PROspective Study Of Pravastatin In The Elderly At Risk Research Articles

Weight loss, visit-to-visit body weight variability and cognitive function in a cohort of older people with or at risk of atherosclerotic cardiovascular disease

Background and Aims : Unintentional weight loss and higher variability in body weight are associated with increased risk of cardiovascular outcomes. We examined whether this extends to cognitive function in a cohort of older people with or at increased risk of atherosclerotic cardiovascular disease.Methods: We studied 4,309 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) with either existing atherosclerosis or at higher risk thereof. Body weight was measured every three months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, Letter-Digit Coding test (LDCT), immediate and delayed Picture-Word learning tests. All tests were performed at month 30.Results: Both larger visit-to-visit body weight variation and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests. Compared to participants who maintained stable weight, participants with significant weight loss scored 5.87 seconds (95%CI 3.78; 7.96) slower on the Stroop test and coded 1.74 digits less (95%CI -2.33; -1.14) on the LDCT. Furthermore, participants with high variability in body weight performed 4.60 seconds (95%CI 2.60; 6.59) slower on the Stroop test and coded 1.97 digits less (95%CI -2.53; -1.41) on the LDCT.Conclusions: In older people with or at increased risk of atherosclerotic cardiovascular disease, higher variability and loss of body weight are independent risk-factors for worse cognitive function. Background and Aims : Unintentional weight loss and higher variability in body weight are associated with increased risk of cardiovascular outcomes. We examined whether this extends to cognitive function in a cohort of older people with or at increased risk of atherosclerotic cardiovascular disease. Methods: We studied 4,309 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) with either existing atherosclerosis or at higher risk thereof. Body weight was measured every three months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, Letter-Digit Coding test (LDCT), immediate and delayed Picture-Word learning tests. All tests were performed at month 30. Results: Both larger visit-to-visit body weight variation and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests. Compared to participants who maintained stable weight, participants with significant weight loss scored 5.87 seconds (95%CI 3.78; 7.96) slower on the Stroop test and coded 1.74 digits less (95%CI -2.33; -1.14) on the LDCT. Furthermore, participants with high variability in body weight performed 4.60 seconds (95%CI 2.60; 6.59) slower on the Stroop test and coded 1.97 digits less (95%CI -2.53; -1.41) on the LDCT. Conclusions: In older people with or at increased risk of atherosclerotic cardiovascular disease, higher variability and loss of body weight are independent risk-factors for worse cognitive function.

Association of cognitive function with increased risk of cancer death and all-cause mortality: Longitudinal analysis, systematic review, and meta-analysis of prospective observational studies.

BackgroundDisturbed cognitive function is associated with several causes of mortality; however, the association between cognitive function and the risk of cancer death has not been extensively investigated yet. We aimed to evaluate the association of cognitive function with the risk of cancer death and all-cause mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) and Leiden 85-plus Study. Additionally, a systematic review and meta-analysis of longitudinal studies were conducted to evaluate the association of cognitive function and risk of cancer death.MethodsRisk of cancer death and all-cause mortality were reported using hazard ratios (HRs) with 95% confidence interval (CI) in tertiles of cognitive function of PROSPER and Leiden85-Plus Study. Additionally, PubMed, Embase, Web of Science, Cochrane, PsycINFO, Academic Search Premier, CINHAL, and Emcare were searched up to November 1st, 2020 to perform a systematic review and meta-analysis. The relative risks (RRs) with 95%CI of cancer death per each standard deviation lower performance in cognitive measurements were calculated.ResultsParticipants of PROSPER had 1.65-fold (95%CI 1.11–2.47) greater risk of cancer death (P for trend = 0.016) and 1.85-fold (95%CI 1.46–2.34) higher risk of all-cause mortality (P for trend<0.001), in multivariable models. Results of the Leiden-85 Plus Study showed that subjects with MMSE score below 24 had a lower chance of cancer death (HR 0.79, 95%CI 0.36–1.70, P for trend = 0.820) but had 2.18-fold (95%CI 1.57–3.02) higher risk of all-cause mortality compared to the reference group (P for trend<0.001). Besides, the results of systematic review and meta-analysis showed that per each standard deviation lower performance in cognitive function, individuals were at a 10% higher chance of cancer death (RR 1.10, 95%CI 1.00–1.20, P-value = 0.044).ConclusionsLower cognitive function performance is associated with a marginally increased risk of cancer death, in line with a significantly greater risk of all-cause mortality.

