD) among breast cancer survivors is not well characterized. We examined the association between diet quality at the time of breast cancer diagnosis and CVD-related outcomes in the Pathways Study, a prospective cohort of 3,415 women diagnosed with invasive breast cancer. Methods: This analysis included four diet quality indices (DQIs) consistent with healthy eating: 1. Dietary Approaches to Stop Hypertension (DASH), 2. healthy plant-based dietary index (hPDI), 3. 2015 Healthy Eating Index (HEI), 4. American Cancer Society nutrition guidelines (ACS). Each DQI was calculated from food frequency questionnaires (FFQ) at or around the time of breast cancer diagnosis, between 2005 and 2013, with a higher score representing a more healthful dietary pattern. DQI scores were categorized into quartiles with the most concordant diets in the highest quartile and the least concordant diets in the lowest quartile, for each DQI. CVD outcomes were ascertained through December 31, 2021 and included ischemic heart disease, heart failure, cardiomyopathy, stroke/transient ischemic attack, arrhythmia, cardiac arrest, valvular disease, venous thromboembolic disease and CVD-related death. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from proportional hazards regression accounting for clinical and demographic factors. Results: FFQs were completed an average 2.2 (range=0.3-7.6) months after a breast cancer diagnosis, and a total 623 (18.2%) incident CVD events and 340 (10.0%) CVD-related deaths were ascertained over 39,263 person-years of follow-up. Participants in the highest quartile of the DASH DQI had substantially reduced risks of heart failure (HR=0.50, 95% CI 0.31-0.81), arrhythmia (HR=0.76, 95% CI 0.62-0.93), cardiac arrest (HR=0.75, 95% CI 0.60-0.93), valvular disease (HR=0.77, 95% CI 0.62-0.96), venous thromboembolic disease (HR=0.74, 95% CI 0.59-0.92), and a 33% reduced risk of CVD-related death (HR=0.67, 95% CI 0.48-0.95) relative to those in the lowest quartile. Tests for trend across quartiles of the DASH DQI were also statistically significant at a p-value &amp;lt; 0.03. The only notable association found in the other three DQIs was between hPDI and lower risk of heart failure (HR=0.61, 95% CI 0.39-0.95) in women in the highest quartile compared to the lowest quartile (Table 1). Summary: These findings suggest that diets concordant with DASH and hPDI dietary patterns, may be beneficial for preventing CVD and CVD-related death after a breast cancer diagnosis. Table 1. Cox proportional hazard ratios and 95% confidence intervals for quartiles of diet quality indices and CVD events and CVD-related death Citation Format: Isaac Ergas, Janise Roh, Lawrence Kushi, Carlos Iribarren, Mai Nguyen-Huynh, Jamal Rana, Eileen Rillamas-Sun, Cecile Laurant, Valerie Lee, Richard Cheng, Heather Greenlee, Marilyn Kwan. Diet quality and cardiovascular disease risk among breast cancer survivors in the Pathways Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-05.

Abstract PO3-27-05: Racioethnic and Ancestral Differences in Risk of Cardiometabolic Conditions and Cardiovascular Disease in Women Treated for Breast Cancer: the Pathways Heart Study

