PROspective Study Of Pravastatin In The Elderly At Risk Research Articles

Blood Pressure Lowering Medication, Visit-to-Visit Blood Pressure Variability, and Cognitive Function in Old Age.

Visit-to-visit blood pressure (BP) variability is associated with cognitive impairment. We assessed to what extent the association between BP variability and cognitive impairment is mediated by the association of BP lowering medication (BPLM) with both BP variability and cognition. We studied 5,606 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). BP was measured every 3 months during 3.2 years; BP variability was defined as the SD of BP measurements during follow-up. Cognitive function was assessed at baseline and during follow-up using the Stroop test, Letter-Digit Coding test, and immediate and delayed Picture-Word Learning tests. Multivariate regression models were used with and without adjustments for BPLM to calculate the percentage to which BPLM mediated the association between BP variability and cognition. Participants taking calcium antagonists had a higher score in baseline Letter-Digit Coding test (mean difference (95% confidence interval (CI) 0.45 (0.06; 0.88). Participants taking beta-blockers had a steeper decline in Stroop test (additional change per year (95% CI) 0.40 (0.09; 0.70) and Letter-Digit Coding test (0.08 (-0.15; -0.02)). Furthermore, a steeper decline in Stroop test was found in participants taking renin-angiotensin system (RAS) inhibitors (0.50 (0.16; 0.85). Systolic BP variability was higher in participants taking beta-blockers and RAS inhibitors (mean difference in systolic BP variability in mm Hg (95% CI) 0.75 (0.45; 1.04) and 1.37 (1.04; 1.71) respectively). Participants taking diuretics, calcium antagonists, and RAS inhibitors had a higher diastolic BP variability (mean difference in diastolic BP variability in mm Hg (95% CI) 0.27 (0.04; 0.49), 0.37 (0.12; 0.62) and 0.65 (0.37; 0.93) SD, respectively). Beta estimates remained essentially the same when we adjusted for BPLM in the association of BP variability with cognitive function. The association between BP variability and cognitive impairment was not mediated by BPLM.

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Objective: To test the cross-sectional and longitudinal association of heart rate variability measured from 10-second electrocardiogram recordings with cognitive function in older subjects at high risk of cardiovascular disease. Design and method: We studied 3,583 men and women, mean age 75.0 years, who were enrolled in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study. From baseline 10-second electrocardiograms the standard deviation of normal-to-normal RR intervals was calculated as the index of heart rate variability. Four domains of cognitive function testing reaction time, processing speed and immediate and delayed memory were assessed at baseline and repeated during a mean follow-up of 3.2 years. Using analyses of covariance, we calculated the adjusted mean values of baseline and annual changes of cognitive scores in thirds of heart rate variability. Results: Participants with lower heart rate variability had worse cognitive function at baseline including reaction time, processing speed and immediate and delayed memory (all p-values < 0.05). In longitudinal analysis, participants with lower heart rate variability had a steeper cognitive decline in reaction time (mean annual change of: 1.49 seconds in the lowest tertile, 0.84 seconds in the middle tertile and 1.06 seconds in the highest tertile, p-value = 0.05) and processing speed (mean annual change of: -0.51 digits coded in the lowest tertile, -0.45 digits coded in the middle tertile and -0.35 digits coded in the highest tertile, p-value = 0.009). There was no significant difference in annual changes of immediate and delayed memory between heart rate variability groups. All these associations remained unchanged after adjustment for medications, cardiovascular risk factors and co-morbidities. Conclusions: The present study indicates that lower heart rate variability measured from 10-second electrocardiogram recording is associated with worse executive function at baseline as well as future decline in executive function independent of cardiovascular risk factors and co-morbidities.

Infratentorial Microbleeds: Another Sign of Microangiopathy in Migraine.