Association of High-Density Lipoprotein Cholesterol With Cognitive Function: Findings From the PROspective Study of Pravastatin in the Elderly at Risk.

Objective: We aimed to examine whether variability in high-density lipoprotein cholesterol (HDL-c) over time was associated with cognitive function. Method: We conducted a post hoc analysis of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. Our sample included 4,428 participants with at least two repeated HDL-c measures between Months 3 and 24 postbaseline and with cognitive assessments at Month 30. HDL-c variability was defined as the intraindividual standard deviation over each person's repeated measurements. Results: Higher HDL-c variability was associated with worse performance on the Letter-Digit Coding Test (β [95% confidence interval] [CI] = -4.39 [-7.36, -1.43], p = .004), immediate recall on the 15-Picture Learning Test (β [95% CI] = -0.98 [-1.86, -0.11], p = .027), and delayed recall on the 15-Picture Learning Test (β [95% CI] = -1.90 [-3.14, -0.67], p = .002). The associations did not vary by treatment group. Discussion: Our findings suggest that variability in HDL-c may be associated with poor cognitive function among older adults.

Ventricular Repolarization is Associated with Cognitive Function, but Not with Cognitive Decline and Brain Magnetic Resonance Imaging (MRI) Measurements in Older Adults.

We aimed to investigate the cross-sectional and longitudinal associations of electrocardiogram (ECG)-based QT, QTc, JT, JTc, and QRS intervals with cognitive function and brain magnetic resonance imaging (MRI) measurements in a cohort of older individuals at increased risk for cardiovascular disease, but free of known arrhythmias. We studied 4627 participants (54% female, mean age 75 years) enrolled in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Ten-second ECGs were conducted at baseline. Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Structural MRIs were conducted in a subgroup of 535 participants. Analyses were performed with multivariable (repeated) linear regression models and adjusted for cardiovascular risk-factors, co-morbidities, and cardiovascular drug use. At baseline, longer QT, JT, JTc—but not QTc and QRS intervals—were associated with a worse cognitive performance. Most notably, on the Stroop Test, participants performed 3.02 (95% CI 0.31; 5.73) seconds worse per standard deviation higher QT interval, independent of cardiovascular risk factors and medication use. There was no association between longer ventricular de- or repolarization and structural brain measurements. Therefore, specifically ventricular repolarization was associated with worse cognitive performance in older individuals at baseline but not during follow-up.

The association of kidney function and cognitive decline in older patients at risk of cardiovascular disease: a longitudinal data analysis

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 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; < 30 ml/min/1.73m2 (stage 4), 30-45 ml/min/1.73m2 (stage 3b), 45-60 ml/min/1.73m2 (stage 3a) and ≥ 60 ml/min/1.73m2 (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 75.3 years and 48.3% participants were male. Mean follow-up was 3.2 years. 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.

The kidney, subclinical thyroid disease and cardiovascular outcomes in older patients.

ObjectiveThyroid 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.MethodsIn 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 m2. The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke.ResultsMean 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).ConclusionsIn 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.

Cognitive Function in Dementia-Free Subjects and Survival in Old Age: The PROSPER Study

BackgroundImpairment in domain-specific cognitive function is associated with the increased risk of mortality. We prospectively evaluated the association of executive function and memory with the risk of long-term mortality in dementia-free older subjects. Moreover, we investigated the role of structural brain abnormalities in this association. MethodsWe included 547 dementia-free participants (mean age 78 years, 56.5% male) from the nested magnetic resonance imaging sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were used to model 10-year risk of all-cause, cardiovascular, and noncardiovascular mortality in relation to performance in executive function and memory. Moreover, we evaluated the role of total brain parenchymal volume, cerebral blood flow, white matter hyperintensity, and the presence of microbleeds and infarcts in the link between cognitive function and mortality. ResultsIn the multivariable model, lower performance in executive function was associated with greater risk of all-cause (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.31-1.70), cardiovascular (HR 1.69; 95% CI, 1.36-2.11), and noncardiovascular (HR 1.36; 95% CI, 1.15-1.62) mortality. Similarly, poorer performance in memory tests associated with higher risk of all-cause (HR 1.47; 95% CI, 1.29-1.68), cardiovascular (HR 1.45; 95% CI, 1.15-1.83), and noncardiovascular (HR 1.49; 95% CI, 1.27-1.76) mortality. The associations were similar in subjects with various levels of brain structural abnormalities and cerebral blood flow (all P for interaction ≫ .05). ConclusionsPoorer performance in both executive function and memory tests associates with all-cause, cardiovascular, and noncardiovascular mortality in elderly individuals. This association is independent of cardiovascular risk factors and diseases, brain structural abnormalities, and cerebral blood flow.

Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease.

We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease. We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice. 14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment.

Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2x10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA) whereas statin treatment weakly lowered GlycA levels. Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk.

Association of diastolic blood pressure with cardiovascular events in older people varies upon cardiovascular history.

In older age, a low DBP has been associated with increased risk of cardiovascular events, especially in frail older people. We tested the hypothesis that low DBP is associated with a high risk of cardiovascular events in people with a previous history of cardiovascular disease, as a proxy of vascular impairment. We included 5804 participants (mean age 75 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) who as part of the trial were intensively monitored for an average period of 3.2 years. DBP was categorized in low (<70 mmHg), normal (70-90 mmHg) or high (>90 mmHg). Cox proportional hazards analyses were used to estimate hazard ratio with 95% confidence intervals (CI); analyses were stratified for cardiovascular history. Participants with low DBP had a 1.24-fold (1.04; 1.49) increased risk of cardiovascular events compared with those with normal DBP. After further adjusting for cardiovascular factors, this association attenuated to 1.05 (0.86; 1.28). A previous history of cardiovascular disease significantly modified the relation between DBP and risk of cardiovascular events (P-interaction 0.042). In participants without a history of cardiovascular disease, DBP was marginally significantly associated with an increased event risk (hazard ratio (95% CI) per 10 mmHg increase in DBP 1.08 (0.99; 1.18), P value = 0.07), whereas in participants with a history of cardiovascular disease, higher DBP was associated with a decreased risk of cardiovascular events (hazard ratio (95% CI) per 10 mmHg increase in DBP 0.92 (0.85; 0.99, P value = 0.018). These risk estimates were independent of potential confounders, including classical cardiovascular risk factors. The association of DBP with cardiovascular events in older people varies upon their previous history, showing that in participants with preexisting cardiovascular diseases, a higher DBP associates with a decreased risk of future cardiovascular events.

Nuclear magnetic resonance-based metabolomics identifies phenylalanine as a novel predictor of incident heart failure hospitalisation: results from PROSPER and FINRISK 1997.

AimsWe investigated the association between quantified metabolite, lipid and lipoprotein measures and incident heart failure hospitalisation (HFH) in the elderly, and examined whether circulating metabolic measures improve HFH prediction.Methods and resultsOverall, 80 metabolic measures from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial were measured by proton nuclear magnetic resonance spectroscopy (n = 5341; 182 HFH events during 2.7‐year follow‐up). We repeated the work in FINRISK 1997 (n = 7330; 133 HFH events during 5‐year follow‐up). In PROSPER, the circulating concentrations of 13 metabolic measures were found to be significantly different in those who were later hospitalised for heart failure after correction for multiple comparisons. These included creatinine, phenylalanine, glycoprotein acetyls, 3‐hydroxybutyrate, and various high‐density lipoprotein measures. In Cox models, two metabolites were associated with risk of HFH after adjustment for clinical risk factors and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP): phenylalanine [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10–1.53; P = 0.002] and acetate (HR 0.81, 95% CI 0.68–0.98; P = 0.026). Both were retained in the final model after backward elimination. Compared to a model with established risk factors and NT‐proBNP, this model did not improve the C‐index but did improve the overall continuous net reclassification index (NRI 0.21; 95% CI 0.06–0.35; P = 0.007) due to improvement in classification of non‐cases (NRI 0.14; 95% CI 0.12–0.17; P < 0.001). Phenylalanine was replicated as a predictor of HFH in FINRISK 1997 (HR 1.23, 95% CI 1.03–1.48; P = 0.023).ConclusionOur findings identify phenylalanine as a novel predictor of incident HFH, although prediction gains are low. Further mechanistic studies appear warranted.