Abstract Background: Despite the established literature of racioethnic disparities in cardiovascular disease (CVD) in the general population, few studies have examined such differences in women after BC treatment, who are at higher risk due to cardiotoxic cancer treatment. Moreover, few prior studies have considered genetic similarity among the participants in the analyses, which can be objectively inferred to delineate the ancestral background of an individual. Methods: The Pathways Heart Study was established to investigate the incidence of cardiometabolic risk factors and CVD events in women with a history of BC at Kaiser Permanente Northern California (KPNC). The main study endpoints for this analysis were cardiometabolic risk factors (hypertension, diabetes, and dyslipidemia) and CVD events, identified by ICD and CPT codes from EHR. Prevalent conditions were identified within 3 years prior to the date of BC diagnosis, and incident conditions were from the date of BC diagnosis to December 31, 2021. Ethnicity was self-reported and classified as non-Hispanic White (NHW), non-Hispanic Black (NHB), Asian, Hispanic, other, or unknown. Global genetic ancestry was estimated to capture the proportion of continental ancestries genetically similar to the reference populations in Africa, Americas, Asia, and Europe from the 1000 Genome Project and Human Genome Diversity Project (HGDP), which, with the current lack of universally accepted labeling, are herein referred to as African, Native American, Asian, and European ancestry, respectively. Multivariable logistic and Cox proportional hazards regression models with all-cause mortality considered as competing risk were used to analyze the associations of race and ethnicity and genetic similarity with prevalent and incident cardiometabolic risk factors and CVD events. Results: Of the 4,071 women with BC in this analysis, 2,713 (66.6%) self-reported as NHW, 305 (7.5%) as NHB, 512 (12.6) as Asian, 447 (11.0%) as Hispanic, and 94 (2.3%) as other or unknown. NHB, Asian, and Hispanic women were more like to have prevalent diabetes than NHW women, the pattern of which persisted after BC diagnosis. Adjusted OR (95% CI) of risk of incident diabetes was 1.74 (1.21-2.49) for NHB, 3.63 (2.59-5.08) for Asian, and 2.19 (1.58-3.04) for Hispanic women, as compared to NHW. Analysis of genetic similarity revealed results consistent with self-reported race and ethnicity (sHR [95% CI] per 25% increment of African ancestry 1.19 [1.07-1.34], Asian ancestry 1.57 [1.44-1.72], and Native American ancestry 1.60 [1.29-2.00]), in comparison to European ancestry. For CVD risk, NHB women were more like to develop any prevalent and incident CVD than NHW women, particularly for ischemic heart disease (incident risk sHR=1.80 [1.10-2.94]). Genetic similarity analyses also showed higher risk of ischemic heart disease associated with African ancestry (incident risk per 25% increment, sHR=1.23 [1.06-1.43]). In contrast, Hispanic women were at lower risk of any incident CVD, serious CVD, arrhythmia, heart failure or cardiomyopathy, and ischemic heart disease. Similarly, lower risk of these CVD conditions was associated with Native American ancestry. Conclusions: Compared with women who self-reported as NHW, those self-reported as NHB, Asian, and Hispanic were at higher risk of diabetes prior to BC diagnosis and the elevated risk persisted after BC diagnosis. Moreover, Black women had higher risk of prevalent and incident CVD, whereas Hispanic women had lower risk of CVD, the latter of which might be related to the admixture of Native American ancestry. To our knowledge, this is the largest multi-ethnic study of disparities in CVD health in women post BC treatment, demonstrating corroborating findings between self-reported race and ethnicity and genetic similarity. The results highlight disparities in cardiometabolic risk factors and CVD among BC survivors that may warrant more research and clinical attentions. Citation Format: Song Yao, Haiyang Sheng, Peter Fiorica, Richard Cheng, Lucas Mendicino, Angela Omilian, Qianqian Zhu, Janise Roh, Cecile Laurant, Valerie Lee, Isaac Ergas, Carlos Iribarren, Jamal Rana, Mai Nguyen-Huynh, Eileen Rillamas-Sun, Dawn Hershman, Christine Ambrosone, Lawrence Kushi, Heather Greenlee, Marilyn Kwan. Racioethnic and Ancestral Differences in Risk of Cardiometabolic Conditions and Cardiovascular Disease in Women Treated for Breast Cancer: the Pathways Heart Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-27-05.

Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies

Use of melatonin supplements has been increasing substantially in both children and adults in the USA; however, their long-term cardiometabolic effects remain unclear. We aimed to assess the associations between regular use of melatonin supplements and the risk of developing type 2 diabetes or cardiovascular disease in adults. In this study, we included individuals from three US cohorts: the Nurses' Health Study (women only), the Health Professionals Follow-up Study (men only), and the Nurses' Health Study II (women only). Women aged 25-55 years and men aged 45-75 years at baseline, who had no diagnosis of cancer at baseline, and who responded to the question about melatonin supplement use (yes or no) were included. We excluded baseline prevalent cardiovascular disease and baseline prevalent type 2 diabetes for the main analyses. The main outcomes were cardiovascular disease and type 2 diabetes incidence. In secondary analyses, we stratified by duration of rotating night shift work in the Nurses' Health Study and Nurses' Health Study II to examine whether the associations with melatonin supplement use differed by rotating night shift work. For the cardiovascular disease analysis, we included 67 202 women from the Nurses' Health Study (follow-up 1998-2019, mean age at baseline: 63·6 years [SD 7·1]), 26 629 men from the Health Professionals Follow-up Study (1998-2020, 62·9 years [8·8], and 65 241 women from the Nurses' Health Study II (2003-19, 48·2 years [4·7]). Follow-up for incident type 2 diabetes was from 1998 to June 30, 2021, for the Nurses' Health Study; 2003 to Jan 31, 2023, for the Nurses' Health Study II; and from 1998 to Jan 31, 2020, for the Health Professionals' Follow-up Study. Melatonin supplement use in the study cohorts doubled over recent decades from less than 2% in 1998-2007 to 4% or higher in 2014-15 (4·0% in men and 5·3% in women). We documented 16 917 incident cardiovascular disease events during 2 609 068 person-years of follow-up and 12 730 incident cases of type 2 diabetes during 2 701 830 person-years of follow-up. In a pooled analysis of the three cohorts, comparing users with non-users of melatonin supplements, the pooled multivariable-adjusted hazard ratios were 0·94 (95% CI 0·83-1·06, p=0·32) for cardiovascular disease and 0·98 (0·86-1·12, p=0·80) for type 2 diabetes. In secondary analyses, melatonin supplement use appeared to attenuate the positive association between long-term shift work (>5 years) and risk of cardiovascular disease (pinteraction=0·013) among the female nurses. With up to 23 years of follow-up of three large prospective cohorts of middle-aged and older men and women, self-reported melatonin supplement use was not associated with risk of type 2 diabetes or cardiovascular disease. Further research is warranted to assess if melatonin supplement use could mitigate the potential risks of type 2 diabetes and cardiovascular disease associated with rotating night shift work. US National Institutes of Health.

Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes.

To investigate whether the sex disparities in type 2 diabetes-associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03-1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the female excess in diabetes-related CVD risk but may benefit from intensive BP control.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs11444867 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Thoracic versus coronary calcification for atherosclerotic cardiovascular disease events prediction

This study compared the prognostic value of quantified thoracic artery calcium (TAC) including aortic arch on chest CT and coronary artery calcium (CAC) score on ECG-gated cardiac CT.MethodsA total of...

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

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. To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events. 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. 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. Incident fatal and nonfatal CVD events adjudicated by medical records. 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]). 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.

Sex differences in incident atherosclerotic cardiovascular disease events among women and men with HIV: Erratum.

Sex differences in incident atherosclerotic cardiovascular disease events among women and men with HIV: Erratum.

Association of a genetic variant in angiopoietin-like 3 with serum HDL-C and risk of cardiovascular disease: A study of the MASHAD cohort over 6 years.

