non-CVD Mortality Research Articles

Reverse epidemiology of obesity paradox: Fact or fiction?

Obesity paradox refers to the clinical observation that when acute cardiovascular decompensation occurs, patients with obesity may have a survival benefit. This apparently runs counter to the epidemiology of obesity, which may increase the risk for non-communicable diseases (NCDs). The scientific community is split on obesity paradox, with some supporting it, while others call it BMI paradox. This review: (a) defines the obesity paradox, and its proposed role in overall mortality in NCDs; (b) delineates evidence for and against obesity paradox; (c) presents the importance of using different indices of body mass to assess the risk in NCDs; (d) examines the role of metabolically healthy obesity in obesity paradox, and emerging importance of cardio-respiratory fitness (CRF) as an independent predictor of CVD risk and all-cause mortality in patients with/without obesity. Evidence suggests that the development of obesity and insulin resistance are influenced by genetic (or ethnic) make up and dietary habits (culture) of the individuals. Hence, this review presents lean diabetes, which has higher total CVD and non-CVD mortality as compared to diabetics with obesity and the possibility of maternal factors programming cardiometabolic risk during fetal development, which may lead to a paradigm shift in our understanding of obesity.

Sleep characteristics in relation to cardiovascular disease incidence and mortality in individuals with diabetes

Abstract Background/Introduction Evidence regarding the potential health effects of sleep characteristics among individuals with type 2 diabetes (T2D) is limited. Purpose We aimed to examine sleep characteristics in relation to subsequent risk of cardiovascular disease (CVD), including coronary heart disease (CHD), and stroke, and all-cause and cause-specific mortality among individuals with T2D. Methods We prospectively followed 21,902 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1986-2018, Health Professionals Follow-Up Study: 1986-2018). Sleep characteristics, including sleep duration, snoring, sleep apnea, and sleep quality, were repeatedly assessed using self-reported questionnaires at baseline and follow-up. Associations of sleep characteristics with CVD risk and mortality were assessed using Cox proportional hazards models with adjustments for demographic, dietary and lifestyle factors, and medical history. Results During 170,355 and 196,458 person-years of follow-up in participants with T2D, there were 2,486 incident CVD events and 3,922 deaths, respectively. Compared with sleeping for 7-8 h/day, the multivariable-adjusted hazard ratios (HRs) of sleeping for ≤5 h/day were 1.21 (1.02, 1.45) for CVD incidence, 1.24 (1.20, 1.51) for CHD incidence, 1.40 (1.24, 1.58) for total mortality, 1.52 (1.20, 1.92) for CVD mortality, and 1.27 (1.01, 1.61) for other non-CVD and non-cancer mortality, while the HRs of ≥10 h/day were 1.42 (1.21, 1.66) for total mortality, and 1.63 (1.20, 2.10) for other non-CVD and non-cancer mortality. Furthermore, compared with participants without habitual snoring, those with habitual snoring had a 21%, 24%, 18%, and 33% higher risk for CVD incidence, CHD incidence, CVD mortality, and total mortality, respectively. Compared with participants without diagnosed sleep apnea, those with sleep apnea had a 27%-58% higher risk for CVD incidence, CVD mortality, and total mortality. In addition, lower habitual sleep quality, including sleep difficulties and restless sleep, was associated with a substantially higher risk of CVD, CHD, or CVD mortality. No associations were observed between sleep characteristics with risk of stroke and cancer mortality in individuals with T2D. Conclusions Short and long sleep durations as well as habitual snoring, sleep apnea, and lower sleep quality were independently associated with higher risks of CVD incidence and mortality, particularly CVD mortality in individuals with T2D.

External validation of the HFA-ICOS risk stratification tool for prediction of cardiovascular complications after cancer treatment

