Background The purpose of this study was to investigate the association between kidney function and arterial calcification in major vascular beds and to establish whether arterial calcification ...mediates the relation between kidney function measures and cardiovascular disease ( CVD ) incidence. Methods and Results In 2241 participants from the Rotterdam Study (mean age 69 years, 52% female), kidney function was assessed using the estimated glomerular filtration rate and urine albumin-to-creatinine ratio. All participants underwent noncontrast computed tomography to quantify the amount of arterial calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. We used linear regression models, adjusted for age, sex, and cardiovascular risk factors, to evaluate the association between kidney function and arterial calcification volume in the 4 vessel beds. Incidence rate of CVD was calculated in 3 groups of participants based on their kidney function and presence of arterial calcification. We conducted mediation analysis to evaluate whether arterial calcification mediates this association. We found that in age- and sex-adjusted models, lower estimated glomerular filtration rate and higher albumin-to-creatinine ratio were associated with larger calcification volumes in all 4 vascular beds. Adjusting for cardiovascular risk factors attenuated the effect estimates. CVD incidence was higher in participants with estimated glomerular filtration rate <60 mL/min per 1.73 m
and presence of arterial calcification compared with individuals with estimated glomerular filtration rate >60 and no calcification. After adjusting for cardiovascular risk factors, arterial calcification did not mediate the association between kidney function measures and CVD incidence. Conclusions The association of impaired kidney function and larger volumes of arterial calcification is partly explained by cardiovascular risk factors. Arterial calcification does not mediate the association between kidney function and CVD beyond cardiovascular risk factors.
Machine learning models are increasingly being used to estimate “brain age” from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of ...accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among
N
= 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.
To develop a healthy aging score (HAS), to assess age and sex differences in HAS, and to evaluate the association of the HAS with survival.
Prospective population-based cohort.
Inhabitants of ...Ommoord, Rotterdam, The Netherlands.
A total of 1405 men and 2122 women, mean (standard deviation) age 75.9 (6.4) years.
We included 7 domains in the total score of HAS: chronic diseases, mental health, cognitive function, physical function, pain, social support, and quality of life; each scored 0, 1, or 2 in each domain. A total score (range 0-14) was constructed and was assessed continuously and in tertiles (13-14: healthy aging, 11-12: intermediate aging, 0-10: poor aging). Sex-specific change in the mean HAS was computed for the age categories of 65-69, 70-74, 75-79, 80-84, and ≥85 years. The association between HAS and mortality was assessed with Cox proportional hazards models.
Mean follow-up was 8.6 (3.4) years. Men had poorer scores in the chronic disease domain than women. However, women had poorer mental health, worse physical function, more pain, and lower quality of life compared with men. The prevalence of healthy aging was higher in men (n = 396, 28.2%), than in women (n = 526, 24.8%). The mean (standard deviation) HAS was 11.1 (2.2) in men and 10.7 (2.3) in women. Mean HAS was higher in men than in women for all age categories. The β for change in mean HAS across the 5 increasing age categories was -0.55 (-0.65 to -0.45) in men and -0.65 (-0.73 to -0.57) in women. The age-adjusted hazard ratio per unit increase in HAS with mortality was 0.86 (0.83-0.89) in men, and 0.89 (0.87-0.91) in women.
Levels of HAS were lower in women compared with men, in all age categories. The HAS declined with increasing age for both sexes, albeit slightly steeper in women. The HAS was strongly associated with mortality in both sexes. A better understanding of population healthy aging and sex differences in this regard could aid to implement strategies for sustainable healthcare in aging populations.
Background Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ...ratio in relation to decline in kidney function. Study Design Prospective cohort study. Setting & Participants 2,479 individuals (mean age, 65.1 ± 5.9 SD years; 43% men) from the population-based Rotterdam Study. Predictors vWF, ADAMTS13, and vWF:ADAMTS13 ratio. Outcomes & Measurements Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR < 60 mL/min/1.73 m2 were assessed. Results During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR < 60 mL/min/1.73 m2 occurred. The population had a mean eGFR decline of 0.96 ± 0.92 mL/min/1.73 m2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, −0.06 95% CI, −0.09 to −0.02 mL/min/1.73 m2 per year) and higher risk for new-onset eGFR < 60 mL/min/1.73 m2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same. Limitations No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13. Conclusions In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease.
Carotid Stiffness Is Associated With Incident Stroke van Sloten, Thomas T., MD, PhD; Sedaghat, Sanaz, PhD; Laurent, Stéphane, MD, PhD ...