Loss-of-function (LOF) variants of the angiopoietin-like 3 (ANGPTL3) gene are reported to be associated with serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations and thereby affect the risk of cardiovascular disease (CVD). In the present study, we examined the association of rs10789117 in the ANGPTL 3 gene locus and the risk of CVD in the group of people who were part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. One thousand and two healthy individuals enrolled in this study of whom 849 subjects were healthy and 153 subjects developed CVD outcomes after 6 years of follow-up. After a 12-h overnight fasting, 20 mL of blood samples were collected for the measurement of fasting blood glucose and lipid profile. DNA was extracted, and the Tetra-ARMS PCR (amplification refractory mutation system) was used for genotyping of rs10789117 in the ANGPTL3 gene. The genotype frequencies of the variant of rs10789117 in the ANGPTL3 gene were estimated using χ2 tests. Eventually, the statistical analysis was done by SPSS version 20. Individuals with AC/CC genotypes (rs10789117) were found to have to greater risk of CVD events compared to AA genotype (OR = 1.43, 95%CI = 1.01-2.02, p = 0.041). There was a 1.3-fold increase in cardiovascular events in individuals carrying the C allele of rs10789117 variant compared to non-carriers (OR = 1.32, 95%CI = 1.06-1.72, p value = 0.038). There were significant differences between different genotypes for serum triglyceride levels within the control group, but this difference was not significant in the group with CVD. Moreover, there was a significant association between CC genotype and CVD risk in the individuals with a normal serum HDL-C. We have found that a rs10789117 C>A in ANGPTL3 gene polymorphism was associated with incident CVD events, and this may be of value as a risk stratification biomarker in CVD in the Iranian population.

Trimethylamine-N-Oxide and Related Metabolites: Assessing Cardiovascular Risk in the Dallas Heart Study

ObjectiveTo evaluate the association between trimethylamine N-oxide (TMAO) and related metabolites with adverse cardiovascular events in a multiethnic urban primary prevention population. MethodsWe performed a case-control study of 361 participants of the Dallas Heart Study, including 88 participants with an incident atherosclerotic cardiovascular disease (ASCVD) event and 273 controls matched for age, sex, and body mass index without an ASCVD event during 12 years of follow-up (January 1, 2000, through December 31, 2015). Plasma levels of TMAO, choline, carnitine, betaine, and butyrobetaine were measured by mass spectrometry. The differential odds for incident ASCVD by metabolite levels between cases and controls were compared by a conditional logistic regression model adjusted for cardiovascular risk factors. ResultsParticipants with incident ASCVD had higher levels of TMAO and related metabolites compared with those without ASCVD (P<.05 for all). Those with plasma TMAO concentrations in quartile 4 had a more than 2-fold higher odds of ASCVD compared with those in quartile 1 (odds ratio, 2.77 [95% CI, 1.05 to 7.7; P=.04] for hard ASCVD and 2.41 [95% CI, 1.049 to 5.709; P=.04]). Similar trends were seen with the related metabolites choline, betaine, carnitine, and butyrobetaine. ConclusionOur results suggest that TMAO and related metabolites are independently associated with ASCVD events. Although further studies are needed, measurement of TMAO and related metabolites may have a role in ASCVD risk stratification for primary prevention.

Abstract 3462: Mendelian randomization analysis of 27 cardiometabolic trait related polygenic scores identifies genetic risk for cardiometabolic and cardiovascular events in a large prospective study of breast cancer survivors