Abstract Background The 2022 ESC Guidelines on Cardio-oncology recommends using the HFA-ICOS (Heart Failure Association and the International Cardio-Oncology Society) four-category risk stratification tool to predict risk of heart failure (HF) and other cardiovascular disease (CVD) complications during and after cancer therapy. However, the actual risk associated with assignment to these categories is unknown. Purpose We aimed to assess the prognostic performance the HFA-ICOS risk stratification tool in a large cancer subpopulation of a general health survey linked to Norwegian health registries. Methods Participants in a large-scale population study diagnosed with cancer between 2006 and 2012 were included (n=2290) and followed for CVD endpoints until Sept 2023. CVD risk factors were measured at baseline between 2006 and 2008. The Norwegian Cancer Registry provided detailed information about cancer characteristics and therapy. We retrieved CVD endpoints from the local hospitals’ registries and the national causes of death registry. Kaplan Meier survival curves were used to estimate the risk of the combined endpoint of HF hospitalization, myocardial infarction (MI), stroke and CVD death, as well as HF hospitalization alone and non-CVD death. Harrel’s C-statistic was used to validate the discriminative abilities. Results Mean (SD) age was 65.8 (12.4) years, 48% were female, cancer types and cardiovascular risk factors are shown in Table 1. During a median (interquartile range) follow-up of 6.9 (1.4 to 12.2) years, there were 460 first CVD events (HF hospitalizations 87 (19%), MIs 161 (35%), strokes 130 (28%), CVD deaths 82 (18%)) and 1003 (44%) non-CVD deaths. When applying the HFA-ICOS tool, 649 (28%) were assigned to the low-risk category, 912 (40%) to medium, 661 (29%) to high-risk and 68 (3%) to the very high-risk category. Between the HFA-ICOS risk categories, there were clear differences in the observed risk of CVD events, HF hospitalizations and non-CVD mortality (Figure 1). CVD incidence was highest in the highest HFA-ICOS risk categories (7% in the low risk group, 21% in the medium risk group, 31% in the high risk group and 37% in the very high-risk group (p-value <0.001)). C-statistics for predicting CVD events was 0.696 (95% CI, 0.674 to 0.718). When only assessing patients with HF hospitalizations as (first) outcome (n=116), the risk of HF was higher in the high and very high-risk groups (0% in the low risk group, 4% in the medium, 9% in high and 21% in the very high risk group (C-statistics 0.794 (95% CI, 0.762 to 0.827)). Conclusion The HFA-ICOS baseline risk assessment was useful to identify patients at risk of both clinical overt heart failure and other major CV complications and non-CV death in a population with a variety of cancers. These results can help communicate absolute risks to cancer patients, which may be helpful in the shared decision-making for cardioprotective treatment and intensified follow-up.

Estimation of individual lifetime cardiovascular disease risk and treatment benefit in patients with established atherosclerotic cardiovascular disease: the updated SMART-REACH2 model

Abstract Background The 2021 ESC Guidelines on Cardiovascular Disease (CVD) Prevention in Clinical Practice recommend using (lifetime) risk to guide preventive treatment intensification. Purpose Updating and systematically recalibrating the SMART-REACH lifetime prediction model for the estimation of lifetime risk of recurrent CVD in patients with established atherosclerotic CVD (ASCVD) to various European and international risk regions. Methods The updated SMART-REACH (i.e., SMART-REACH2) model was derived using data from 9,477 individuals between 40-90 years with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms included in the UCC-SMART cohort in whom 2,090 ASCVD events were observed during a median follow-up of 8.9 years (interquartile range 4.5–14.1). Coefficients for type of CVD, estimated glomerular filtration rate, non-high density lipoprotein cholesterol, systolic blood pressure, duration of CVD, C-reactive protein, current smoking, and presence of diabetes were derived using sex-stratified cause-specific Cox models with age as the time axis, adjusted for the competing risk of non-CVD mortality. Lifetables were used to estimate 10-year and lifetime CVD-risk and CVD-free life expectancy. The SMART-REACH2 model was externally validated in 121,701 patients from the NOR-COR, Nor-COAST, HUNT3, SWEDEHEART, Bialystok PLUS/Polaspire, REACH-EU, and REACH non-EU (Asia, Japan, Latin America, North America) covering 43 countries. The model was recalibrated to specific risk regions based on the expected-observed ratios from representative cohorts. Performance was assessed by calibration of predicted and observed risk and Harrel’s C-statistic for discrimination. Results 16,689ASCVD events were observed in the external validation cohorts. The model was visually well calibrated for the various risk regions. The pooled C-statistic across risk regions was 0.665 [95% confidence interval 0.640-0.691], with adequate performance in the separate regions (Figure 1). Using SMART-REACH2 to estimate potential gain in CVD-free life expectancy upon treatment initiation showed varying projections. For example, two comparable 55-year-old males from the low-risk region and very high-risk region would gain an estimated 2.2 and 3.9 CVD-free life years as a result of smoking cessation (Figure 2). Conclusion(s) By using larger and more contemporary data sources, considering geographical differences, and extending the age range, the updated SMART-REACH2 model provides an improved algorithm for the estimation of lifetime risk and CVD-free life expectancy for individuals with established ASCVD, facilitating shared decision-making for cardiovascular prevention as recommended by the 2021 ESC Prevention of CVD guidelines.C-statistics across global risk regionsCase vignette

