Background: The prevalence of end-stage renal disease (ESRD) is increasing worldwide, with the majority of new ESRD cases diagnosed in patients >60 years of age. These older patients are at... Show moreBackground: The prevalence of end-stage renal disease (ESRD) is increasing worldwide, with the majority of new ESRD cases diagnosed in patients >60 years of age. These older patients are at increased risk for impaired cognitive functioning, potentially through cerebral small vessel disease (SVD). Novel markers of vascular integrity may be of clinical value for identifying patients at high risk for cognitive impairment. Methods: We aimed to associate the levels of angiopoietin-2 (Ang-2), asymmetric dimethylarginine and a selection of eight circulating angiogenic microRNAs (miRNAs) with SVD and cognitive impairment in older patients reaching ESRD that did not yet initiate renal replacement therapy (n = 129; mean age 75.3 years, mean eGFR 16.4 mL/min). We assessed brain magnetic resonance imaging changes of SVD (white matter hyperintensity volume, microbleeds and the presence of lacunes) and measures of cognition in domains of memory, psychomotor speed and executive function in a neuropsychological test battery. Results: Older patients reaching ESRD showed an unfavourable angiogenic profile, as indicated by aberrant levels of Ang-2 and five angiogenic miRNAs (miR-27a, miR-126, miR-132, miR-223 and miR-326), compared with healthy persons and patients with diabetic nephropathy. Moreover, Ang-2 was associated with SVD and with the domains of psychomotor speed and executive function, while miR-223 and miR-29a were associated with memory function. Conclusions: Taken together, these novel angiogenic markers might serve to identify older patients with ESRD at risk of cognitive decline, as well as provide insights into the underlying (vascular) pathophysiology. Show less
The prevalence of end-stage kidney disease (ESKD) is rapidly increasing and mostly occurring in patients aged 65 years or older. The main cause of death in these patients is cardiovascular disease ... Show moreThe prevalence of end-stage kidney disease (ESKD) is rapidly increasing and mostly occurring in patients aged 65 years or older. The main cause of death in these patients is cardiovascular disease (CVD). Novel markers of vascular integrity may thus be of clinical value for identifying patients at high risk for CVD. Here we associated the levels of selected circulating angiogenic miRNAs, angiopoietin-2 (Ang-2) and asymmetric dimethylarginine (ADMA) with cardiovascular structure and function (as determined by cardiovascular MRI) in 67 older patients reaching ESKD that were included from 'The Cognitive decline in Older Patients with End stage renal disease' (COPE) prospective, multicentered cohort study. We first determined the association between the vascular injury markers and specific heart conditions and observed that ESKD patients with coronary heart disease have significantly higher levels of circulating ADMA and miR-27a. Moreover, circulating levels of miR-27a were higher in patients with atrial fibrillation. In addition, the circulating levels of the vascular injury markers were associated with measures of cardiovascular structure and function obtained from cardiovascular MRI: pulse wave velocity (PWV), ejection fraction (EF) and cardiac index (CI). We found Ang-2 and miR-27a to be strongly correlated to the PWV, while Ang-2 also associated with ejection fraction. Finally, we observed that in contrast to miR-27a, Ang-2 was not associated with a vascular cause of the primary kidney disease, suggesting Ang-2 may be an ESKD-specific marker of vascular injury. Taken together, among older patients with ESKD, aberrant levels of vascular injury markers (miR-27a, Ang-2 and ADMA) associated with impaired cardiovascular function. These markers may serve to identify individuals at higher risk of CVD, as well as give insight into the underlying (vascular) pathophysiology. Show less
As the population is aging worldwide, and in spite of all preventive efforts, age-related diseases are increasingly prevalent, such as cardiovascular diseases and cognitive impairment. Different... Show moreAs the population is aging worldwide, and in spite of all preventive efforts, age-related diseases are increasingly prevalent, such as cardiovascular diseases and cognitive impairment. Different vascular risk factors, both the ‘traditional’ modifiable factors, such as hypertension or diabetes, and non-modifiable factors, such as age or gender, can lead to different kind of intertwined micro- and macrovascular diseases in various or multiple simultaneous organs. There is a growing need for knowledge regarding the interplay between different (co)morbidities, the relation of (co)morbidities with the various underlying pathophysiological mechanisms and treatment options of these (co)morbidities. Therefore, the aims of this thesis were to identify patients at high cardiovascular risk and to optimize treatment for these patients. We further unravelled the complexity of various interacting (poly) vascular diseases, ultimately leading to an increased risk of not only cognitive impairment, but also MACE including death. Identification of these patients and better understanding of the interplay and underlying mechanisms of these diseases is the first step towards preventive strategies. Treating these high risk patients can be a therapeutic challenge, but there is growing knowledge regarding both established and evolving therapies to optimize efficacy and efficiency. Show less
BackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in... Show moreBackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).ObjectiveTo determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.MethodsCombined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged >= 65 years for TRUST (n=737) and >= 80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.ResultsThe median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38 +/- SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 +/- 3.3 mIU/L in the placebo group, compared with 3.66 +/- 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 mu g. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.ConclusionTreatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age. Show less
BackgroundChronic kidney disease (CKD) has been identified as a significant direct marker for cognitive decline, but controversy exists regarding the magnitude of the association of kidney function... Show moreBackgroundChronic kidney disease (CKD) has been identified as a significant direct marker for cognitive decline, but controversy exists regarding the magnitude of the association of kidney function with cognitive decline across the different CKD stages. Therefore, the aim of this study was to investigate the association of kidney function with cognitive decline in older patients at high risk of cardiovascular disease, using data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).MethodsData of 5796 patients of PROSPER were used. Strata were made according to clinical stages of CKD based on estimated glomerular filtration rate; <30ml/min/1.73m(2) (stage 4), 30-45ml/min/1.73m(2) (stage 3b), 45-60ml/min/1.73m(2) (stage 3a) and >= 60ml/min/1.73m(2) (stage 1-2). Cognitive function and functional status was assessed at six different time points and means were compared at baseline and over time, adjusted for multiple prespecified variables. Stratified analyses for history of vascular disease were executed.ResultsMean age was 75.3years and 48.3% participants were male. Mean follow-up was 3.2years. For all cognitive function tests CKD stage 4 compared to the other stages had the worst outcome at baseline and a trend for faster cognitive decline over time. When comparing stage 4 versus stage 1-2 over time the estimates (95% CI) were 2.23 (0.60-3.85; p=0.009) for the Stroop-Colour-Word test, -0.33 (-0.66-0.001; p=0.051) for the Letter-Digit-Coding test, 0.08 (-0.06-0.21; p=0.275) for the Picture-Word-Learning test with immediate recall and-0.07 (-0.02-0.05; p=0.509) for delayed recall. This association was most present in patients with a history of vascular disease. No differences were found in functional status.ConclusionIn older people with vascular burden, only severe kidney disease (CKD stage 4), but not mild to modest kidney disease (CKD stage 3a and b), seem to be associated with cognitive impairment at baseline and cognitive decline over time. The association of severe kidney failure with cognitive impairment and decline over time was more outspoken in patients with a history of vascular disease, possibly due to a higher probability of polyvascular damage, in both kidney and brain, in patients with proven cardiovascular disease. Show less
The Dutch prospective multicenter cohort study COPE (Cognitive decline in Older Patients with End stage renal disease) aimed to investigate the association of cardiovascular structure and function... Show moreThe Dutch prospective multicenter cohort study COPE (Cognitive decline in Older Patients with End stage renal disease) aimed to investigate the association of cardiovascular structure and function with cerebrovascular changes and cognitive function in 85 older patients with chronic kidney disease stage 4 and 5, awaiting either dialysis or conservative care. MRI was performed measuring aortic stiffness (pulse wave velocity [PWV]) and cardiac systolic function (ejection fraction and cardiac index). Outcomes were MRI-derived cerebrovascular changes (microbleeds, lacunes and white matter hyperintensities) and cognitive function (memory, executive function and psychomotor speed). Mean age was 76 years and 66% were male. No statistically significant associations were observed between cardiovascular parameters and cerebrovascular changes. Cognitive function was worse in patients with high compared to low PWV in all three cognitive domains. Although there were clinically relevant associations of high PWV with poor cognition in all domains, after adjustment for age, sex and education only the Trail Making Test A remained statistically significant (p=0.030). In conclusion, this study suggests that a higher PWV might be associated with lower cognitive function, suggesting that arterial stiffness may be an underlying mechanism of development of cognitive impairment in older patients with ESRD. Larger studies should replicate and extend these findings. Show less