Abstract Background: CVD is the most common cause of non-cancer death in breast cancer patients. Due to cancer treatment-related cardiotoxicities, breast cancer survivors are at increased risk of cardiometabolic disease (CMD) and cardiovascular disease (CVD). In addition to treatment-related factors, behavioral risk factors such as diet, smoking, and obesity are shared between CVD and breast cancer. While clinical factors influencing the risk of CVD in breast cancer patients are well studied, the effects of genetic factors are less known. Methods: To investigate genetic factors contributing to risk of CMD and CVD in women with a history of breast cancer, we performed a Mendelian randomization analysis to explore the relationships between 27 polygenic scores (PGS) for CMD and CVD phenotypes selected from the PGS Catalog and literature and 13 incident CMD and CVD events in a large prospective cohort of 3,699 breast cancer survivors in the Pathways Study. Fine-Gray sub-distribution hazard ratios (HRs) and 95% confidence intervals (CIs) associated with one standard deviation of PGS were derived with adjustment for epidemiologic, clinical, and treatment factors. The time scale was defined as time since date of breast cancer diagnosis to first of incident event, health plan disenrollment, death, or end of study (12/31/2019). The proportional hazards assumption was tested using Schoenfeld residuals, and no violation was found. Results: We identified 19 PGS-CMD/CVD associations that met Bonferroni significance (P&amp;lt;1.17 × 10−4). Five PGS were associated with increased risk of dyslipidemia: apolipoprotein B (HR=1.52, 95% CI,1.38-1.65), LDL cholesterol (1.49, 1.36-1.63), total cholesterol (1.43, 1.31-1.56), triglyceride levels (1.24, 1.14-1.34), and coronary artery disease (1.22, 1.13-1.33). Four PGS were associated with increased risk of hypertension: systolic blood pressure (1.36, 1.25-1.48), diastolic blood pressure (1.21, 1.11-1.32), fasting glucose adjusted for BMI (1.19, 1.09-1.30), and hypertension (1.41, 1.29-1.54). PGS for atrial fibrillation was associated with increased risk of arrhythmia (1.40, 1.25-1.57) and any cardiovascular disease (1.22, 1.12-1.32). PGS for coronary artery disease and myocardial infarction were both associated with increased risk of ischemic heart disease (1.43, 1.21-1.70 and 1.38, 1.17-1.62, respectively). Conclusion: Our study provides strong evidence for the potential use of PGS to predict the risk of CVD and CMD in women with a history of breast cancer. Future studies may explore the use of PGS to identify women with breast cancer at high risk of CVD-related outcomes and strategies to mitigate this risk. Citation Format: Peter N. Fiorica, Haiyang Sheng, Cecile A. Laurent, Janise M. Roh, Valerie S. Lee, Alexa Zimbalist, Isaac J. Ergas, Qianqian Zhu, Richard K. Cheng, Eileen Rillamas-Sun, Carlos Iribarren, Jamal S. Rana, Mai Nguyen-Huynh, Dawn L. Hershman, Lawrence H. Kushi, Christine B. Ambrosone, Marilyn L. Kwan, Heather Greenlee, Song Yao. Mendelian randomization analysis of 27 cardiometabolic trait related polygenic scores identifies genetic risk for cardiometabolic and cardiovascular events in a large prospective study of breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3462.

Long-Term Body Mass Index Variability and Adverse Cardiovascular Outcomes

Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by genetic and lifestyle factors. Marked weight gain and loss could be associated with adverse biological processes. To evaluate the association between BMI variability and incident cardiovascular disease (CVD) events in 2 distinct cohorts. This cohort study used data from the Million Veteran Program (MVP) between 2011 and 2018 and participants in the UK Biobank (UKB) enrolled between 2006 and 2010. Participants were followed up for a median of 3.8 (5th-95th percentile, 3.5) years. Participants with baseline CVD or cancer were excluded. Data were analyzed from September 2022 and September 2023. BMI variability was calculated by the retrospective SD and coefficient of variation (CV) using multiple clinical BMI measurements up to the baseline. The main outcome was incident composite CVD events (incident nonfatal myocardial infarction, acute ischemic stroke, and cardiovascular death), assessed using Cox proportional hazards modeling after adjustment for CVD risk factors, including age, sex, mean BMI, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes status, and statin use. Secondary analysis assessed whether associations were dependent on the polygenic score of BMI. Among 92 363 US veterans in the MVP cohort (81 675 [88%] male; mean [SD] age, 56.7 [14.1] years), there were 9695 Hispanic participants, 22 488 non-Hispanic Black participants, and 60 180 non-Hispanic White participants. A total of 4811 composite CVD events were observed from 2011 to 2018. The CV of BMI was associated with 16% higher risk for composite CVD across all groups (hazard ratio [HR], 1.16; 95% CI, 1.13-1.19). These associations were unchanged among subgroups and after adjustment for the polygenic score of BMI. The UKB cohort included 65 047 individuals (mean [SD] age, 57.30 (7.77) years; 38 065 [59%] female) and had 6934 composite CVD events. Each 1-SD increase in BMI variability in the UKB cohort was associated with 8% increased risk of cardiovascular death (HR, 1.08; 95% CI, 1.04-1.11). This cohort study found that among US veterans, higher BMI variability was a significant risk marker associated with adverse cardiovascular events independent of mean BMI across major racial and ethnic groups. Results were consistent in the UKB for the cardiovascular death end point. Further studies should investigate the phenotype of high BMI variability.