Life’s Essential 8 and Mortality in US Adults With Obesity: A Cohort Study

ObjectiveThis study evaluates the relationship between the Life’s Essential 8 (LE8) scoring system and all-cause and cause-specific mortality among obese individuals using National Health and Nutrition Examination Survey data. MethodsData from 9143 obese participants (BMI ≥30 kg/m2) collected between 2005 and 2018 were analyzed. Participants were categorized based on their LE8 scores: low cardiovascular health (Low CVH, n = 2264), moderate cardiovascular health (Moderate CVH, n = 6541), and high cardiovascular health (High CVH, n = 338). Associations between LE8 scores and mortality were assessed using Kaplan-Meier survival analysis and Cox proportional hazards models. ResultsOver a median follow-up of 7.3 years, there were 867 all-cause deaths (9.5%), including 246 cardiovascular disease (CVD) deaths (2.7%) and 621 non-CVD deaths (6.8%). In multivariable Cox regression analysis, compared to the Low CVH group, the Moderate CVH group had an adjusted hazard ratio (HR) for all-cause mortality of 0.63 (95% CI: 0.55-0.72), and the High CVH group had an HR of 0.25 (95% CI: 0.10-0.60). For CVD mortality, the HRs were 0.61 (95% CI: 0.47-0.78) for Moderate CVH and 0.19 (95% CI: 0.03-1.38) for High CVH. For non-CVD mortality, the HRs were 0.64 (95% CI: 0.54-0.75) for Moderate CVH and 0.27 (95% CI: 0.10-0.72) for High CVH. Each 10-point increase in LE8 score was associated with a 20% reduction in all-cause mortality (P < .001), 21% reduction in CVD mortality (P < .001), and 20% reduction in non-CVD mortality (P < .001). ConclusionHigher LE8 scores are significantly associated with lower rates of all-cause, CVD, and non-CVD mortality among obese individuals. These findings support the LE8 scoring system as an effective predictor of health status and mortality risk.

Sleep-disordered breathing increases mortality in patients with diabetes.

Sleep-disordered breathing (SDB) and diabetes mellitus (DM) are often concomitant; however, data on the impact of SDB on mortality in the population with diabetes remain scarce. The population from the Sleep Heart Health Study, a multicenter prospective observational study representing 5780 patients with polysomnography and mortality data, including 453 patients with DM, was analyzed to assess the impact of SDB variables and the presence of DM on all-cause, cardiovascular disease (CVD), and non-CVD associated mortality. Survival analysis and proportional hazard regression models were used to calculate the adjusted hazard ratios (aHR) for mortality. Patients with DM and the average SpO2 >91.4% had significantly lower all-cause (aHR 0.52, CI 0.34-0.80) and CVD mortality risk (aHR 0.44, CI 0.22-0.87) as compared with patients with SpO2 below this value. Apnea-hypopnea index >31 (aHR 1.58, CI 1.10-2.28) and oxygen desaturation index >13.3 (aHR 1.58, CI 1.10-2.25) were associated with increased all-cause mortality in participants with DM on treatment. Sleep efficiency and proportion of rapid-eye movement (REM) sleep did not have any impact on mortality in patients with DM and thus differed significantly from individuals without DM, where increased all-cause mortality was observed in those with sleep efficiency <81.4% (aHR 0.77, CI 0.68-0.87) or REM sleep <14.9% (aHR 0.78, CI 0.68-0.89). Patients with diabetes on treatment and moderate to severe sleep-disordered breathing experience increased all-cause mortality. Reduced average oxygen saturation predicted both all-cause and cardiovascular death in the population with diabetes.

Conventional and genetic associations of BMI with major vascular and non-vascular disease incidence and mortality in a relatively lean Chinese population: U-shaped relationship revisited.

Higher body mass index (BMI) is associated with higher incidence of cardiovascular and some non-cardiovascular diseases (CVDs/non-CVDs). However, uncertainty remains about its associations with mortality, particularly at lower BMI levels. The prospective China Kadoorie Biobank recruited >512 000 adults aged 30-79years in 2004-08 and genotyped a random subset of 76 000 participants. In conventional and Mendelian randomization (MR) analyses, Cox regression yielded adjusted hazard ratios (HRs) associating measured and genetically predicted BMI levels with incident risks of major vascular events (MVEs; conventional/MR 68 431/23 621), ischaemic heart disease (IHD; 50 698/12 177), ischaemic stroke (IS; 42 427/11 897) and intracerebral haemorrhage (ICH; 7644/4712), and with mortality risks of CVD (15 427/6781), non-CVD (26 915/4355) and all causes (42 342/6784), recorded during ∼12years of follow-up. Overall, the mean BMI was 23.8 (standard deviation: 3.2) kg/m2 and 13% had BMIs of <20 kg/m2. Measured and genetically predicted BMI showed positive log-linear associations with MVE, IHD and IS, but a shallower positive association with ICH in conventional analyses. Adjusted HRs per 5 kg/m2 higher genetically predicted BMI were 1.50 (95% CI 1.41-1.58), 1.49 (1.38-1.61), 1.42 (1.31-1.54) and 1.64 (1.58-1.69) for MVE, IHD, IS and ICH, respectively. These were stronger than associations in conventional analyses [1.21 (1.20-1.23), 1.28 (1.26-1.29), 1.31 (1.29-1.33) and 1.14 (1.10-1.18), respectively]. At BMIs of ≥20 kg/m2, there were stronger positive log-linear associations of BMI with CVD, non-CVD and all-cause mortality in MR than in conventional analyses. Among relatively lean Chinese adults, higher genetically predicted BMI was associated with higher risks of incident CVDs. Excess mortality risks at lower BMI in conventional analyses are likely not causal and may reflect residual reverse causality.

Differential impacts of fat and muscle mass on cardiovascular and non-cardiovascular mortality in individuals with type 2 diabetes.