Journal of the American College of Cardiology,
11/2015, Letnik:
66, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Abstract Background Carotid stiffening is considered a key element in the pathogenesis of stroke. However, results of studies evaluating the association between carotid stiffness and incident stroke ...have been inconsistent. Objectives This study investigated whether carotid stiffness (as determined by ultrasonography) is associated with incident stroke and whether this association is independent of aortic stiffness as estimated by carotid-femoral pulse wave velocity (cfPWV). Additionally, we evaluated the incremental value of carotid stiffness for stroke risk prediction beyond Framingham risk factors and cfPWV. Methods This study included a systematic review and meta-analyses of aggregate and individual participant data (IPD), the latter of which was obtained by requesting individual-level data of all cohort studies with available data on carotid stiffness and cfPWV. Results Ten studies (n = 22,472) were included in the aggregate data meta-analysis and 4 (n = 4,540) in the IPD meta-analysis. After adjusting for cardiovascular (CV) factors, the aggregate data meta-analysis showed that greater carotid stiffness (per SD) was associated with stroke (hazard ratio: 1.18; 95% confidence interval: 1.05 to 1.33). In addition, carotid stiffness was associated with total CV events and CV and all-cause mortality, but not with coronary heart disease events. In the IPD meta-analysis, additional adjustment for cfPWV did not materially change these associations. Carotid stiffness did improve stroke risk prediction beyond Framingham and cfPWV (integrative discrimination improvement: 0.4 percentage point 95% confidence interval: 0.1 to 0.6 percentage point and continuous net reclassification improvement: 18.6% 95% confidence interval: 5.8% to 31.3%). Conclusions Carotid stiffness is associated with incident stroke independently of CV factors and aortic stiffness. In addition, carotid stiffness improves stroke risk prediction beyond Framingham and aortic stiffness.
Cystatin C and Cardiovascular Disease van der Laan, Sander W., MSc; Fall, Tove, PhD; Soumaré, Aicha, PhD ...
Journal of the American College of Cardiology,
08/2016, Letnik:
68, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Abstract Background Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. ...It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. Objectives The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. Methods We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. Results Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval CI: 1.56 to 2.13; p = 2.12 × 10−14 ). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10−211 ), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10−5 ). A causal effect of cystatin C was not detected for any individual component of CVD. Conclusions Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly ...and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 95% confidence interval (CI), 0.47-0.78; P < 0.0001 and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001 or Alzheimer's disease adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002 and with Alzheimer's disease adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001, compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.
Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden ...of disease. We investigated whether specific AHM classes reduced the risk for dementia.
We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure SBP ≥140 mm Hg or diastolic blood pressure DBP ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses.
Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7–22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio HR 0·88, 95% CI 0·79–0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73–0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease.
Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia.
The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.
Carotid stiffening is considered a key element in the pathogenesis of stroke. However, results of studies evaluating the association between carotid stiffness and incident stroke have been ...inconsistent.
This study investigated whether carotid stiffness (as determined by ultrasonography) is associated with incident stroke and whether this association is independent of aortic stiffness as estimated by carotid-femoral pulse wave velocity (cfPWV). Additionally, we evaluated the incremental value of carotid stiffness for stroke risk prediction beyond Framingham risk factors and cfPWV.
This study included a systematic review and meta-analyses of aggregate and individual participant data (IPD), the latter of which was obtained by requesting individual-level data of all cohort studies with available data on carotid stiffness and cfPWV.
Ten studies (n = 22,472) were included in the aggregate data meta-analysis and 4 (n = 4,540) in the IPD meta-analysis. After adjusting for cardiovascular (CV) factors, the aggregate data meta-analysis showed that greater carotid stiffness (per SD) was associated with stroke (hazard ratio: 1.18; 95% confidence interval: 1.05 to 1.33). In addition, carotid stiffness was associated with total CV events and CV and all-cause mortality, but not with coronary heart disease events. In the IPD meta-analysis, additional adjustment for cfPWV did not materially change these associations. Carotid stiffness did improve stroke risk prediction beyond Framingham and cfPWV (integrative discrimination improvement: 0.4 percentage point 95% confidence interval: 0.1 to 0.6 percentage point and continuous net reclassification improvement: 18.6% 95% confidence interval: 5.8% to 31.3%).
Carotid stiffness is associated with incident stroke independently of CV factors and aortic stiffness. In addition, carotid stiffness improves stroke risk prediction beyond Framingham and aortic stiffness.
Abstract Stroke is a leading cause of death in the United States across all race/ethnicity and sex groups, though disparities exist. We investigated the potential for primary prevention of total ...first stroke for Americans aged 20 and older, stratified by sex and race/ethnicity. Specifically, we calculated population attributable fractions (PAF) of first stroke for 7 potentially modifiable risk factors: smoking, physical inactivity, poor diet, obesity, hypertension, diabetes, and atrial fibrillation. PAFs are a function of (1) the relative risk of first stroke for people with the exposure and (2) the prevalence of the risk factor in the population. Relative risks came from recent meta-analyses and sex-race/ethnicity-specific prevalence estimates came from the 2015-2018 NHANES or Multi-Ethnic Study of Atherosclerosis (for atrial fibrillation only). Approximately 1/3 (35.7% CI: 21.6%-49.0%) for women, 32.7% CI: 19.2%-45.1% for men) of strokes were attributable to the 7 risk factors we considered. A 20% proportional reduction in stroke risk factors would result in approximately 37,000 fewer strokes annually in the United States. The estimated PAF was highest for non-Hispanic Black women (39.3% CI: 24.8%-52.3%) and lowest for non-Hispanic Asian men (25.5% CI: 14.6%-36.2%). For most groups, obesity and hypertension were the largest contributors to stroke rates.
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