Migraine is a risk factor for clinical stroke and for subclinical white matter hyperintensities and infratentorial infarcts. These subclinical lesions are linked to small-vessel pathology. Cerebral microbleeds (CMBs) are another biomarker of small-vessel disease but have not yet been studied in migraine. Identification of CMBs in 63 migraineurs (25 with aura/35 without aura/3 unknown aura status) and 359 controls (aged, 73-85 years) from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) magnetic resonance imaging study. We assessed the modifying role of migraine in the co-occurrence of CMBs, infarcts, and white matter hyperintensity-load. Infratentorial microbleeds were more prevalent in migraine without aura patients than controls (14% versus 4%). Prevalence of other CMBs, infarcts, and white matter hyperintensities did not differ between groups. Migraineurs with CMBs had more often infarcts than controls with CMBs (65% versus 43%). In comparison with controls with infarcts, migraineurs with infarcts had more commonly CMBs (55% versus 30%). Migraine, notably without aura, is associated with infratentorial CMBs at older age. CMBs and infarcts co-occur more often in migraine than in controls. This supports the hypothesis of small-vessel involvement in migraine pathophysiology.

Ezetimibe: rescued by randomization (clinical and mendelian).

Since its market launch in the early 2000s, ezetimibe has had a stormy history of acceptance and use by the clinical community. Ezetimibe’s initial approval by regulatory bodies was based primarily on its low side effect profile together with its ability to consistently reduce low-density lipoprotein (LDL) cholesterol by ≈20% either as monotherapy or as an additive to statin therapy. Notably, approval was granted despite the absence from ezetimibe’s portfolio of studies, demonstrating reductions in hard clinical cardiovascular outcomes, such as myocardial infarction or stroke. By 2006, ezetimibe accounted for >15% of all prescriptions for lipid-lowering medications in the United States,1 reflecting that era’s stout faith in the reliability of LDL cholesterol as a surrogate marker for clinical end points, together with practitioners’ positive real-world experiences with ezetimibe’s biochemical efficacy and good tolerability. It was tacitly anticipated that the pending cardiovascular outcome studies would be positive, eventually vindicating the early confidence that clinicians placed in the drug. However, the waters grew rough for ezetimibe in 2008. First, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial conducted for 24 months in 720 patients with familial hypercholesterolemia showed that combined therapy with ezetimibe and simvastatin did not significantly change carotid intima–media thickness when compared with simvastatin alone, despite decreased levels of LDL cholesterol.2 Next, the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial conducted for 52 months in 1873 elderly nondiabetic patients with aortic stenosis showed that ezetimibe plus simvastatin did not reduce the composite outcome of combined aortic valve events and ischemic events.3 To add insult to injury, the 2009 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6-HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study demonstrated that when combined with a statin, extended-release niacin caused a significant …

Associations Between Thrombin Generation and the Risk of Cardiovascular Disease in Elderly Patients: Results From the PROSPER Study.

Hypercoagulability may be an important contributor to the pathophysiology of atherosclerosis and atherothrombosis. As thrombin fulfills a central role in coagulation and links to several cellular mechanisms involved in arterial disease, we hypothesized that thrombin generation is associated with cardiovascular events in elderly patients. We studied the relationship between plasma thrombin generation and incident coronary heart disease (CHD) and stroke in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). From this multicenter prospective cohort, 4,932 samples of subjects (70-82 years) with pre-existing vascular disease or risk factors were available for thrombin generation measurements. Within the 3.2 years of follow-up incident stroke and CHD was observed in 227 and 545 subjects, respectively. Baseline thrombin generation was significantly decreased in subjects with incident stroke compared with subjects without: normalized peak height 71.1±40.8% versus 82.3±44.9%, p = .0002, and normalized endogenous thrombin potential 79.1±23.3% versus 87.0±24.8%, p < .0001 (mean and SDs). Thrombin generation was independently and inversely associated with stroke risk: hazard ratio 0.71 (95%CI: 0.60-0.85), 0.68 (95%CI: 0.58-0.79), for normalized peak height and normalized endogenous thrombin potential, respectively (all p < .001). In subjects with incident CHD, thrombin generation was comparable to subjects without a coronary event. Only an increased normalized peak height was significantly associated with incident CHD (hazard ratio 1.17 [95% CI: 1.06-1.28], p = .002). We demonstrate that a delayed and decreased thrombin generation is a strong and independent predictor for stroke in elderly people at increased risk of vascular disease. However, no convincing consistent association could be demonstrated between thrombin generation and incident CHD.