The distribution of fat and muscle mass in different regions of the body can reflect different pathways to mortality in individuals with diabetes. Therefore, we investigated the associations between whole-body and regional body fat and muscle mass with cardiovascular disease (CVD) and non-CVD mortality in type 2 diabetes (T2D). Within the National Health and Nutrition Examination Survey 1999-2006, 1417 adults aged ≥50years with T2D were selected. Dual-energy X-ray absorptiometry was used to derive whole-body, trunk, arm, and leg fat mass and muscle mass indices (FMI and MMI). Mortality data until 31 December 2019 were retrieved from the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. A total of 1417 participants were included in this study (weighted mean age [standard error]: 63.7 [0.3] years; 50.5% female). Over a median follow-up of 13.6years, 797 deaths were recorded (371 CVD-related and 426 non-CVD deaths). Higher FMI in the arm was associated with increased risk of non-CVD mortality (fourth quartile [Q4] vs. first quartile [Q1]: HR 1.82 [95% CI 1.13-2.94]), whereas higher FMI in the trunk or leg was not significantly associated with CVD or non-CVD mortality. Conversely, higher arm MMI was associated with a lower risk of both CVD (Q4 vs. Q1: HR 0.51 [95% CI 0.33-0.81]) and non-CVD (Q4 vs. Q1: HR 0.56 [95% CI 0.33-0.94]) mortality. There was a significant interaction between smoking status and arm FMI on non-CVD mortality (P for interaction=0.007). Higher arm FMI was associated with a higher risk of non-CVD mortality among current or former smokers (Q4 vs. Q1: HR 2.67 [95% CI 1.46-4.88]) but not non-smokers (Q4 vs. Q1: HR 0.85 [95% CI 0.49-1.47]). Fat mass and muscle mass, especially in the arm, are differently associated with CVD and non-CVD mortality in people with T2D. Our findings underscore the predictive value of body compositions in the arm in forecasting mortality among older adults with T2D.

In T1DM without CVD, the LIFE-T1D model predicted lifetime risk for CVD and non-CVD mortality.

Helmink MAG, Hageman SHJ, Eliasson B, et al. Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: the LIFE-T1D model. Diabetes Obes Metab. 2024;26:2229-2238. 38456579.

Renal Hyperfiltration as a New Mechanism of Smoking-Related Mortality.

Renal hyperfiltration (RHF), an established risk factor for mortality, is prevalent among tobacco smokers. The aim of this study was to assess the mediating role of RHF in the association between smoking and mortality. Data of this study were retrieved from the cohort of the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), including 2064 males from Finland. Study participants were followed over a 35-year period. Using classic and counterfactual mediation analysis approaches, we estimated the mediative effect of RHF in the association between smoking and each of the following outcomes: All-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. The risk of all-cause mortality in smokers was twice that in nonsmokers (hazard ratio [HR], 2.06; 95% confidence interval [CI]: 1.84 to 2.31). Under the counterfactual framework the direct effect of smoking on all-cause mortality, controlled for RHF, corresponded to an HR of 2.00 (95% CI: 1.78 to 2.30). Of the effect of smoking on mortality, 5% (p-value = .016) was mediated by RHF. This finding concerned particularly non-CVD mortality. RHF mediated the effect of smoking on non-CVD and all-cause mortality, but not on CVD mortality. The generalizability of our study results is however limited by its focus on a Finnish male cohort, underscoring the need for further investigation into RHF's broader implications across diverse populations. This study elucidates the complex interplay between smoking, renal hyperfiltration (RHF), and mortality, offering novel insights into the mediating role of RHF. Our findings demonstrate that RHF significantly mediates the relationship between smoking and non-cardiovascular disease (non-CVD), but not CVD mortality. This distinction underscores the multifaceted role of RHF beyond its established association with cardiovascular events. By highlighting the specific pathways through which RHF mediates some of the smoking-attributed mortality, this research contributes to our understanding of the mechanisms linking smoking to mortality.

The relationship between cardiometabolic abnormalities and mortality among women with and without cancer in the Women’s Health Initiative (WHI).

