Cumulative remnant cholesterol burden increases the risk of cardiovascular disease among young adults.

BACKGROUND: Previous studies have shown that remnant cholesterol (RC) was associated with cardiovascular disease (CVD) among middle-aged or older adults. However, lack of evidence on long-term exposures to RC and their role in CVD risk among young adults. We thus aimed to explore the association between cumulative RC burden and CVD in young adults. METHODS: We enrolled participants younger than 45 years free of CVD history in the Kailuan Study who completed the first three health examinations from 2006 to 2010. Cumulative RC burden included cumulative RC burden score, time-weighted cumulative RC, exposure duration of high RC, and time course of RC accumulation. The outcome was the incidence of CVD. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) between cumulative RC burden and CVD risk. RESULTS: A total of 15,219 participants were included (73.70% male, median age 39.13 years). During a median follow-up duration of 8.71 years (interquartile range: 8.4-9.15 years), 502 individuals developed CVD. After adjustment for traditional cardiovascular risk factors, highest risk of CVD was observed in participants with the highest cumulative RC burden score (HR, 1.66; 95% CI, 1.29-2.12), the highest quartile time-weighted cumulative RC (HR,1.50; 95% CI, 1.15-1.96), the longest exposure duration of high RC (HR, 1.71; 95% CI, 1.21-2.42), and those with cumulative RC burden and positive slope (HR, 1.79; 95% CI, 1.35-2.36). CONCLUSIONS: Cumulative RC burden increased the risk of CVD among young adults, suggesting that maintaining low RC levels throughout young adulthood may minimize CVD risk.

Influence of loneliness burden on cardio-cerebral vascular disease among the Chinese older adult: a national cohort study.

Background: Adverse psychosocial factors play an important role in cardio-cerebral vascular disease (CCVD). The aim of this study was to evaluate the impact of the cumulative burden of loneliness on the risk of CCVD in the Chinese older adult. Methods: A total of 6,181 Chinese older adult over the age of 62 in the monitoring survey of the fourth Sample Survey of the Aged Population in Urban and Rural China (SSAPUR) were included in this study. The loneliness cumulative burden (scored by cumulative degree) was weighted by the loneliness score for two consecutive years (2017-2018) and divided into low- and high-burden groups. The outcome was defined as the incidence of CCVD 1 year later (2018-2019). A multivariate logistic regression model was used to examine the relationship between the cumulative burden of loneliness and the new onset of CCVD. Results: Among participants, 18.9% had a higher cumulative burden of loneliness, and 11.5% had a CCVD incidence within 1 year. After multivariate adjustment, the risk of developing CCVD in the high-burden group was approximately 37% higher than that in the low-burden group (OR 1.373, 95%CI 1.096-1.721; p = 0.006). Similar results were obtained when calculating the burden based on cumulative time. Longitudinal change in loneliness was not significantly associated with an increased risk of CCVD. A higher cumulative burden of loneliness may predict a higher risk of developing CCVD in older adult individuals aged 62-72 years or in those with diabetes. Conclusion: The cumulative burden of loneliness can be used to assess the risk of new-onset CCVD in the older adult in the short term.

The cumulative burden of self-reported, clinically relevant outcomes in long-term childhood cancer survivors and implications for survivorship care: A DCCSS LATER study.

BACKGROUND: The aim of this study is to evaluate how cumulative burden of clinically relevant, self-reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. METHODS: The authors invited 5925 5-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self-reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30-year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30-year MCC, and compared the ranking to levels of care according to existing risk stratifications. RESULTS: At median 18.5 years after 5-year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30-year MCC = 0.79; 95% confidence interval [CI], 0.74-0.85 vs. 30-year MCC = 0.29; 95% CI, 0.25-0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30-year MCC often did not correspond with levels of care in existing risk stratifications. CONCLUSIONS: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity.

Cumulative exposure to metabolic syndrome in a national population-based cohort of young adults and sex-specific risk for type 2 diabetes.