Abstract P235: Subjective Well-Being as Compared With Traditional Risk Factors in Relation to Incident Cardiovascular Diseases

Introduction: Emerging evidence suggests a role of subjective well-being (SWB) in modifying the risk of developing cardiovascular disease (CVD), while supportive data from prospective studies are scarce. Hypothesis: Low SWB is independently associated with higher incidence of CVD, comparable in magnitude to several established traditional risk factors. Methods: The study included a total of 154,217 women and men from the UK Biobank study, free of CVD at baseline and with measurements of SWB based on general happiness, personal health, family relationships, friendships, and financial situation, followed up until May 31, 2021. Cox proportional hazards models were used to estimate associations between SWB and incident CVD. The relative importance of SWB in terms of predicting outcomes was measured by explained R 2 values. Results: During a median follow-up of 11.3 years, there were 11,662 incident CVD events (8,474 coronary heart disease [CHD] cases and 1,804 ischemic strokes). Individuals with low SWB had an approximately 2-fold higher risk of CVD compared to those with high SWB (Hazard Ratio [95% Confidence Interval], 1.99 [1.75-2.27] for CVD, 1.98 [1.71-2.30] for CHD, and 1.90 [1.34-2.69] for ischemic stroke) after adjusting for traditional risk factors. Of 12 factors examined, SWB was ranked as the fourth-strongest CVD risk factor, following hypertension, smoking, and body mass index ( Figure ). SWB was ranked as the sixth- and third-strongest risk factor for CHD and ischemic stroke, respectively. Conclusions: Our study indicates that SWB is robustly associated with the risk of incident CVD, potentially as one of the strongest modifiable risk factors for CVD prediction.

Abstract 27: Chronotype, Life’s Essential 8, and Risk of Cardiovascular Disease: A Prospective Cohort Study in UK Biobank