e24007 Background: Prior studies of women with obesity-associated cancers in the Women’s Health Initiative (WHI) showed higher overall and mortality due to cardiovascular disease (CVD) for women with a higher number of cardiometabolic risk factors at baseline. It is unclear if this risk differs from women without cancer. In order to determine if this relationship differs among both groups, we compared the association between cardiometabolic risk factors and mortality among women in the WHI with and without cancer. Methods: Women with one of five early-stage obesity-associated cancers (breast, colorectal, endometrial, ovarian, non-Hodgkin lymphoma), and matched controls without history of cancer, were selected from the WHI-Life and Longevity After Cancer (LILAC) study. Cardiometabolic risk factors included high waist circumference (WC) (≥88 cm), systemic hypertension ( &gt; 130/85 mm Hg) measured at study visits, and self-reported history of diabetes and elevated cholesterol. Multivariable Cox proportional hazards models (all-cause mortality) and Fine-Gray models (CVD and non-CVD mortality) were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the association between baseline cardiometabolic risk factors and survival outcomes for the cancer and non-cancer cohorts in separate models. Sensitivity analyses included women in the cancer-cohort who received cardiotoxic chemotherapy. Results: A total of 7,491 and 35,508 women were analyzed in the cancer and non-cancer cohorts respectively. CVD was the most common cause of death (excluding cancer) in both non-cancer (41.4%) and cancer (41.5%) cohorts. Adjusted Cox models showed that the proportion of deaths due to any cause, by number of cardiometabolic risk factors, was significantly higher in the non-cancer compared to the cancer cohort (p-value = 0.02), with the HR values being higher for those with 3-4 risk factors compared to 1-2. Similar results were seen for each individual risk factor except for WC. Regarding CVD and non-CVD mortality, in competing risks models, there were no significant differences in the risk of death by number of risk factors, between the cancer and non-cancer cohorts (p = 0.21 and 0.22) respectively. Sensitivity analyses for women who received a cardiotoxic regimen, (81.5% anthracyclines alone, 13.4% anti-HER2 alone, and 5.1% both) showed no differences in the results for all-cause mortality, and CVD mortality. However, for non-CVD mortality, the proportion of deaths was significantly higher for women in the non-cancer cohort (p = 0.03). Conclusions: Cardiometabolic risk factors had a greater impact on mortality among women without cancer compared to those with cancer, except for death due to CVD which was similar between groups, suggesting that CVD risk reducing interventions are of equal importance for women with and without cancer.

ASSOCIATION OF BLOOD PRESSURE WITH MORTALITY IN OLDEST OLD PEOPLE WITH FRAILTY IN CHINA: RESULTS FROM CHINESE LONGITUDINAL HEALTHY LONGEVITY SURVEY (CLHLS)

Objective: To determine the target blood pressure in old people (80+ years) with frailty. Design and method: In this community based, longitudinal prospective study, we enrolled 3,134 oldest old people with frailty. The exposure-response associations between blood pressure and all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality were assessed by the penalized cubic splines fitted in Cox models. Results: During 5 years follow-up, 2,532 deaths were documented. An approximate L-shaped association between systolic blood pressure (SBP) and 5-year all-cause mortality was identified. Compared with 140 mmHg (inflection point), the risk of all-cause mortality significantly increased for SBP below 127 mmHg, which varied from HR of 1.050 (95% CI: 1.003-1.100) to 1.576 (95% CI: 1.128-2.203). After 140 mmHg, mortality risk gradually fell with increasing SBP, although not reaching statistical significance. Diastolic blood pressure (DBP) suggested a significant U-shaped association with 5-year all-cause mortality with 90 mmHg conferred the lowest risk. Before that, the risk of all-cause mortality rose with decreasing DBP, which varied from HR of 1.041 (95% CI: 1.001-1.082) to 1.304 (95% CI: 1.005-1.692). After 90 mmHg, although the observed differences were not statistically significant, mortality risk tended to rise with increasing DBP. Among the 2,037 participants with a confirmed cause of death, 346 died from CVDs and 1,691 died from non-CVDs. In comparison with 120 mmHg, SBP above 134 mm Hg exhibited a significantly elevated CVD mortality risk; when SBP below 121 mmHg, significantly increased non-CVD mortality risk could be found in comparison with SBP at 140 mmHg. As for DBP, it could not predict CVD mortality risk; there was an approximate U-shaped association between DBP and non-CVD mortality that DBP below 69 mmHg was associated with a higher risk with 85 mmHg as the reference. Stratified and sensitivity analyses showed robustness of main findings. Conclusions: In the oldest old people with frailty, in addition to all-cause mortality, blood pressure management should balance CVDs risk and non-CVD risk. Maintaining blood pressure at 120-140/80-100 mmHg can reduce all-cause mortality risk and meanwhile may prevent the adverse events due to excessively higher or lower blood pressure.

Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study

Abstract Background and Aims Emerging evidence has raised an obesity paradox in observational studies of body mass index (BMI) and health among the oldest-old (aged ≥80 years), as an inverse relationship of BMI with mortality was reported. This study was to investigate the causal associations of BMI, waist circumference (WC), or both with mortality in the oldest-old people in China. Methods A total of 5306 community-based oldest-old (mean age 90.6 years) were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 1998 and 2018. Genetic risk scores were constructed from 58 single-nucleotide polymorphisms (SNPs) associated with BMI and 49 SNPs associated with WC to subsequently derive causal estimates for Mendelian randomization (MR) models. One-sample linear MR along with non-linear MR analyses were performed to explore the associations of genetically predicted BMI, WC, and their joint effect with all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. Results During 24 337 person-years of follow-up, 3766 deaths were documented. In observational analyses, higher BMI and WC were both associated with decreased mortality risk [hazard ratio (HR) 0.963, 95% confidence interval (CI) 0.955–0.971 for a 1-kg/m2 increment of BMI and HR 0.971 (95% CI 0.950–0.993) for each 5 cm increase of WC]. Linear MR models indicated that each 1 kg/m2 increase in genetically predicted BMI was monotonically associated with a 4.5% decrease in all-cause mortality risk [HR 0.955 (95% CI 0.928–0.983)]. Non-linear curves showed the lowest mortality risk at the BMI of around 28.0 kg/m2, suggesting that optimal BMI for the oldest-old may be around overweight or mild obesity. Positive monotonic causal associations were observed between WC and all-cause mortality [HR 1.108 (95% CI 1.036–1.185) per 5 cm increase], CVD mortality [HR 1.193 (95% CI 1.064–1.337)], and non-CVD mortality [HR 1.110 (95% CI 1.016–1.212)]. The joint effect analyses indicated that the lowest risk was observed among those with higher BMI and lower WC. Conclusions Among the oldest-old, opposite causal associations of BMI and WC with mortality were observed, and a body figure with higher BMI and lower WC could substantially decrease the mortality risk. Guidelines for the weight management should be cautiously designed and implemented among the oldest-old people, considering distinct roles of BMI and WC.

