OBJECTIVETo investigate the relationship between baseline white matter hyperintensities (WMH) in patients with ischemic stroke and long-term risk of dementia, functional impairment, recurrent stroke, ...and mortality.
METHODSFollowing the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO protocolCRD42018092857), we systematically searched Medline and Scopus for cohort studies of ischemic stroke patients examining whether MRI- or CT-assessed WMH at baseline are associated with dementia, functional impairment, recurrent stroke, and mortality at 3 months or later poststroke. We extracted data and evaluated study quality with the Newcastle–Ottawa scale. We pooled relative risks (RR) for the presence and severity of WMH using random-effects models.
RESULTSWe included 104 studies with 71,298 ischemic stroke patients. Moderate/severe WMH at baseline were associated with increased risk of dementia (RR 2.17, 95% confidence interval CI 1.72–2.73), cognitive impairment (RR 2.29, 95% CI 1.48–3.54), functional impairment (RR 2.21, 95% CI 1.83–2.67), any recurrent stroke (RR 1.65, 95% CI 1.36–2.01), recurrent ischemic stroke (RR 1.90, 95% CI 1.26–2.88), all-cause mortality (RR 1.72, 95% CI 1.47–2.01), and cardiovascular mortality (RR 2.02, 95% CI 1.44–2.83). The associations followed dose-response patterns for WMH severity and were consistent for both MRI- and CT-defined WMH. The results remained stable in sensitivity analyses adjusting for age, stroke severity, and cardiovascular risk factors, in analyses of studies scoring high in quality, and in analyses adjusted for publication bias.
CONCLUSIONSPresence and severity of WMH are associated with substantially increased risk of dementia, functional impairment, stroke recurrence, and mortality after ischemic stroke. WMH may aid clinical prognostication and the planning of future clinical trials.
Elucidating the causes of stroke is key to developing effective preventive strategies. The Mendelian randomization approach leverages genetic variants related to an exposure of interest to ...investigate the effects of varying that exposure on disease risk. The random allocation of genetic variants at conception reduces confounding from environmental factors and thus strengthens causal inference, analogous to treatment allocation in a randomized controlled trial. With the recent explosion in the availability of human genetic data, Mendelian randomization has proven a valuable tool for studying risk factors for stroke. In this review, we provide an overview of recent developments in the application of Mendelian randomization to unravel the pathophysiology of stroke subtypes and identify therapeutic targets for clinical translation. The approach has offered novel insight into the differential effects of risk factors and antihypertensive, lipid-lowering, and anticoagulant drug classes on risk of stroke subtypes. Analyses have further facilitated the prioritization of novel drug targets, such as for inflammatory pathways underlying large artery atherosclerotic stroke and for the coagulation cascade that contributes to cardioembolic stroke. With continued methodological advances coupled with the rapidly increasing availability of genetic data related to a broad range of stroke phenotypes, the potential for Mendelian randomization in this context is expanding exponentially.
•Surgical menopause is associated with faster cognitive decline and worse cognitive performance later in life.•The younger the age at surgery, the more rapid the decline in cognitive function.•Early ...surgical menopause at ≤45 years of age is further associated with higher risk of dementia.•The limited number of available studies highlights the need for large cohorts to further examine this research question.
Experimental and epidemiological studies suggest female sex hormones to have long-lasting neuroprotective and anti-ageing properties. Surgically-induced menopause leads to a premature cessation of exposure to female sex hormones and could thus impact late-life cognitive function. Yet, evidence remains controversial.
We systematically reviewed literature for articles investigating the association of surgical menopause (defined as bilateral oophorectomy before the onset of menopause) with risk of dementia, cognitive performance, cognitive decline, and Alzheimer’s disease neuropathological indices later in life. We evaluated study quality with the Newcastle-Ottawa scale and performed random-effects meta-analyses.
We identified 11 eligible studies (N = 18,867). Although surgical menopause at any age was not associated with risk of dementia (4 studies; HR: 1.16, 95%CI: 0.96–1.43), early surgical menopause (≤45 years of age) was associated with a statistically significantly higher risk (2 studies; HR: 1.70, 95%CI: 1.07–2.69). Surgical menopause at any age was associated with faster decline in verbal memory, semantic memory, and processing speed, whereas early surgical menopause was further associated with faster global cognitive decline. No heterogeneity was noted. Among women undergoing surgical menopause, a younger age at surgery was associated with faster decline in global cognition, semantic and episodic memory, worse performance in verbal fluency and executive function, and accumulation of Alzheimer’s neuropathology.
