Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia.

Importance: Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease. Objective: To identify proteins in the circulation associated with HDPs. Design, Setting, and Participants: Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease-related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins' dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP-related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease-related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023. Exposures: Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs). Main Outcomes and Measures: Gestational hypertension and preeclampsia. Results: Genetic association data for cardiovascular disease-related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro-brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP-related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins. Conclusions and Relevance: Study findings suggest genetic associations of 4 cardiovascular disease-related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.

Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.

BACKGROUND AND AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. METHODS: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. RESULTS: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR. CONCLUSIONS: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study.

AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence. METHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686). CONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.

Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. OBJECTIVES: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. METHODS: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. RESULTS: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). CONCLUSIONS: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

Polygenic prediction of preeclampsia and gestational hypertension.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.

Sex Differences in Temporal Trends of Cardiovascular Health in Young US Adults.

Background Favorable cardiovascular health (CVH) in young adulthood has been associated with lower future cardiovascular risk. We determined whether CVH and its sex differences in young adults have changed from 2007 to 2018. Methods and Results We identified 10 206 individuals, aged 20 to 39 years, from the National Health Examination and Nutrition Survey data. CVH was assessed on the basis of the American Heart Association's Life's Simple 7 metrics (of 7). Changes in the mean number of ideal CVH components and the ideal proportion of individual components were calculated using linear regression analysis. Changes in sex difference trends were assessed with an interaction term between sex and calendar year. The mean (SD) age of the study population was 29.3 (5.8) years, and 5260 (51.5%) individuals were women. The mean (SD) ideal CVH component remained unchanged for both women (4.40 [1.22] to 4.48 [1.15]; P=0.94) and men (3.97 [1.27] to 3.93 [1.24]; P=0.87), with stable sex differences (P for interaction=0.94). Nonetheless, sex differences in blood pressure widened as ideal blood pressure decreased in men (54.0% to 46.9%; P=0.03) but not in women (P for interaction <0.001). Concurrently, the proportion with ideal physical activity declined in women (57.3% to 49.4%; P=0.04) but remained stable in men (P for interaction=0.03). Nonsmoking increased to a greater extent in women (64.1% to 70.5%; P=0.05) than in men (P for interaction=0.01). Conclusions Sex disparities in CVH have persisted with exacerbated differences in blood pressure, physical activity, and smoking. These insights provide opportunities to promote equitable CVH.

Ideal cardiovascular health duration and risk of chronic kidney disease and cardiovascular disease.

OBJECTIVE: Increasing number of clinical guidelines are adopting comprehensive cardiovascular risk assessment tools for treatment decision and disease management. Yet, little is known regarding cardiovascular risks associated with the length of favourable cardiometabolic profile. In this context, we examined whether the duration of strictly ideal cardiovascular health (CVH), based on body mass index, blood pressure, fasting glucose, total cholesterol, cigarette smoking, alcohol drinking and physical activity, in middle age is associated with risk of developing chronic kidney disease (CKD) and cardiovascular disease (CVD) in mid-to-late life. METHODS: From the Korean Genome and Epidemiology Study Ansung-Ansan cohort, we included 8020 participants (median age 50.0 years, 47.9% male), of whom, 7854 without CKD and 7796 without CVD at baseline. Cox proportional hazards models were employed to assess CKD and CVD risks, adjusting for age, sex, education level, examination sites and renal markers. RESULTS: Over a median follow-up of 15.0 years, 1401 cases of CKD and 493 cases of CVD were newly developed. Compared with participants with <5 years of ideal CVH duration, HR (95% CI) of those who maintained for 5-<10 years or ≥10 years had negatively graded risks for CKD (5-<10 years, 0.63 (0.39 to 0.93); ≥10 years, 0.33 (0.15 to 0.74)) and CVD (5-<10 years, 0.83 (0.54 to 1.27); ≥10 years, 0.22 (0.08 to 0.60)). In parallel, participants with delayed decline to suboptimal level had lower disease risks compared with counterparts with consistently suboptimal CVH. CONCLUSION: Our findings confer that maintaining favourable health behaviours and clinical risk factor levels in midlife will improve later-life cardiovascular outcomes.

Sex- and Age-Specific Trends in Cardiovascular Health in Korea, 2007-2018.