Introduction: Individuals with evening chronotype often experience circadian misalignment, which may disrupt health behaviors and circadian regulation of cardiometabolic functions such as blood pressure and heart rate. However, the association of chronotype with cardiovascular disease (CVD) and the interplay with other CVD risk factors are not fully understood. Hypothesis: We assessed the hypothesis that individuals with an evening chronotype, compared to those with a morning chronotype, have a poorer cardiovascular health as measured by the Life’s Essential 8 (LE8), and consequently an increased CVD risk. We further explored if the associations differed by sex. Methods: We conducted a prospective study in the UK Biobank among 477,878 adults aged 39-74 years and free of CVD at baseline in 2006-2010. Chronotype was self-reported using a single representative question from the Morningness-Eveningness Questionnaire. The LE8 score was calculated based on 8 modifiable CVD risk factors, and ranged from 0 to 100 with higher scores indicating better cardiovascular health. Incident CVD was defined as first myocardial infarction (MI) or stroke leading to hospitalization or death, identified via validated algorithms that mapped national medical records and death certificates to ICD-10 codes until May 2022. We used Cox proportional hazards models to estimate the association between chronotype and CVD risk. Models were adjusted for demographics, shift work, and family history of CVD. We applied causal mediation framework to decompose the total chronotype-CVD effect into estimated natural direct effect (i.e., independent of LE8) and natural indirect effect (i.e., mediated by LE8; NIE). Results: Participants with a “definite evening” chronotype were 75% more likely to have a low LE8 score (&lt;50) compared to “intermediate” type (prevalence ratio 95% CI: 1.67, 1.84). This association was notably stronger among women ( P -interaction: 0.0001). Over 12.7 years of follow-up, there were 27,346 documented incident CVD events (17,180 MI; 11,329 stroke). The hazard ratio (HR) for total CVD was 1.03 (95% CI: 1.00, 1.06) for the “definite morning” and 1.15 (95% CI: 1.10, 1.20) for “definite evening” compared with “intermediate” chronotype ( P -trend: 0.06). This association was stronger in women ( P -interaction: 0.05), and similar for MI and stroke. The NIE of the chronotype-CVD association comparing “definite evening” to “intermediate” was 1.11 (95% CI: 1.09, 1.13), equivalent to 95% of the association being mediated by LE8. Conclusions: Evening chronotype was associated with a modest increase in CVD risk, compared to intermediate chronotype, which appeared to be mainly explained by overall poor cardiovascular health. Our results suggest potential benefits of targeted interventions in evening chronotype for CVD prevention. Ongoing work is exploring potential effect modification by night shift work.

Abstract 65: Association Between Life’s Essential 8 and Incident Cardiovascular Disease in Women With a History of Adverse Pregnancy Outcomes

Background: Women with a history of adverse pregnancy outcomes (APOs) are at increased risk of developing cardiovascular disease (CVD). Whether maintaining higher cardiovascular health is associated with a lower risk of CVD in this population is not known. Aims: To evaluate the association between Life’s Essential 8 (LE8) and incident CVD in women with a history of APOs. Methods: We included 2,263 participants with a prior diagnosis of APOs (including hypertensive disorders of pregnancy, gestational diabetes, placental abruption, small for gestational age, or preterm birth) and 107,260 parous participants without a history of APOs from the UK Biobank, all of whom were free of CVD at baseline. LE8 was calculated at baseline (range 0-100). Multivariable-adjusted Cox models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) between LE8 score and incident total and subtypes of CVD. We also examined the interaction between LE8 score and incident CVD among individuals with and without a history of APOs. Results: Over a mean 13.5 years of follow-up, 197 incident CVD events were documented in women with a history of APOs. Compared to women in the bottom tertile of LE8 score (&lt;67), those in the top tertile (&gt;76) had a lower incidence of total CVD, HR (95% CI) of 0.43 (0.29, 0.65), CHD [0.31 (0.17, 0.56)] and AF [0.46 (0.23, 0.91)]. We observed a significant interaction between history of APOs, LE8 score, and incident CVD ( Table 1 ). Women with a history of APO who maintained high LE8 score were at similar risk as those without APO with a high LE8 score, 0.95 (0.63-1.43), whereas there was an excess risk observed for those with an intermediate (HR with vs. without APO: 1.73 vs 1.25) and low LE8 scores (HR with vs. without APO: 2.48 vs 1.81). Conclusion: Among women with a history of APOs, better cardiovascular health as assessed using the LE8 score was associated with a significantly lower incidence of incident CVD. Additionally, women with a history of APOs who maintained high LE8 scores had similar risk of CVD as women without a history of APOs.