Current evidence is limited, but suggests surgical menopause induced by bilateral oophorectomy at ≤45 years of age to be associated with higher risk of dementia and cognitive decline. Additional large-scale cohort studies are necessary to replicate these findings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy of ...anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm for lowering residual vascular risk. Efforts to target the inflammasome–interleukin-1β–interleukin-6 pathway have been highly successful, but inter-individual variations in drug response, a lack of reduction in all-cause mortality, and a higher rate of infections also highlight the need for a second generation of anti-inflammatory agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates inflammatory monocyte trafficking between the bone marrow, circulation, and atherosclerotic plaques by binding to its cognate receptor CCR2. Adding to a strong body of data from experimental atherosclerosis models, a coherent series of recent large-scale genetic and observational epidemiological studies along with data from human atherosclerotic plaques highlight the relevance and therapeutic potential of the CCL2–CCR2 axis in human atherosclerosis. Here, we summarize experimental and human data pinpointing the CCL2–CCR2 pathway as an emerging drug target in cardiovascular disease. Furthermore, we contextualize previous efforts to interfere with this pathway, scrutinize approaches of ligand targeting vs. receptor targeting, and discuss possible pathway-intrinsic opportunities and challenges related to pharmacological targeting of the CCL2–CCR2 axis in human atherosclerotic disease.
Graphical Abstract
Triangulation of evidence supporting the translational potential of targeting the CCL2–CCR2 axis in atherosclerotic disease. (A) Studies in atheroprone mice (Ldlr–/– or Apoe–/–) show that deletion of Ccl2 or Ccr2 is associated with smaller plaques in the aortic root and arch, as well as decreased monocyte infiltration.66–69 (B) A meta-analysis of preclinical studies testing pharmacological inhibition of either Ccl2 or Ccr2 in atheroprone mice shows a beneficial effect of either approach on plaque size and plaque stability as depicted by the forest plots for aortic arch/root lesion size. The lines and the dots depict the individual study effects (standardized mean differences) and their 95% confidence intervals (CIs), whereas the diamonds the pooled effect sizes, as derived from random-effects meta-analyses (Hedge’s g: −0.93, 95% CI: −1.46 to −0.40, P-value: 0.0006 for CCL2 inhibition and g: −0.73, 95% CI: −1.22 to −0.24, P-value: 0.003 for CCR2 inhibition). The vertical dotted line represents the reference (null effect) with studies on the left favouring interventions targeting Ccl2 or Ccr2 and studies on the right favouring the control group.70 The detailed results along with the data on the individual studies and the inhibitors used by each study are presented in Supplementary material online, Figure S1. (C) Meta-analyses of prospective cohort studies show significant associations between higher midlife circulating CCL2 levels and higher risk of incident ischaemic stroke71 or vascular death72 in the general population over follow-up periods extending beyond 15 years (P-values for trend as derived from the Cox regression analyses adjusted for demographic and vascular risk factors: 0.009 for ischaemic stroke, 0.17 for coronary artery disease, and 0.004 for vascular death). The squares represent the hazard ratios for the second to fourth quartile of CCL2 levels (Q2–Q4), when compared with the first (Q1), and the lines correspond to 95% CIs, as derived from the Cox regression analyses adjusted for demographic and vascular risk factors. The horizontal dotted line at 1 represents the reference (null effect) with hazard ratios above it representing significant associations with higher risk of ischaemic stroke, coronary artery disease, or cardiovascular death. (D) Mendelian randomization analyses exploring multiple cytokines reveal that higher genetically predicted CCL2 levels are associated with a higher lifetime risk of atherosclerotic stroke and coronary artery disease.73 The presented results are derived from fixed-effects inverse-variance weighted two-sample Mendelian randomization analyses. (E) In patients undergoing carotid endarterectomy, plaque CCL2 levels are associated with histopathological plaque vulnerability as revealed by an index of high macrophage content, low collagen deposition, high smooth muscle cell content, intraplaque haemorrhage, and large lipid core (range 0–5, left graph, P-value from ordinal regression analyses adjusted for demographic and vascular risk factors: 5.4 × 10−13).74 Moreover, CCL2 levels are higher in symptomatic vs. asymptomatic plaques (right graph, P = 0.0001 derived from the Mann–Whitney U test).74 Shown are the median plaque CCL2 values (central line), the upper and lower quartiles (box limits), and the 1.5× interquartile range (whiskers). (F) Small early-phase II randomized trials have been conducted for CCL2 or CCR2 inhibition in the context of atherosclerosis; one of them found MLN1202 (a CCR2 antagonist) to decrease the levels of high-sensitivity C-reactive protein (CRP) among individuals with high CRP and vascular risk factors (P < 0.05 in the Mann–Whitney U test in all timepoints from 29 to 85 days post-treatment).75
IMPORTANCE: Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with ...individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. OBJECTIVE: To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS DATA SOURCES: Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204 402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms eg, insomnia and hypersomnia) as measured with the Patient Health Questionnaire 9 (up to 117 907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386 533 individuals); body mass index (BMI) (up to 322 154 individuals); and height (up to 253 280 individuals). DESIGN: In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant–based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. RESULTS: Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)–controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate SE, 0.035 0.010; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. CONCLUSIONS AND RELEVANCE: This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strategy for suicide prevention.