Left Ventricular Hypertrophy and Cognitive Decline in Old Age.

Patients with advanced heart failure run a greater risk of dementia. Whether early cardiac structural changes also associate with cognitive decline is yet to be determined. We tested whether left ventricular hypertrophy (LVH) derived from electrocardiogram associates with cognitive decline in older subjects at risk of cardiovascular disease. We included 4,233 participants (mean age 75.2 years, 47.8% male) from PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). LVH was assessed from baseline electrocardiograms by measuring the Sokolow-Lyon index. Higher levels of Sokolow-Lyon index indicate higher degrees of LVH. Cognitive domains involving selective attention, processing speed, and immediate and delayed memory were measured at baseline and repeated during a mean follow-up of 3.2 years. At baseline, LVH was not associated with worse cognitive function. During follow-up, participants with higher levels of LVH had a steeper decline in cognitive function including in selective attention (p = 0.009), processing speed (p = 0.010), immediate memory (p < 0.001), and delayed memory (p = 0.002). These associations were independent of cardiovascular risk factors, co-morbidities, and medications. LVH assessed by electrocardiogram associates with steeper decline in cognitive function of older subjects independent of cardiovascular risk factors and co-morbidities. This study provides further evidence on the link between subclinical cardiac structural changes and cognitive decline in older subjects.

Complement receptor 1 gene polymorphisms are associated with cardiovascular risk

Background and aimsInflammation plays a key role in atherosclerosis. The complement system is involved in atherogenesis, and the complement receptor 1 (CR1) plays a role facilitating the clearance of immune complexes from the circulation. Limited evidence suggests that CR1 may be involved in cardiovascular disease. We investigated the relationship between CR1 gene polymorphisms and cardiovascular risk. MethodsSingle nucleotide polymorphisms (SNPs) within the CR1 region (n = 73) on chromosome 1 were assessed in 5244 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. Logistic regression, adjusted for gender, age, country and use of pravastatin, was used to assess the association between the SNPs and cardiovascular disease. ResultsAll 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. In this region, strong LD was present leading to the occurrence of two haploblocks. Twelve of the 73 investigated CR1 SNPs were significantly associated with the risk of fatal or nonfatal myocardial infarction (all p < 0.05). Moreover, most of the associated SNPs were also associated with levels of serum C-reactive protein (CRP). The global p-value for the tail strength method to control for multiple testing was 0.0489, implying that the null hypothesis of no associated SNPs can be rejected. ConclusionsThese data indicate that genetic variation within the CR1 gene is associated with inflammation and the risk of incident coronary artery disease.

High-sensitivity cardiac troponin T is associated with cognitive decline in older adults at high cardiovascular risk.

Cardiac troponin T (cTnT), measured with a high-sensitivity (hs) assay, is associated with cognitive decline, but the underlying mechanism is unknown. We investigated the association of hs-cTnT with cognitive function and decline, and studied whether this association was independent of cardiovascular diseases or risk factors, and N-terminal pro-brain natriuretic peptide (NT-proBNP). We studied 5407 participants (mean age 75.31 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), who all had cardiovascular diseases or risk factors thereof. Participants with pre-existent advanced clinical heart failure were excluded. Hs-cTnT and NT-proBNP obtained after 6 months of follow-up were related with cognitive function, tested repeatedly during a mean follow-up of 3.2 years. Participants with higher hs-cTnT performed worse at baseline on Stroop test (mean baseline score (standard error (SE)) lowest vs highest third 65.91 (1.16) vs 69.40 (1.10) seconds, p < 0.001), Letter-Digit Coding test (23.35 (0.32) vs 22.40 (0.31) digits coded, p < 0.001), immediate Picture-Word Learning test (9.45 (0.09) vs 9.31 (0.08) pictures remembered, p = 0.002) and delayed Picture-Word Learning test (10.33 (0.12) vs 10.10 (0.12) pictures remembered, p = 0.013). Furthermore, participants with higher hs-cTnT had steeper decline on Stroop test (mean annual change (SE) lowest vs highest third 0.34 (0.12) vs 1.06 (0.12) seconds, p = 0.013), Letter-Digit Coding test (-0.29 (0.03) vs -0.46 (0.03) digits coded, p < 0.001), immediate Picture-Word Learning test (0.01 (0.01) vs -0.06 (0.01) pictures remembered, p < 0.001) and delayed Picture-Word Learning test (-0.03 (0.01) vs -0.12 (0.02) pictures remembered, p = 0.001). Associations were independent of cardiovascular diseases risk factors or Apolipoprotein E genotype. Further adjusting for NT-proBNP levels revealed the same results. Higher levels of hs-cTnT associate with worse cognitive function and steeper cognitive decline in older adults independent of cardiovascular diseases, risk factors and NT-proBNP.