Biological correlates of blood pressure variability in elderly at high risk of cardiovascular disease.

Visit-to-visit variability in blood pressure is an independent predictor of cardiovascular disease. This study investigates biological correlates of intra-individual variability in blood pressure in older persons. Nested observational study within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) among 3,794 male and female participants (range 70-82 years) with a history of, or risk factors for cardiovascular disease. Individual visit-to-visit variability in systolic and diastolic blood pressure and pulse pressure (expressed as 1 SD in mm Hg) was assessed using nine measurements over 2 years. Correlates of higher visit-to-visit variability were examined at baseline, including markers of inflammation, endothelial function, renal function and glucose homeostasis. Over the first 2 years, the mean intra-individual variability (1 SD) was 14.4mm Hg for systolic blood pressure, 7.7mm Hg for diastolic blood pressure, and 12.6mm Hg for pulse pressure. After multivariate adjustment a higher level of interleukin-6 at baseline was consistently associated with higher intra-individual variability of blood pressure, including systolic, diastolic, and pulse pressure. Markers of endothelial function (Von Willebrand factor, tissue plasminogen activator), renal function (glomerular filtration rate) and glucose homeostasis (blood glucose, homeostatic model assessment index) were not or to a minor extent associated with blood pressure variability. In an elderly population at risk of cardiovascular disease, inflammation (as evidenced by higher levels of interleukin-6) is associated with higher intra-individual variability in systolic, diastolic, and pulse pressure.

Contrasting associations of insulin resistance with diabetes, cardiovascular disease and all-cause mortality in the elderly: PROSPER long-term follow-up.

Insulin resistance is commonly proposed as a precursor to both type 2 diabetes and cardiovascular disease (CVD), yet few studies have directly compared insulin resistance with both outcomes simultaneously and determined whether associations with each outcome differ in strength or are comparable. We assessed the association of fasting insulin and HOMA-IR with incident CVD and diabetes in older people. In the long-term follow-up of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) cohort, HOMA-IR measurement was available in 4,742 older people (70-82 years) without diabetes at baseline. Of these, 283 developed diabetes during the 3.2 year within-trial follow-up, while 1,943 all-cause deaths, 470 CHD deaths (identified from death records) and 590 fatal/non-fatal CVD events (identified from medical record linkage in the Scottish participants) occurred during an extended 8.6 years of total follow-up. Cause-specific Cox proportional-hazards models were fitted using multivariable models. Higher HOMA-IR was associated with incident diabetes: HR 4.80 (95% CI 3.14, 7.33) comparing extreme thirds after adjustment for confounders. However, HOMA-IR in the top third was not associated with all-cause mortality, CHD mortality or fatal/non-fatal CVD: HR 1.02 (95% CI 0.90, 1.17), 1.03 (0.79, 1.36) and 0.94 (0.74, 1.20), respectively. Results were similar when fasting insulin was considered as an exposure. Our data support insulin resistance as a predictor of diabetes in later life but, perhaps surprisingly, suggest this pathway is of negligible importance to CVD outcomes in the elderly.

ALTERED PERICYTE MORPHOLOGY AND NG2 EXPRESSION IN HIPPOCAMPUS OF PATIENTS WITH ALZHEIMER'S DISEASE

lowering medication on both blood pressure variability and cognitive function. We studied the association of different classes of blood pressure lowering medication with blood pressure variability and cognitive function and decline, independent of average blood pressure. Methods: We prospectively studied 2,229 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), who used only one blood pressure lowering medication. Blood pressure was measured at baseline and every three months during an average period of 3.3 years follow-up at the study center; blood pressure variability was defined as the standard deviation of all blood pressure measurements during follow up. Cognitive function was tested at baseline and repeatedly during follow-up using the Stroop test, Letter-Digit Coding test and immediate and delayed Picture-Word Learning tests.Results: Participants taking thiazide diuretics had the lowest systolic blood pressure variability and participants taking ACE-inhibitors had the highest systolic blood pressure variability (mean (SE) 14.16 (0.23) vs. 15.28 (0.25) mmHg respectively, p-value between classes 1⁄40.005). This association remained significant after additional adjustments for average systolic blood pressure and cardiovascular diseases and risk factors. No significant differences on all four cognitive tests were found at baseline between medication classes (p-value between classes >0.05). Participants taking loop diuretics showed the steepest decline on Stroop test (mean annual change (SE) 1.77 (0.52) and immediate Picture-Word Learning test (-0.07 (0.04), while participants taking ACE-inhibitors showed the least decline on both tests (-0.04 (0.29) vs. 0.03 (0.02), p-value between classes respectively 1⁄4 0.002 and 0.019). Conclusions: Although blood pressure lowering medication class was associated with blood pressure variability, medication could not explain the relationship between blood pressure variability and cognitive impairment.

ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment

AimsOur goals were to examine the relationships of a specific ATP-binding cassette transporter A1 (ABCA1) variant, rs2230806 (R219K), on baseline lipids, low-density lipoprotein cholesterol (LDL-C) lowering due to pravastatin, baseline heart disease, and cardiac endpoints on trial. Methods and resultsThe ABCA1 R219K variant was assessed in 5414 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Of these subjects 47.6% carried the variant, with 40.0% carrying one allele, and 7.6% carrying both alleles. No effects on baseline LDL-C levels were noted, but mean HDL-C increased modestly according to the number of variant alleles being present (1.27 vs 1.28 vs 1.30 mmol/L, p = 0.024). No relationships between the presence or absence of this variant and statin induced LDL-C lowering response or CHD at baseline were noted. However within trial those with the variant as compared to those without the variant, the overall adjusted hazard ratio for new cardiovascular disease (fatal CHD, non-fatal myocardial infarction, or fatal or non-fatal stroke) was 1.22 (95% CI 1.06–1.40, p = 0.006), while for those in the pravastatin group it was 1.41 (1.15–1.73, p = 0.001), and for those in the placebo group it was 1.08 (0.89–1.30, p = 0.447) (p for interaction 0.058). ConclusionOur data indicate that subjects with the ABCA1 R219K variant may get significantly less heart disease risk reduction from pravastatin treatment than those without the variant.

Homocysteine Levels and Treatment Effect in the Prospective Study of Pravastatin in the Elderly at Risk

ObjectivesTo assess the effect of preventive pravastatin treatment on coronary heart disease (CHD) morbidity and mortality in older persons at risk for cardiovascular disease (CVD), stratified according to plasma levels of homocysteine.DesignA post hoc subanalysis in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), started in 1997, which is a double-blind, randomized, placebo-controlled trial with a mean follow-up of 3.2 years.SettingPrimary care setting in two of the three PROSPER study sites (Netherlands and Scotland).ParticipantsIndividuals (n = 3,522, aged 70–82, 1,765 male) with a history of or risk factors for CVD were ranked in three groups depending on baseline homocysteine level, sex, and study site.InterventionPravastatin (40 mg) versus placebo.MeasurementsFatal and nonfatal CHD and mortality.ResultsIn the placebo group, participants with a high homocysteine level (n = 588) had a 1.8 higher risk (95% confidence interval (CI) = 1.2–2.5, P = .001) of fatal and nonfatal CHD than those with a low homocysteine level (n = 597). The absolute risk reduction in fatal and nonfatal CHD with pravastatin treatment was 1.6% (95% CI = −1.6 to 4.7%) in the low homocysteine group and 6.7% (95% CI = 2.7–10.7%) in the high homocysteine group (difference 5.2%, 95% CI = 0.11–10.3, P = .046). Therefore, the number needed to treat (NNT) with pravastatin for 3.2 years for benefit related to fatal and nonfatal CHD events was 14.8 (95% CI = 9.3–36.6) for high homocysteine and 64.5 (95% CI = 21.4–∞) for low homocysteine.ConclusionIn older persons at risk of CVD, those with high homocysteine are at highest risk for fatal and nonfatal CHD. With pravastatin treatment, this group has the highest absolute risk reduction and the lowest NNT to prevent fatal and nonfatal CHD.