BACKGROUND: Metabolic syndrome is associated with type 2 diabetes and its prevalence is increasing worldwide in young adults. We aimed to determine whether cumulative exposure to metabolic syndrome is associated with type 2 diabetes risk in young adults. METHODS: Data of 1,376,540 participants aged 20-39 years without a history of type 2 diabetes and who underwent four annual health check-ups were collected. In this large-scale prospective cohort study, we evaluated the incidence rates and hazard ratios (HRs) of diabetes according to cumulative frequencies of metabolic syndrome over 4 years of consecutive annual health check-ups (burden score 0-4). Subgroup analyses were performed by sex and age. RESULTS: During 5.18 years of follow-up, 18,155 young adults developed type 2 diabetes. The incidence of type 2 diabetes increased with burden score (P < 0.0001). The multivariable-adjusted HRs for type 2 diabetes were 4.757, 10.511, 18.288, and 31.749 in participants with a burden score of 1 to 4, respectively, compared to those with 0. In subgroup analyses, the risk of incident diabetes was greater in women than men and in the 20-29 years age group than the 30-39 years age group. The HRs were 47.473 in women and 27.852 in men with four burden scores. CONCLUSION: The risk of type 2 diabetes significantly increased with an increase in the cumulative burden of metabolic syndrome in young adults. Additionally, the association between cumulative burden and diabetes risk was stronger in women and the 20s age group.

Cumulative burden of abnormal visceral adiposity index and its components on the risk of hyperuricemia.

BACKGROUND AND AIMS: The visceral adiposity index (VAI), a gender-specific surrogate maker of adipose tissue distribution and function, is associated with risk of hyperuricemia. However, the impact of time-burden of abnormal VAI and its components on the risk of hyperuricemia remains unknown. METHODS AND RESULTS: We included 56,537 participants without hyperuricemia and underwent two health examinations during 2006-2008 from the Kailuan study. Abnormal VAI burdens were evaluated as follows: (1) cumulative number of abnormal VAI presented at each examination (0-2 times); (2) cumulative number of each abnormal VAI component presented at each examination (0-2 times per component); (3) cumulative number of total abnormal VAI components presented at each examination (0-8 times). During a median follow-up of 8.81 years, 10,762 participants were diagnosed with hyperuricemia. The risk of hyperuricemia showed a positive association with cumulative number of abnormal VAI, the adjusted hazard ratio (HR) with 95% confidence interval (CI) of 2 times compared to 0 times was 1.69 (1.58-1.81). All four components of abnormal VAI, when diagnosed repeatedly, were independently associated with an increased risk of hyperuricemia, adjusted HR (95% CI) from 1.15 (1.02-1.28) for low high-density lipoprotein to 1.68 (1.58-1.79) for elevated triglyceride. The risk of hyperuricemia also gradually as abnormal components was accumulated from 0 to 8 counts, reaching an adjusted HR (95% CI) of 3.72 (2.64-5.23). Furthermore, the effect of cumulative abnormal VAI was more pronounced in females than males (P-interaction < 0.0001). CONCLUSIONS: Cumulative abnormal VAI burdens were positively associated with the risk of hyperuricemia, especially in females.

Long-Term Adiposity and Midlife Carotid Intima-Media Thickness Are Linked Partly Through Intermediate Risk Factors.

OBJECTIVE: This study aims to determine quantitatively the mediation effects of multiple cardiovascular risk factors on the associations of childhood body mass index (BMI) and its cumulative burden with adult carotid intima-media thickness (cIMT). METHODS: The longitudinal cohort consisted of 1391 adults who had been examined for BMI 4-15 times over 35.0 years on average since childhood and had data on adult cIMT, systolic blood pressure, low-density lipoprotein cholesterol, atherogenic index of plasma, and serum glucose. The area under the curve was used as a measure of cumulative burden of BMI. RESULTS: After adjusting for covariates, the total effects (standardized regression coefficient) of childhood BMI (0.138), adult BMI (0.111), and area under the curve of BMI (0.150) on cIMT were all significant (P<0.001) without mediators included in the model. The mediation effects of adult systolic blood pressure, glucose, atherogenic index of plasma and low-density lipoprotein cholesterol were 8.0%, 4.3%, 3.6%, and 0.0%, respectively, in the model with childhood BMI as the predictor, 23.4%, 15.3%, 12.6%, and 7.2%, respectively, with adult BMI as the predictor, and 14.7%, 8.7%, 6.0%, and 2.0%, respectively, with area under the curve of BMI as the predictor. The direct effects on cIMT were 0.117 (P<0.001) for childhood BMI, 0.046 (P=0.224) for adult BMI, and 0.103 (P<0.001) for area under the curve of BMI after removing the mediation effects. CONCLUSIONS: The long-term deleterious impact of adiposity on subclinical changes in vascular structure begins early in life and is accumulated over lifetime. Excess adiposity and higher cIMT are linked partly through other cardiovascular risk factors in later life, especially elevated blood pressure and glucose.

C-reactive protein and atrial fibrillation: Insights from epidemiological and Mendelian randomization studies.