Non-response to (statin) therapy: the importance of distinguishing non-responders from non-adherers in pharmacogenetic studies.

PurposeIn pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers.MethodsBaseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis.ResultsNon-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased.ConclusionOur results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.

Risk stratification and treatment effect of statins in secondary cardiovascular prevention in old age: Additive value of N-terminal pro-B-type natriuretic peptide.

To date, no validated risk scores exist for prediction of recurrence risk or potential treatment effect for older people with a history of a cardiovascular event. Therefore, we assessed predictive values for recurrent cardiovascular disease of models with age and sex, traditional cardiovascular risk markers, and 'SMART risk score', all with and without addition of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Treatment effect of pravastatin was assessed across low and high risk groups identified by the best performing models. Post-hoc analysis in 2348 participants (age 70-82 years) with a history of cardiovascular disease within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Composite endpoint was a recurrent cardiovascular event/cardiovascular mortality. The models with age and sex, traditional risk markers and SMART risk score had comparable predictive values (area under the curve (AUC) 0.58, 0.61 and 0.59, respectively). Addition of NT-proBNP to these models improved AUCs with 0.07 (p for difference ((pdiff)) = 0.003), 0.05 (pdiff = 0.009) and 0.06 (pdiff < 0.001), respectively. For the model with age, sex and NT-proBNP, the hazard ratio for the composite endpoint in pravastatin users compared with placebo was 0.67 (95% confidence interval 0.49-0.90) for those in the highest third of predicted risk and 0.91 (0.57-1.46) in the lowest third, number needed to treat 12 and 115 (pdiff = 0.038) respectively. In secondary cardiovascular prevention in old age addition of NT-proBNP improves prediction of recurrent cardiovascular disease, cardiovascular mortality and treatment effect of pravastatin. A minimal model including age, sex and NT-proBNP predicts as accurately as complex risk models including NT-proBNP.

Abstract 16852: Left Ventricular Hypertrophy and Cognitive Decline in Dementia-free Older Subjects at Risk of Cardiovascular Disease

Background: Impaired cardiac function in patients with heart failure has been linked with structural and functional alterations in the brain. Left ventricular hypertrophy (LVH) is associated with lower cardiac output which can jeopardize cerebral perfusion. In this study, we investigated whether LVH is related with accelerated cognitive decline in dementia-free older subjects at risk of cardiovascular disease. Methods: We studied 4240 men and women dementia-free subjects, mean age 75.1 years, who were enrolled in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). From baseline electrocardiograms Sokolow-Lyon Product, a measure of LVH, was calculated. Four domains of cognitive functional 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. The association between Sokolow-Lyon Product and annual decline in various cognitive domains were evaluated using linear regression models adjusted for socio-demographic and cardiovascular factors. Results: At baseline higher Sokolow-Lyon Product, indicating higher degrees of LVH, was associated lower cognitive scores in reaction time (p&lt;0.001) and processing speed (p&lt;0.001). However, the associations attenuated after adjustments for demographic and cardiovascular factors. In the longitudinal analyses, higher Sokolow-Lyon Product was associated with steeper decline in processing speed (p=0.001), immediate (p=0.001) and delayed (p=0.003) memory function. All these associations were independent of cardiovascular factors and events during follow up. Conclusion: Higher degrees of LVH are independently associated with steeper cognitive decline, in particular in processing speed and memory domains. Older subjects with LVH need to be recognized as high risk groups for cognitive impairment.

Resting heart rate, heart rate variability and functional decline in old age.