BACKGROUND AND OBJECTIVES: We illustrated sex- and age-specific temporal trends in cardiovascular health among Korean adults. METHODS: From the Korean National Health and Nutrition Examination Survey 2007-2018, we included 61,408 participants aged 20 years or older. The ideal levels of 6 components of cardiovascular health metrics were defined as never-smoking, ≥75 min/week of vigorous or ≥150 min/week of moderate-to-vigorous physical activity, body mass index (BMI) <23 kg/m², total cholesterol <200 mg/dL, blood pressure (BP) <120/80 mmHg, and fasting glucose <100 mg/dL. Temporal trends in the number of ideal cardiovascular health components and distribution of each component were assessed by sex and age. RESULTS: The average number of ideal cardiovascular health components decreased from 3.37 in 2007-2009 to 2.86 in 2016-2018. Never smoking increased from 56.0% to 59.2%, largely contributed by young men. Ideal physical activity halved (41.4-21.3%); such decline was more pronounced in women and with older age. Ideal BMI decreased from 44.3% to 42.2%, more apparently in young and elderly men. In contrast, ideal BMI increased in middle-aged and elderly women. Ideal cholesterol decreased from 65.5% to 50.3%, profoundly in young adults and relatively greater in men. Ideal BP declined from 55.1% to 46.9%, more evidently in men. However, ideal BP discernibly increased in middle-aged women. Ideal glucose decreased from 74.6% to 66.0%, comparatively greater and earlier in men. CONCLUSIONS: The proportion of Korean adults with ideal cardiovascular health decreased between 2007 and 2018, but the course of responsible factors differed across sex and age groups.

Korea Heart Disease Fact Sheet 2020: Analysis of Nationwide Data.

BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. To provide an overview of the temporal trends in the burden of CVD, the Korean Society of Cardiology has published the Korea Heart Disease Fact Sheet in 2020. METHODS: We analyzed anonymized data of the Causes of Death Statistics, National Health Insurance Claims Database, and Korea National Health and Nutrition Examination Survey to assess mortality, hospitalizations, and risk factors for CVD. RESULTS: The CVD mortality decreased until 2010, then steadily increased up to 123 per 100,000 persons in 2018. Since 2002, the number and rate of CVD hospitalization have continued to grow. In 2018, approximately 12.1 million Korean adults had hypertension, 4.3 million had diabetes, 8.7 million had hypercholesterolemia, 14.9 million had obesity, and 8.8 million were currently smoking. The number of risk factors increased markedly with older age; 58.4% of adults age ≥70 years had ≥2 risk factors. CONCLUSIONS: CVD mortality and hospitalization have gradually increased in the last decade, and a substantially high proportion of adults were carrying more than 1 cardiovascular risk factor in 2018. With the rapid population aging, a continued increase in CVD appears inevitable in Korea. Concerted and sustained approaches are essential to achieve early prevention and reduce the burden of CVD.

Adherence to Antihypertensive Medication and Incident Cardiovascular Events in Young Adults With Hypertension.

[Figure: see text].

Association between physical activity and inflammatory markers in community-dwelling, middle-aged adults.

Physical activity has been known to deter inflammatory process; yet, the evidence is scarce in healthy, middle-aged population. We assessed the association between physical activity and inflammatory biomarkers, including high sensitivity (hs) C-reactive protein, interleukin (IL)-1α, -1ß, and -6, tumor necrosis factor (TNF) -α and -ß, and monocyte chemotactic protein (MCP) -1 and -3. Functional and leisure-time physical activity was assessed by the International Physical Activity Questionnaire. Inflammatory biomarkers were measured by multiplex enzyme-linked immunosorbent assay. Compared with highly physically active participants based on total metabolic equivalent of task, the most sedentary group had significantly higher odds ratio and [95% confidence interval] for ≥75th percentile of TNF-α (1.64 [1.10-2.44]), TNF-ß (1.50 [1.09-2.07]), IL-1ß (2.14 [1.49-3.09]), hsIL-1ß (1.72 [1.15-2.58]), IL-6 (1.84 [1.24-1.73]), hsIL-6 (2.05 [1.35-3.12]), and MCP-1 (1.91 [1.28-2.87]) levels. Results for IL-1α and MCP-3 were inconsistent, as the least active group had lower odds for above the median IL-1α (0.65 [0.49-0.95]) and MCP-3 (0.71 [0.54-0.93]) yet higher odds for ≥75th percentile IL-1α (2.36 [1.63-3.42]) and MCP-3 (2.44 [1.63-3.64]) levels. Based on duration of moderate-to-vigorous physical activity, sedentary participants had significantly higher odds for above median (1.40 [1.13-1.73]) and ≥75th percentile (1.33 [1.00-1.77]) IL-1ß compared with those fulfilling the guideline recommendation. Subgroup analyses showed minimal sex differences. Routine inflammatory assessment may help to achieve primordial prevention of cardiovascular and metabolic diseases. Novelty: Healthy, middle-aged adults with physically active lifestyle were generally at lower odds for elevated inflammatory status. The associations persisted regardless of sex, age, comorbidities, adiposity, and diet.