BACKGROUND AND AIMS: This study aimed to investigate the role of C-reactive protein (CRP) in atrial fibrillation (AF) from epidemiological and genetic perspectives. METHODS AND RESULTS: Individual-level data from the Kailuan cohort recruited between 2006 and 2017 were included. Serum CRP levels were measured at baseline and at biennial follow-up visits, and incident AF was ascertained from biennial 12-lead ECG assessment and medical records. Cox proportional hazards models were used to assess the association between baseline CRP levels or cumulative exposure to CRP and incident AF. A meta-analysis including nine prospective cohort studies and our current study was also conducted. Mendelian randomization (MR) analysis was performed to evaluate the aetiological role of CRP in AF. In our observational study (n = 86,424), high baseline CRP levels (>3 mg/L), compared with low CRP (<1 mg/L), were not significantly associated with AF risk (HR: 1.18; 95% CI: 0.99-1.40). High cumulative exposure to CRP (HR: 1.49; 95%CI: 1.01-2.21) was significantly associated with an increased risk of AF. Our meta-analysis suggested a positive association between elevated CRP levels and incident AF (relative risk: 1.27; 95% CI: 1.14-1.42). However, no significant association between genetically determined CRP and AF risk was observed in the MR analysis. CONCLUSION: Evidence from observational studies suggested that elevated serum CRP levels were positively associated with incident AF, while the causal effects of CRP on AF were not supported by the MR analysis. CLINICAL TRIAL REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-TNRC-11001489.

Effects of individual and integrated cumulative burden of blood pressure, glucose, low-density lipoprotein cholesterol, and C-reactive protein on cardiovascular risk.

AIM: This study aimed to demonstrate the impact of cumulative burden of cardiovascular risk factors (CVRFs) on risk of cardiovascular events (CVEs). METHODS AND RESULTS: A total of 34 959 participants were enrolled who participated in the four surveys during 2006-2013. Cumulative CVRF burden was calculated as number of years (2006-2013) multiplied by the values of CVRFs including systolic blood pressure, fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), and high-sensitive C-reactive protein (hs-CRP). The primary outcome was defined as the CVE during 2012-2017, including ischaemic stroke, myocardial infarction, and all-cause mortality. During 4.62 (±0.71) years follow-up on average, there were 2118 (6.06%) CVE, including 847 (2.42%) ischaemic stroke, 221 (0.63%) myocardial infarction, and 1185 (3.39%) all-cause mortality. Higher cumulative burden of individual CVRF was significantly associated with increased risk of outcomes, except for LDL-C for all-cause mortality, FBG for myocardial infarction, and hs-CRP for ischaemic stroke. In Cox proportional hazards model, compared with the group, of the lower quartile of integrated cumulative burden, the hazard ratio (95% confidence intervals) of the upper quartile was 2.45 (2.03-2.94) for CVE, 3.65 (2.68-4.96) for ischaemic stroke, 4.51 (2.19-9.27) for myocardial infarction, and 1.73 (1.36-2.21) for all-cause mortality. CONCLUSION: We demonstrated the correlation between cumulative burden of CVRFs and cardiovascular risk, except for cumulative burden of hs-CRP and ischaemic stroke. Thus, our study suggests the necessity to extend the observation duration of CVRFs in order to elucidate the life-course cumulative effect.

The impact of the cumulative burden of LDL-c and hs-CRP on cardiovascular risk: a prospective, population-based study.

BACKGROUND: This study aims to demonstrate the impact of the cumulative burden of low density lipoprotein-cholesterol (cumLDL-c) and high sensitivity C-reactive protein (cumhs-CRP) on cardiovascular risk. RESULTS: During the 4.62 (±0.70) years of follow-up, 2,148 (5.92%) participants had MACE. Both of cumLDL-c and cumhs-CRP were independent risk factors for MACE. In participants without cumLDL-c during 2006-2013, the participants with cumhs-CRP had higher MACE risk during the subsequent 5 years, than those without cumhs-CRP (hazard ratio [HR]: 1.24, 95% confidence interval [CI]:1.04-1.47). In addition, cumhs-CRP correlated with MACE in a cumhs-CRP level-dependent pattern. CONCLUSION: This study validated the effects of residual inflammation risk in patients with low LDL-c Level in a general population, using long-term burdens of hs-CRP or LDL-c other than a single time-point level. METHOD: The Kailuan study is a prospective, population-based study began in 2006. These total 36,421 participants completed 4 measurements of hs-CRP and LDL-c biennially from 2006-2013. Cumhs-CRP or cumLDL-c levels were calculated as the number of interval years multiplied by the Δhs-CRP (more than 2.0 mg/L) or ΔLDL-c (more than 2.6 mmol/L). Outcomes measured during follow-up (2012-2017) were defined as major adverse cardiac events (MACE), including ischemic stroke, myocardial infarction, and all-cause mortality.