Objective: Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate... Show moreObjective: Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate whether kidney function modifies the association of subclinical thyroid dysfunction and the risk of cardiovascular outcomes.Methods: In total, 5804 patients were included in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). For the current analysis, 426 were excluded because of overt thyroid disease at baseline or 6 months, 266 because of inconsistent thyroid function at baseline and 6 months, 294 because of medication use that could influence thyroid function, and 16 because of missing kidney or thyroid values. Participants with normal fT4 were classified, based on TSH both at inclusion and 6 months, into three groups: subclinical hypothyroidism (TSH >4.5 mIU/L); euthyroidism (TSH = 0.45-4.5 mIU/L); and subclinical hyperthyroidism (TSH <0.45 mIU/L). Strata of kidney function were made based on estimated glomerular filtration rate into three clinically relevant groups: <45, 45-60, and >60 mL/min/1.73 m(2). The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke.Results: Mean age was 75.3 years, and 49.0% patients were male. Mean follow-up was 3.2 years. Of all participants, 109 subjects (2.2%) had subclinical hypothyroidism, 4573 (94.0%) had euthyroidism, and 182 (3.7%) subclinical hyperthyroidism. For patients with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, primary outcome occurred in 9 (8.3%), 712 (15.6%), and 23 (12.6%) patients, respectively. No statistically significant relationship was found between subclinical thyroid dysfunction and primary endpoint with adjusted hazard ratios of 0.51 (0.24-1.07) comparing subclinical hyperthyroidism and 0.90 (0.58-1.39) comparing subclinical hypothyroidism with euthyroidism. Neither was this relationship present in any of the strata of kidney function, nor did kidney function interact with subclinical thyroid dysfunction in the association with primary endpoint (P interaction = 0.602 for subclinical hyperthyroidism and 0.388 for subclinical hypothyroidism).Conclusions: In this secondary analysis from PROSPER, we found no evidence that the potential association between thyroid hormones and cardiovascular disease is modified by kidney function in older patients with subclinical thyroid dysfunction. Show less
BACKGROUND: Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C... Show moreBACKGROUND: Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C <15 mg/dL. This prespecified analysis was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. We hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and of history of cerebrovascular disease.METHODS: Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed.RESULTS: Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72 [95% CI, 0.57-0.91]) and ischemic stroke (HR, 0.73 [95% CI, 0.57-0.93]) without increasing hemorrhagic stroke (HR, 0.83 [95% CI, 0.42-1.65]). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of <80, 80 to 100, and >100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity (P-interaction=0.31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease (P-interaction=0.37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group.CONCLUSIONS: In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group. Show less
Patients presenting with chest pain suggestive of coronary artery disease (CAD) who at coronary arteriography appear to be free of obstructive disease have presented a diagnostic and therapeutic... Show morePatients presenting with chest pain suggestive of coronary artery disease (CAD) who at coronary arteriography appear to be free of obstructive disease have presented a diagnostic and therapeutic challenge since the 1970's. Studies in female patient populations have suggested that this is predominantly a women's syndrome usually caused by microvascular endothelial dependent and independent dysfunction. A critical review of the literature focusing on studies including both women and men revealed that apart from a higher incidence of this syndrome in women there are no clinical relevant differences between both sexes. In women a lower coronary flow reserve has been reported but this appears to be mainly due to a higher basal flow. Important questions with regard to the clinical implications of microvascular dysfunction have yet to be resolved in studies involving women as well as men in which a distinction is made between patients with normal coronary arteries and those with nonobstructive disease. Show less