Abstract 62: Association of Cardiovascular Health Trajectories Through Young Adulthood With Later-Life Incident Cardiovascular Disease and Mortality: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Introduction: Associations of mid-life cardiovascular health (CVH) and incident cardiovascular disease (CVD) are well-studied. Less is known about patterns of young adulthood (YA) CVH, including its changes, and associations with later-life CVD outcomes. Methods: CVH was defined by Life’s Essential 8 (LE8) score. First, we used latent class modeling (SAS Proc Traj) to determine trajectories of continuous CVH scores (0-100) for CARDIA participants with ≥3 CVH measurements in YA (from year [Y]0, mean age 25, to Y20, mean age 45). Second, we examined direction and magnitude of change in CVH status (low, moderate, or high) between 2 CVH measurements (at Y0 and Y20), comparing participants with increased, decreased, or stable CVH status. Outcomes included incident CVD (MI, heart failure, stroke, CVD death) after Y20. Cox proportional hazards regression was used to estimate HRs for associations of YA CVH patterns with incident CVD. Results: There were 4,257 participants in YA (44% female, 48% Black) included. In the trajectory analysis, we identified four distinct CVH trajectory groups ( Figure 1A ): compared to the Persistently-High CVH group, the Moderate-Low-Declining and Moderate-Declining CVH trajectory groups had substantially higher hazards for incident CVD ( Figure 1B ). In the CVH status change analysis (N=2,884; Figure 1B ), compared to Stable High CVH in YA, Stable Low CVH had a 19-fold higher risk for incident CVD, and both increasing and decreasing CVH status in YA had greater risk for incident CVD as well. Conclusions: Trajectories of declining moderate and low CVH in YA had substantially higher risk for later-life incident CVD events. Those with decreasing CVH and those who started with lower CVH and improved it through YA, were also at higher risk. These data suggest that early life CVH and maintaining high CVH through YA are both important for prevention of later-life CVD.

Exposure to green spaces, cardiovascular risk biomarkers and incident cardiovascular disease in older adults: The Seniors-Enrica II cohort

IntroductionThe impact of residential green spaces on cardiovascular health in older adults remains uncertain. MethodsCohort study involving 2114 adults aged ≥ 65 years without cardiovascular disease (CVD), residing in five dense municipalities (Prince et al., 2015) of the Madrid region and with detailed characterization of their socioeconomic background, health behaviors, CVD biological risk factors, and mental, physical, and cognitive health. Greenness exposure was measured using the Normalized Difference Vegetation Index (NDVI) at varying distances from participants' homes. Traffic exposure, neighborhood environment, neighborhood walkability, and socioeconomic deprivation at the census level were also assessed. Serum N-terminal pro-B-type natriuretic peptide (NT-ProBNP), high-sensitivity troponin T (hs-TnT), interleukin 6 (IL-6), and Growth Differentiation Factor 15 (GDF‐15) were measured at baseline, and incident CVD events identified through electronic medical records (International Classification of Primary Care-2 codes K74, K75, K77, K90, and K92). ResultsAfter adjusting for sex, age, educational attainment, financial hardship and socioeconomic deprivation at the census level, an interquartile range (IQR) increase in NDVI at 250, 500, 750, and 1000 m around participants' homes was associated with mean differences in ProBNP of −5.56 % (95 %CI: −9.77; −1.35), −5.05 % (-9.58; −0.53), −4.24 % (-8.19, −0.19), and −4.16 % (-7.59; −0.74), respectively; and mean differences in hs-TnT among diabetic participants of −8.03 % (95 %CI: −13.30; −2.77), −9.52 % (-16.08; −2.96), −8.05 % (-13.94, −2.16) and −5.56 % (-10.75; −0.54), respectively. Of similar magnitude, although only statistically significant at 250 and 500 m, were the observed lower IL-6 levels with increasing greenness. GDF-15 levels were independent of NDVI. In prospective analyses (median follow-up 6.29 years), an IQR increase in residential greenness at 500, 750, and 1000 m was associated with a lower risk of incident CVD. The variables that contributed most to the apparent beneficial effects of greenness on CVD were lower exposure to traffic, improved cardiovascular risk factors, and enhanced physical performance. Additionally, neighborhood walkability and increased physical activity were notable contributors among individuals with diabetes. ConclusionIncreased exposure to residential green space was associated with a moderate reduction in CVD risk in older adults residing in densely populated areas.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.