Heart rate and heart rate variability, markers of cardiac autonomic function, have been linked with cardiovascular disease. We investigated whether heart rate and heart rate variability are associated with functional status in older adults, independent of cardiovascular disease. We obtained data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). A total of 5042 participants were included in the present study, and mean follow-up was 3.2 years. Heart rate and heart rate variability were derived from baseline 10-second electrocardiograms. Heart rate variability was defined as the standard deviation of normal-to-normal RR intervals (SDNN). Functional status in basic (ADL) and instrumental (IADL) activities of daily living was measured using Barthel and Lawton scales, at baseline and during follow-up. The mean age of the study population was 75.3 years. At baseline, higher heart rate was associated with worse ADL and IADL, and lower SDNN was related to worse IADL (all p values < 0.05). Participants in the highest tertile of heart rate (range 71-117 beats/min) had a 1.79-fold (95% confidence interval [CI] 1.45-2.22) and 1.35-fold (95% CI 1.12-1.63) higher risk of decline in ADL and IADL, respectively (p for trend < 0.001 and 0.001, respectively). Participants in the lowest tertile of SDNN (range 1.70-13.30 ms) had 1.21-fold (95% CI 1.00-1.46) and 1.25-fold (95% CI 1.05-1.48) higher risk of decline in ADL and IADL, respectively (both p for trends < 0.05). All associations were independent of sex, medications, cardiovascular risk factors and comorbidities. Higher resting heart rate and lower heart rate variability were associated with worse functional status and with higher risk of future functional decline in older adults, independent of cardiovascular disease. This study provides insight into the role of cardiac autonomic function in the development of functional decline.

Executive function, but not memory, associates with incident coronary heart disease and stroke.

To evaluate the association of performance in cognitive domains executive function and memory with incident coronary heart disease and stroke in older participants without dementia. We included 3,926 participants (mean age 75 years, 44% male) at risk for cardiovascular diseases from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with Mini-Mental State Examination score ≥24 points. Scores on the Stroop Color-Word Test (selective attention) and the Letter Digit Substitution Test (processing speed) were converted to Z scores and averaged into a composite executive function score. Likewise, scores of the Picture Learning Test (immediate and delayed memory) were transformed into a composite memory score. Associations of executive function and memory were longitudinally assessed with risk of coronary heart disease and stroke using multivariable Cox regression models. During 3.2 years of follow-up, incidence rates of coronary heart disease and stroke were 30.5 and 12.4 per 1,000 person-years, respectively. In multivariable models, participants in the lowest third of executive function, as compared to participants in the highest third, had 1.85-fold (95% confidence interval [CI] 1.39-2.45) higher risk of coronary heart disease and 1.51-fold (95% CI 0.99-2.30) higher risk of stroke. Participants in the lowest third of memory had no increased risk of coronary heart disease (hazard ratio 0.99, 95% CI 0.74-1.32) or stroke (hazard ratio 0.87, 95% CI 0.57-1.32). Lower executive function, but not memory, is associated with higher risk of coronary heart disease and stroke. Lower executive function, as an independent risk indicator, might better reflect brain vascular pathologies.

Subclinical Thyroid Dysfunction and Depressive Symptoms among the Elderly: A Prospective Cohort Study

Background: Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. Methods: In the Leiden substudy of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), thyroid-stimulating hormone and free T₄ levels were measured at baseline and repeated after 6 months in adults aged 70-82 years with preexisting cardiovascular disease or known cardiovascular risk factors to define persistent thyroid functional status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS-15) at baseline and after 3 years. All analyses were adjusted for age, gender and education. Results: In 606 participants (41% women; mean age 75 years) without antidepressant medication, GDS-15 scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS-15 score 1.75, 95% CI 1.29-2.20, p = 0.53) or subclinical hyperthyroidism (n = 13; GDS-15 score 1.64, 95% CI 0.78-2.51, p = 0.96) compared to euthyroid participants (n = 546; mean GDS-15 score 1.60, 95% CI 1.46-1.73). After 3 years, compared to the euthyroid participants, changes in GDS-15 scores did not differ for participants with subclinical hypothyroidism (ΔGDS-15 score -0.03, 95% CI -0.50 to 0.44, p = 0.83), while subclinical hyperthyroidism was associated with an increase in GDS scores (ΔGDS-15 score 1.13, 95% CI 0.32-1.93, p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. Conclusions: In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study.