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

INTRODUCTION: 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. AIMS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPLICATIONS: 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.

Meaningfulness and mortality: exploring the sense of coherence in Eastern Finnish men.

AIMS: The sense of coherence scale has been shown to have an epidemiological relationship with mortality. This study aimed to investigate how the three components of sense of coherence (meaningfulness, comprehensibility and manageability) and the individual items of these components relate to mortality. METHODS: Eastern Finnish men (n=2315) aged 42-60 years at baseline in the 1980s completed a 12-item sense of coherence scale and were followed for 25 years, on average, until death or until the end of 2019. Hazard ratios for mortality were calculated using two models: one adjusted for age and the second for an additional 12 mortality risk factors. RESULTS: Of the three sense of coherence components, only meaningfulness was associated with all-cause mortality, and in the fully adjusted model, those in the weakest tertile had a 1.14 (95% confidence interval 1.01-1.29, P=0.042) times higher hazard ratio for mortality than those in the strongest tertile. Of the individual sense of coherence items, only the first question, 'How often do you have the feeling that you really don't care about what is going on around you?', was associated with all-cause mortality, and in the fully adjusted Cox model, the hazard ratio of weak versus strong was 1.18 (95% confidence interval 1.03-1.36, P=0.020). CONCLUSIONS: The sense of coherence component related to meaningfulness, including its first item, 'Caring about what goes on around you', plays a significant role in the association with mortality among middle-aged men in Eastern Finland. This item should be considered a noteworthy patient-reported variable when predicting mortality in public health settings.

DXA-based Fat Mass With Risk of Worsening Insulin Resistance in Adolescents: A 9-Year Temporal and Mediation Study.

CONTEXT: Surrogate measures of childhood and adolescent obesity have impaired the understanding of the relationship of body composition with insulin resistance in the young population. OBJECTIVE: We aim to examine the longitudinal associations of directly measured total fat mass, trunk fat mass, and lean mass with the risk of hyperglycemia, hyperinsulinemia, and insulin resistance from ages 15 to 24 years, the mediation path through which lipids and inflammation influence insulin resistance, and whether increased fat mass temporally precede insulin resistance. METHODS: We studied 3160 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, who had complete dual-energy x-ray absorptiometry measure and fasting blood samples at age 15 years and repeated measures at ages 17- and 24-years clinic visit. Fasting glucose greater than 6.1 mmol/L, insulin greater than 11.78 mU/L, and homeostatic model assessment for insulin resistance (HOMA-IR) greater than or equal to the 75th percentile were categorized as hyperglycemia, hyperinsulinemia, and high insulin resistance, respectively. Longitudinal associations were examined with generalized logit-mixed-effect models, while mediation and temporal path analyses were examined using structural equation models, adjusting for cardiometabolic and lifestyle factors. RESULTS: Among 3160 participants (51% female), fat mass and lean mass increased linearly both in males and females, while glucose, insulin, and HOMA-IR had a U-shaped course from age 15 through 24 years. After full adjustment, each 1-kg cumulative increase in total fat mass (odds ratio 1.12 [95% CI, 1.11-1.13]) and trunk fat mass (1.21 [1.19-1.23]) from ages 15 through 24 years were associated with a progressively worsening risk of high insulin resistance as well as hyperglycemia and hyperinsulinemia. The association of increased total fat mass with increased insulin resistance was partly mediated by triglycerides (9% mediation). In the temporal path analysis, higher total fat mass at age 15 years was associated with higher insulin resistance at age 17 years, but not vice versa. Higher total fat mass at age 17 years was bidirectionally associated with higher insulin resistance at 24 years. CONCLUSION: Mid-adolescence may be an optimal time for interrupting the worsening fat mass-insulin resistance pathologic cycle and attenuating the risk of progressively worsening metabolic dysfunction before young adulthood.

Accelerometer-based sedentary time, light physical activity, and moderate-to-vigorous physical activity from childhood with arterial stiffness and carotid IMT progression: A 13-year longitudinal study of 1339 children.

AIMS: We examined the longitudinal associations of sedentary time (ST), light physical activity (LPA), and moderate-to-vigorous PA (MVPA) from childhood with carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness and carotid intima-media thickness (cIMT). METHODS: We studied 1339 children, aged 11 years from Avon Longitudinal Study of Parents and Children, UK, followed up for 13 years. Accelerometer-based ST, LPA, and MVPA were assessed at ages 11, 15, and 24 years clinic visits. cfPWV and cIMT were measured with Vicorder and ultrasound, respectively, at ages 17 and 24 years. RESULTS: Among 1339 [56.4% female] participants, mean ST increased from ages 11 through 24 years, while mean LPA and MVPA decreased. Persistently high ST tertile from childhood was associated with increased cfPWV progression, effect estimate 0.047 m/s; [(95% CI 0.005 to 0.090); p = 0.030], but not cIMT progression. Persistently high LPA tertile category was associated with decreased cfPWV progression in males -0.022 m/s; [(-0.028 to -0.017); p < 0.001] and females -0.027 m/s; [(-0.044 to -0.010); p < 0.001]. Cumulative LPA exposure decreased the odds of progressively worsening cfPWV [Odds ratio 0.994 (0.994-0.995); p < 0.0001] and cIMT. Persistent exposure to ≥60 min/day of MVPA was paradoxically associated with increased cfPWV progression in males 0.053 m/s; [(0.030 to 0.077); p < 0.001] and females 0.012 m/s; [(0.002 to 0.022); p = 0.016]. Persistent exposure to ≥60 min/day of MVPA was inversely associated with cIMT progression in females -0.017 mm; [(-0.026 to -0.009); p < 0.001]. CONCLUSION: LPA >3 h/day from childhood may attenuate progressively worsening vascular damage associated with increased ST in youth.

In vivo vitamin D targets reveal the upregulation of focal adhesion-related genes in primary immune cells of healthy individuals.

Vitamin D modulates innate and adaptive immunity, the molecular mechanisms of which we aim to understand under human in vivo conditions. Therefore, we designed the study VitDHiD (NCT03537027) as a human investigation, in which 25 healthy individuals were supplemented with a single vitamin D3 bolus (80,000 IU). Transcriptome-wide differential gene expression analysis of peripheral blood mononuclear cells (PBMCs), which were isolated directly before and 24 h after supplementation, identified 452 genes significantly (FDR < 0.05) responding to vitamin D. In vitro studies using PBMCs from the same individuals confirmed 138 of these genes as targets of 1α,25-dihydroxyvitamin D3. A subset of the 91 most regulated in vivo vitamin D target genes indicated focal adhesion as the major pathway being upregulated by vitamin D3 supplementation of healthy individuals. Differences in the individual-specific responsiveness of in vivo vitamin D target genes in relation to the increase of the person's vitamin D status allowed a segregation of the VitDHiD participants into 9 high, 12 mid and 4 low responders. The expression profile of nearly 600 genes elucidate the difference between high and low vitamin D responders, the most prominent of which is the HLA-C (major histocompatibility complex, class I, C) gene.