Associations of total homocysteine and kidney function with all-cause and cause-specific mortality in hypertensive patients: a mediation and joint analysis.

Plasma total homocysteine (tHcy) and kidney function are both associated with mortality risk, but the degree to which kidney function modifies the impact of tHcy on mortality remains unknown. This prospective cohort study included a total of 14,225 hypertensive adults. Cox proportional hazard regression was used to analyze the separate and combined association of tHcy and estimated glomerular filtration rate (eGFR) with all-cause and cause-specific mortality. Mediation analysis was conducted to explore the mediating effect of eGFR. During a median follow-up of 4.0 years, 805 deaths were identified, including 397 deaths from cardiovascular disease (CVD). There were significant, positive relationships of tHcy with all-cause mortality (per 5 μmol/L; HR: 1.09; 95% CI: 1.07, 1.11), CVD mortality (HR: 1.11; 95% CI: 1.08, 1.13), and non-CVD mortality (HR: 1.07; 95% CI: 1.04, 1.10). The proportions of eGFR mediating these relationships were 39.1%, 35.7%, and 49.7%, respectively. There were additive interactions between tHcy and eGFR. Compared with those with low tHcy (<15 μmol/L) and high eGFR (≥90 mL·min-1·1.73 m-2), participants with high tHcy (≥20 μmol/L) and low eGFR (<60 mL·min-1·1.73 m-2) had the highest risk of all-cause mortality (HR: 4.89; 95% CI: 3.81, 6.28), CVD mortality (HR: 5.80; 95% CI: 4.01, 8.40), and non-CVD mortality (HR: 4.25; 95% CI: 3.02, 5.97). In conclusion, among Chinese hypertensive adults, high tHcy and impaired kidney function were independently and jointly associated with higher risks of all-cause and cause-specific mortality. Importantly, kidney function explained most (nearly 40%) of the increased risk of mortality conferred by high tHcy.

Association of aerobic and muscle-strengthening physical activity with all-cause and cardiovascular disease mortality among adults with type 2 diabetes: A prospective cohort of US adults

ObjectiveTo investigate the relationship of moderate physical activity (MPA), vigorous physical activity (VPA), and muscle strengthening activity (MSA), independently and jointly, with all-cause, cardiovascular disease (CVD), and non-CVD mortality in individuals with type 2 diabetes (T2D). Material and methodsThis cohort study included 47,538 adults with T2D and 561,963 adults without T2D from the National Health Interview Survey 1997–2018 who provided data on self-reported physical activity (PA). Mortality data were obtained from the National Death Index through 2019. Cox regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). ResultsIn analyses mutually adjusted, versus no MPA adults with T2D, performing the recommendations of MPA (150–299 min/week) associated with lower all-cause mortality (HR, 0.72; 95% CI, 0.66–0.78), CVD mortality (HR, 0.68; 95% CI, 0.58–0.79), and non-CVD mortality (HR, 0.72; 95% CI, 0.65–0.79). Similar benefits were observed in those meeting recommendations for VPA and MSA. Higher levels of PA beyond current recommendations may provide a few additional benefits without adverse effects on mortality risk, regardless of diabetes onset age, duration of diabetes, and medication status. The joint analysis indicates that combining MSA with aerobic PA could further lower mortality risk, and lowest all-cause mortality was observed among individuals engaging in either 75–150 min/week of VPA and 1 time/week of MSA (HR, 0.30; 95% CI, 0.13–0.70) or 150–299 min/week of MPA and 1 time/week of MSA (HR, 0.33; 95% CI, 0.20–0.55). ConclusionOur study supports the current PA guidelines and suggests that there may be limited benefits gained from exercising beyond recommended levels in adults with T2D, combining recommended levels of aerobic and resistance exercises could yield the greatest benefits.

Trends in All-Cause, Cardiovascular, and Noncardiovascular Mortality Among US Adults With Hypertension.