Subclinical Thyroid Dysfunction and Functional Capacity Among Elderly

Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity but with conflicting data. The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. We included 5182 participants with a mean age of 75.2 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (BI) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944). The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. At baseline, compared to euthyroid participants (BI 19.73±SE 0.06; IADL 13.52±0.02), there was no difference in functional capacity for participants with subclinical hyperthyroidism (BI 19.60±0.09; IADL 13.51±0.12, p>0.05) or subclinical hypothyroidism (BI 19.82±0.06; IADL 13.55±0.08, p>0.05). Over a mean 3.2-year follow-up period, there was no association between thyroid function and annual decline of either BI or IADL (p>0.05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow-up (p>0.05). Results were similar after excluding participants with a maximum BI and/or IADL score at baseline. Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity.

Long-term effects of statin treatment in elderly people: extended follow-up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).

BackgroundThe PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), a placebo-controlled trial of pravastatin, demonstrated a 19% reduction in coronary outcomes (p = 0.006) after a mean of 3.2 years, with no impact on stroke outcomes or all-cause mortality. However, there was a suggestion of increased cancer risk. Our aim is to determine the long-term benefits and safety of pravastatin treatment in older people using post-trial follow-up of the PROSPER participants.Methods5,804 (2,520 Scottish) men and women aged 70–82 years with either pre-existing vascular disease or increased risk of such disease because of smoking, hypertension or diabetes, were randomised to 40 mg pravastatin or matching placebo. Using record linkage to routinely collected health records, all participants (full cohort) were linked to death and cancer registries, and the Scottish cohort additionally to hospital admissions, to provide composite fatal/non-fatal cardiovascular outcomes (total mean follow-up 8.6 years).ResultsPravastatin treatment for 3.2 years reduced CHD death in the full cohort, hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.68–0.95, p = 0.0091 and fatal coronary events or coronary hospitalisations in the Scottish cohort (HR 0.81, 95% CI 0.69–0.95, p = 0.0081) over 8.6 years. There was no reduction in stroke or all-cause mortality. Cancer risk was not increased in the full cohort (HR 1.08, 95% CI 0.96–1.21, p = 0.22).ConclusionsPravastatin treatment of elderly high-risk subjects for 3.2 years provided long-term protection against CHD events and CHD mortality. However, this was not associated with any increase in life expectancy, possibly due to competing mortality with deaths from other causes. There was no evidence of long-term increased risk of cancer.Trial registration ISRCTN40976937.

Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study

Objective To investigate the association between visit-to-visit variability in blood pressure and cognitive function in old age (>70 years). Design Prospective cohort study.Setting PROSPER (PROspective Study of Pravastatin in the...

Subclinical Thyroid Dysfunction and Cognitive Decline in Old Age

BackgroundSubclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).MethodsProspective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.ResultsSubclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.ConclusionWe found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.

Circulating interleukin‐6 concentration and cognitive decline in old age: the PROSPER study

Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age. Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months). In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045). Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.

Non-Homologous End-Joining Pathway Associated with Occurrence of Myocardial Infarction: Gene Set Analysis of Genome-Wide Association Study Data

PurposeDNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.MethodsThe PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.ResultsThe NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.ConclusionThis is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.

PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10(-12)), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events.

PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10(-12)), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events.

Blood Pressure Variability and Cardiovascular Risk in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects.

Genetic variation in galectin-3 gene associates with cognitive function at old age

Inflammation plays an important role in the development of cognitive decline and dementia in old age. Galectin-3 is known for its role in acute and chronic inflammation. We assessed whether genetic variation in the LGALS3 gene, encoding for galectin-3, associates with cognitive function in the 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The rs4644, rs4652, and rs1009977 polymorphisms were genotyped to cover the genomic region of the LGALS3 gene. Subjects carrying the variant alleles of each LGALS3 single nucleotide polymorphism (SNP) had significantly higher baseline C-reactive protein concentrations (p < 0.01). Carriers of the variant alleles had significantly worse performance at baseline compared with carriers of the wild-type allele (all p < 0.05). In the longitudinal analysis, we found that carriers of the variant alleles had worse performance at the attention tasks compared with carriers of the wild-type allele. Although observed differences were small, these data suggest that genetic variation in the LGALS3 gene might be associated with cognitive function in an elderly population. Further research is warranted to confirm these results.