Interictal Burden of Cluster Headache: Results of the EUROLIGHT Cluster Headache Project, an Internet-Based, Cross-Sectional Study of People With Cluster Headache.

OBJECTIVE: The aim of this study was to measure the interictal burden (IIB) associated with cluster headache (CH). BACKGROUND: CH is characterized by an alternation of excruciatingly painful attacks and pain-free periods. Absence of pain does not necessarily imply absence of symptoms, though. Some may persist or improve more slowly than pain; others may arise in between attacks. METHODS: Participants filled out an online survey based on the EUROLIGHT questionnaire. Inclusion criteria were a reported diagnosis of CH and residency in a European country; exclusion criteria were refusal to give informed consent and to complete the questionnaire. RESULTS: Most of the burden was related to higher headache frequencies: ongoing symptoms despite pain freedom, impaired autonomy due to avoidance of triggers, reluctance to tell others about the disease, and the feeling of not being understood by family and friends, employers and colleagues. Irreversible, potentially accumulating burden may occur if headache frequency is high; examples are impairment of career options, relationships, and family planning issues. Worrying about future attacks and avoiding potential triggers occur independently from attack frequency and disease duration. There were no differences between the in-bout and the out-bout period among participants with episodic CH. Participants with chronic CH reported greater IIB. CONCLUSIONS: Even between attacks CH can have a huge and potentially irreversible impact on life. Different types of IIB were identified, all of which may contribute to the total burden of disease. As cumulative burden might be irreversible, prevention strategies need to be developed.

Interactive Cumulative Burden Assessment: Engaging Stakeholders in an Adaptive, Participatory and Transdisciplinary Approach.

Cumulative burden assessment (CuBA) has the potential to inform planning and decision-making on health disparities related to multiple environmental burdens. However, scholars have raised concerns about the social complexity to be dealt with while conducting CuBA, suggesting that it should be addressed in an adaptive, participatory and transdisciplinary (APT) approach. APT calls for deliberation among stakeholders by engaging them in a process of social learning and knowledge co-production. We propose an interactive stakeholder-based approach that facilitates a science-based stakeholder dialogue as an interface for combining different knowledge domains and engendering social learning in CuBA processes. Our approach allows participants to interact with each other using a flexible and auditable CuBA model implemented within a shared workspace. In two workshops we explored the usefulness and practicality of the approach. Results show that stakeholders were enabled to deliberate on cumulative burdens collaboratively, to learn about the technical uncertainties and social challenges associated with CuBA, and to co-produce knowledge in a realm of both technical and societal challenges. The paper identifies potential benefits relevant for responding to social complexity in the CuBA and further recommends exploration of how our approach can enable or constraint social learning and knowledge co-production in CuBA processes under various institutional, social and political contexts.

Relation of long-term patterns in caregiving activity and depressive symptoms to telomere length in older women.

BACKGROUND: Research links psychological stress to accelerated cellular aging. Here we examined whether long-term patterns of depression and caregiving burden, forms of chronic psychological stress, were associated with shorter telomere length, a biomarker of cellular aging. METHODS: The study included 1250 healthy older women (mean: 68.0; range: 60-81 years) in the Nurses' Health Study. Long-term patterns in depressive symptoms and caregiving activity (separated into care of children/grandchildren vs. ill or disabled family members/others) incorporated questionnaire data between 1992 and 2000; relative leukocyte telomere lengths (LTLs) were measured in 2000-2001. Least-squares means LTL z-scores were calculated across categories of depression patterns and caregiving intensity. RESULTS: Six empirically-derived latent classes of depressive symptom trajectories were identified: minimal-stable (63.7%), mild-worsening (3.9%), subthreshold-improving (22.8%), subthreshold-worsening (2.7%), clinical range depressive-improving (6.2%), and clinical range depressive-persistent (0.6%). After collapsing trajectory patterns into 4 groups (combining those with minimal and mild symptoms into one group and those with clinical range depressive symptoms into one group) due to very small sample sizes in some groups, we observed marginal associations (p = 0.07): e.g., the least-squares means LTL z-scores were lowest (-0.08; 95% CI: -0.22 to 0.06) for the clinical range depressive symptoms group and highest (0.12; 0.04-0.20) for the subthreshold-improving group (Tukey's post-hoc pairwise p = 0.07). With six depressive symptom trajectories, no significant associations were observed with regard to telomere lengths. There were no significant associations between caregiving intensity and LTLs. CONCLUSIONS: There were no associations between long-term patterns of caregiving burden and telomere lengths among older women. Possible differences in telomere lengths by types of long-term depressive symptom trajectories may warrant further investigation.