Death certificate data indicate that hypertension may have increased as a contributing cause of death among US adults. Hypertension is not commonly recorded on death certificates although it contributes to a substantial proportion of cardiovascular disease (CVD) deaths. We estimated changes in all-cause, CVD, and non-CVD mortality over 5 years of follow-up among 4 cohorts of US adults with hypertension using mortality follow-up data from National Health and Nutrition Examination Survey III in 1988 to 1994, and National Health and Nutrition Examination Survey cycles from 1999 to 2000 through 2015 to 2016 (n=20 927). Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or antihypertensive medication use. Participants were grouped according to the date of their National Health and Nutrition Examination Survey study visit (1988-1994, 1999-2004, 2005-2010, 2011-2016). There were 2646, 1048, and 1598 all-cause, CVD, and non-CVD deaths, respectively. After age, gender, and race/ethnicity adjustment and compared with the 1988 to 1994 cohort, the hazard ratio of all-cause mortality was 0.88 (95% CI, 0.76-1.01) for the 1999 to 2004 cohort, 0.82 (95% CI, 0.70-0.95) for the 2005 to 2010 cohort, and 0.89 (95% CI, 0.75-1.05) for the 2011 to 2016 cohort (P trend=0.123). The age, gender, and race/ethnicity-adjusted hazard ratios for CVD mortality compared with the 1988 to 1994 cohort were 0.74 (95% CI, 0.60-0.90) for the 1999 to 2004 cohort, 0.61 (95% CI, 0.50-0.74) for the 2005 to 2010 cohort, and 0.57 (95% CI, 0.44-0.74) for the 2011 to 2016 cohort (P trend <0.001). There was no evidence of a change in CVD mortality between the 2005 to 2010 and 2011 to 2016 cohorts (P=0.661). Noncardiovascular mortality did not decline over the study period (P trend=0.145). The decline in CVD mortality among US adults with hypertension stalled after 2005 to 2010.

Association of circulating fibroblast growth factor 21 levels with all-cause and cardiovascular mortality: The multi-ethnic study of atherosclerosis

BackgroundFibroblast growth factor 21 (FGF21) levels are often elevated in cardiovascular disease (CVD). However, no study has assessed its association with cardiovascular and all-cause mortality in a population free of clinically evident CVD. MethodsA total of 5543 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age 62.7 years, 47.5 % male), free of clinically evident CVD at baseline, were studied. From baseline (2000–2002), 1606 deaths (including 387 CVD deaths) were observed over a median follow-up of 17.7 years. Multivariable Cox regression analysis was performed to assess the association of plasma FGF21 levels with mortality. ResultsFGF21 levels at baseline were associated with all-cause mortality, even after adjustment for traditional risk factors, including demographic, socioeconomic and cardiovascular risk factors (adjusted hazard ratio 1.08 [95% confidence interval 1.01, 1.16] per 1 SD increase in ln-transformed levels; 1.27 for the highest vs, lowest quartile). Baseline FGF21 levels were significantly associated with both CVD and non-CVD mortality in unadjusted models. However, the association with non-CVD mortality, but not CVD mortality, remained statistically significant after adjusting for covariates. Similar results were obtained in FGF21 quartile analyses and also when using competing risk regression or matched case-control cohort in sensitivity analyses. ConclusionsIn subjects without clinically-evident CVD at baseline, over 17.7 years follow-up there is a modest association of baseline FGF21 levels with all-cause mortality. The finding that this is driven primarily by a significant association with non-CVD mortality over almost two decades merits further investigation.

Combined effects of vitamin D deficiency and systemic inflammation on all-cause mortality and cause-specific mortality in older adults

BackgroundVitamin D deficiency and systemic inflammation share common pathological mechanisms in muscle loss, cardio-pulmonary function decline, and abnormal metabolism, which are linked to chronic conditions, senescence, and early mortality. However, their combined effect on mortality in older adults has not been well established. This study longitudinal aimed to explore the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] and high sensitivity C-reactive protein (hs-CRP) with mortality risk in Chinese community-based older people.Methods3072 older adults (86.07 ± 11.87 years, 54.52% female) from the Chinese Longitudinal Healthy Longevity Survey (2012–2018) were enrolled. Baseline 25(OH)D and hs-CRP levels were collected, and survival information was recorded in the 2014 and 2018 follow-up waves. Cox proportional hazard regressions were conducted to explore the associations between 25(OH)D, hs-CRP, and mortality. Demographic characteristics, health behaviors, and chronic disease biomarkers were adjusted.ResultsDuring 10,622.3 person-years of follow-up (median: 3.51 years), 1321 older adults died, including 448 deaths due to cardiovascular disease (CVD). Increased mortality risk was associated with lower 25(OH)D and higher hs-CRP quantiles, even after adjusting for each other and multiple covariates (all P-trend < 0.05). In combined analyses, the highest all-cause mortality (HR: 2.18, 95% CI: 1.73 ~ 2.56), CVD mortality (HR: 2.30, 95% CI: 1.64 ~ 3.21), and non-CVD mortality (HR: 2.19, 95% CI: 1.79 ~ 2.49) were obtained in participants with both 25(OH)D deficiency (< 50 nmol/L) and high hs-CRP (≥ 3.0 mg/L), respectively. We observed significant additive interactions of 25(OH)D and hs-CRP on all-cause mortality and non-CVD mortality (RERIS>0).ConclusionsLow 25(OH)D and high hs-CRP, both independently and jointly, increase mortality risk in Chinese community-dwelling older adults. Thus, priority should be given to early detection and appropriate intervention in older individuals with combined vitamin D deficiency and systemic inflammation. Molecular mechanisms of related adverse health effect are worthy of further investigation.