BACKGROUND:Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and ...repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.
METHODS:Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.
RESULTS:Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01–1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00–1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04–2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83–1.32).
CONCLUSIONS:Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.
Background Observational studies have indicated that depression is associated with coronary artery disease (CAD) and myocardial infarction. Nevertheless, causal associations between depression and ...cardiovascular diseases remain controversial. Hence, we conducted a Mendelian randomization and mediation analysis to evaluate the associations of depression-related genetic variants with CAD and myocardial infarction. Methods and Results Summary statistics from genome-wide association studies of depression (807 553 individuals), and CAD (60 801 cases, including 43 676 with myocardial infarction, and 123 504 controls) were used. We pooled Mendelian randomization estimates using a fixed-effects inverse-variance weighted meta-analysis and multivariable Mendelian randomization. The mediation effects of potential cardiovascular risk factors on depression-CAD and myocardial infarction risk were investigated by using mediation analysis. We also explored the relationship of genetic liability to depression with heart failure, atrial fibrillation, and ischemic stroke. Genetic liability to depression was associated with higher CAD (odds ratio OR, 1.14; 95% CI, 1.06-1.24;
=1.0×10
) and myocardial infarction (OR, 1.21; 95% CI, 1.11-1.33;
=4.8×10
) risks. Results were consistent in all sensitivity analyses. Type 2 diabetes mellitus and smoking demonstrated significant mediation effects. Furthermore, our Mendelian randomization analyses revealed that the genetic liability to depression was associated with higher risks of heart failure and small vessel stroke. Conclusions Genetic liability to depression is associated with higher CAD and myocardial infarction risks, partly mediated by type 2 diabetes mellitus and smoking. The potential preventive value of depression treatment on cardiovascular diseases should be investigated in the future.
BACKGROUND AND PURPOSE—FXI (factor XI) is involved in thrombus propagation and stabilization. It is unknown whether lower FXI levels have a protective effect on risk of ischemic stroke (IS) or ...myocardial infarction. This study investigated the effect of genetically determined FXI levels on risk of IS, myocardial infarction, and intracerebral hemorrhage.
METHODS—Two-sample Mendelian randomization analysis was performed. Instruments and genetic association estimates for FXI levels were obtained from a genome-wide association study of 16 169 individuals. Genetic association estimates for IS and its etiological subtypes were obtained from a study of 16 851 cases and 32 473 controls. For myocardial infarction, estimates were obtained from a study of 43 676 cases and 123 504 controls and for intracerebral hemorrhage from a study of 1545 cases and 1481 controls.
RESULTS—After applying a Bonferroni correction for multiple testing, the Mendelian randomization analysis supported a causal effect of higher, genetically determined FXI levels on risk of any IS (odds ratio OR per 1-unit increase in natural logarithm-transformed FXI levels, 2.54; 95% CI, 1.68–3.84; P=1×10) but not myocardial infarction (OR, 1.01; 95% CI, 0.76–1.34; P=0.94) or intracerebral hemorrhage (OR, 1.81; 95% CI, 0.44–7.38; P=0.41). Examining IS subtypes, the main results supported an effect of higher, genetically determined FXI levels on risk of cardioembolism (OR, 4.23; 95% CI, 1.94–9.19; P=3×10) and IS of undetermined cause (OR, 3.44; 95% CI, 1.79–6.60; P=2×10) but not large artery atherosclerosis (OR, 2.73; 95% CI, 1.15–6.45; P=0.02) or small artery occlusion (OR, 1.19; 95% CI, 0.50–2.82; P=0.69). However, the statistically significant result for IS of undetermined cause was not replicated in all sensitivity analyses.
CONCLUSIONS—We find Mendelian randomization evidence supporting FXI as a possible target to reduce risk of the cardioembolic subtype of IS.
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