Sex-, Age-, and Metabolic Disorder-Dependent Distributions of Selected Inflammatory Biomarkers among Community-Dwelling Adults.

Background: Inflammatory cytokines are increasingly utilized to detect high-risk individuals for cardiometabolic diseases. However, with large population and assay methodological heterogeneity, no clear reference currently exists. Methods: Among participants of the Cardiovascular and Metabolic Diseases Etiology Research Center cohort, of community-dwelling adults aged 30 to 64 without overt cardiovascular diseases, we presented distributions of tumor necrosis factor (TNF)-α and -ß, interleukin (IL)-1α, -1ß, and 6, monocyte chemoattractant protein (MCP)-1 and -3 and high sensitivity C-reactive protein (hsCRP) with and without non-detectable (ND) measurements using multiplex enzyme-linked immunosorbent assay. Then, we compared each markers by sex, age, and prevalence of type 2 diabetes mellitus, hypertension, and dyslipidemia, using the Wilcoxon Rank-Sum Test. Results: In general, there were inconsistencies in direction and magnitude of differences in distributions by sex, age, and prevalence of cardiometabolic disorders. Overall, the median and the 99th percentiles were higher in men than in women. Older participants had higher TNF-α, high sensitivity IL-6 (hsIL-6), MCP-1, hsCRP, TNF-ß, and MCP-3 median, after excluding the NDs. Participants with type 2 diabetes mellitus had higher median for all assayed biomarkers, except for TNF-ß, IL-1α, and MCP-3, in which the medians for both groups were 0.00 due to predominant NDs. Compared to normotensive group, participants with hypertension had higher TNF-α, hsIL-6, MCP-1, and hsCRP median. When stratifying by dyslipidemia prevalence, the comparison varied significantly depending on the treatment of NDs. Conclusion: Our findings provide sex-, age-, and disease-specific reference values to improve risk prediction and diagnostic performance for inflammatory diseases in both population- and clinic-based settings.

Associations between age and dyslipidemia are differed by education level: The Cardiovascular and Metabolic Diseases Etiology Research Center (CMERC) cohort.

BACKGROUND: Dyslipidemia is a multifactorial disorder, which arises from complex interactions among genetic and environmental risk factors. Previous studies have established the deteriorating effect of aging on lipid profiles. However, little is known about the role of education level, a stable marker of socioeconomic status, which reflect modifiability of lifestyle risk factors. Therefore, we examined the association between age and individual dyslipidemia parameter across education level among healthy, middle-aged Korean women. METHODS: From 2049 middle-aged women, education attainment was classified into completion of elementary school or below, middle school, high school, college or above. Dyslipidemia was assessed in adherence to the 2018 Korean Dyslipidemia Treatment Guideline. Multivariable logistic regression and generalized linear model tested for associations between age and dyslipidemia parameter across education level and other known risk factors, including menopause, obesity, and current drinking and smoking. RESULTS: In this cross-sectional analysis, the prevalence of each dyslipidemia parameter was significantly different by age and education level. The odds ratio (OR) for dyslipidemia was higher among participants who were older and had received higher education (OR = 2.31, p for interaction = 0.008) than younger and low education counterpart. The interaction between age and education level remained significant for hypercholesterolemia (p for interaction = 0.003) and hyper-LDL-cholesterolemia (p for interaction = 0.002). CONCLUSIONS: Separate examination of individual dyslipidemia parameter indicated varying degree of interaction with age and education level. Such results imply that each type of lipid abnormality may arise from and be exacerbated by heterogeneous composition of biological and lifestyle risk factors, which may be reflected by education level.