Excess mortality and its causes among older adults with schizophrenia versus those with bipolar disorder and major depressive disorder: a 5-year prospective multicenter study.

Excess mortality observed in people with schizophreniamay persist in later life. The specific causes of increased mortality observed in older adults with schizophrenia and the potential influence of psychotropic medications remain partly unknown. We compared 5-year mortality and its causes of older adults with schizophrenia to bipolar disorder (BD) or major depressive disorder (MDD). We used a 5-year prospective cohort, including 564 older inpatients and outpatients with schizophrenia, BD or MDD (mean age: 67.9years, SD = 7.2years). Causes of death were cardiovascular disorder (CVD) mortality, non-CVD disease-related mortality (e.g., infections), suicide, and unintentional injury. The primary analysis was a multivariable logistic model with inverse probability weighting (IPW) to reduce the effects of confounders, including sociodemographic factors, duration and severity of the disorder, and psychiatric and non-psychiatric comorbidity. Five-year all-cause mortality among older participants with schizophrenia and with BD or MDD were 29.4% (n = 89) and 18.4% (n = 45), respectively. Following adjustments, schizophrenia compared to MDD or BD was significantly associated with increased all-cause mortality (AOR = 1.35; 95%CI = 1.04-1.76; p = 0.024) and cardiovascular mortality (AOR = 1.50; 95%CI = 1.13-1.99; p = 0.005). These associations were significantly reduced among patients taking antidepressants [interaction odds ratio (IOR) = 0.42; 95%CI = 0.22-0.79; p = 0.008 and IOR = 0.39: 95%CI = 0.16-0.94; p = 0.035, respectively]. Schizophrenia was associated with higher mortality compared to BD or MDD. Cardiovascular diseases explained most of this excess mortality. Exploratory analyses suggested that psychotropic medications did not influence this excess mortality, except for antidepressants, which were associated with significantly reduced between-group difference in all-cause and cardiovascular mortality.

Potential cardioprotective effects of acetylcholinesterase inhibitors in patients with Alzheimer's disease

Abstract Background In patients with mild to moderate Alzheimer's disease (AD), acetylcholinesterase inhibitors (AChE-I) are commonly employed to improve cognitive function. They increase the amount of acetylcholine (ACh) in the neuronal synapses, but bradycardia, cardiac electrical conduction blocks and hypotension due to muscarinic M2 receptor stimulation are potential side effects. However, whether these "side effects" could play a potential protective effect on cardiovascular (CV) events is not yet well defined. Purpuses To evaluate potential beneficial cardiac effects of AChE-Is in patients with AD, in terms of reduction of major adverse cardiovascular events (MACEs). Methods We conducted a retrospective, monocentric, observational cohort study in patients referred to our hospital. Two groups were considered: the interventional group included AD patients treated with AChE-I. The control group enrolled a cohort of subjects matched for age and comorbidities, recruited between caregivers of intervention group subjects that were cognitively unimpaired and not taking AchE-I. The primary endpoint was a composite of hospitalization for heart failure (HF), non-fatal acute myocardial infarction (AMI), myocardial revascularization, hospitalization for cardiovascular (CV) causes, cardiovascular mortality and occurrence of stroke and/or TIA during total 5 year follow-up period (MACEs). Secondary endpoints were each individual component of the primary end point, total deaths, non-cardiovascular death and incidence of pacemaker implant. Results 221 AD patients treated with AChE-I (91 with Donepezil, 130 with Rivastigmine) were included in intervention group and 221 non-AD patients in control group. Groups were homogeneous in terms of age, gender and main cardiovascular risk factors, except for family history of cardiovascular diseases (CVD), which was more frequent in control group. During a median follow-up of 3.1 years the primary endpoint occurred in 24 patients in intervention group (2.1 per 100 patient-years) compared to 56 patients in the control group (5.0 per 100 patient-years). Therefore, AChE-I therapy resulted a protective factor from primary endpoint (HR 0.48, 95% CI 0.24-0.95; p= 0.036). Even not significant, the difference was mainly driven by myocardial revascularization (3.2% in intervention group vs 6.8% in controls) and hospitalization for heart failure (4.5% in intervention group vs 14.5% in controls). Non-CVD mortality was significantly higher in treatment group (13,6% in intervention group vs 2,7% in controls). No significant difference was observed between groups in terms of other secondary outcomes. Conclusions Among patients with AD, use of AChE-I may be protective for CV outcomes, especially reducing HF hospitalisation and myocardial revascularization.Kaplan-Meier of cumulative MACEsNumber of Event/Years