J. Shepherd

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment : individual patient meta-analysis of 13,677 subjects

Background—Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. Methods and Results—A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. Conclusions—The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Effect of Pravastatin in People with Diabetes and Chronic Kidney Disease

Although diabetes is a major cause of chronic kidney disease (CKD), limited data describe the cardiovascular benefit of hydroxymethyl glutaryl CoA reductase inhibitors (statins) in people with both of these conditions. This study sought to determine whether pravastatin reduced the incidence of first or recurrent cardiovascular events in people with non-dialysis-dependent CKD and concomitant diabetes, using data from three randomized trials of pravastatin 40 mg daily versus placebo. CKD was defined by estimated GFR <60 or 60 to 89.9 ml/min per 1.73 m2 with proteinuria. Of 19,737 patients, 4099 (20.8%) had CKD but not diabetes at baseline, 873 (4.4%) had diabetes but not CKD, and 571 (2.9%) had both conditions. The primary composite outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Median follow-up was 64 mo. After adjustment for trial and random treatment assignment, the incidence of the primary outcome was lowest in individuals with neither CKD nor diabetes (15.2%), intermediate in individuals with only CKD (18.6%) or only diabetes (21.3%), and highest in individuals with both characteristics (27.0%). Pravastatin reduced the relative likelihood of the primary outcome to a similar extent in subgroups defined by the presence or absence of CKD and diabetes. For example, pravastatin was associated with a significant reduction in the relative risk of the primary outcome by 25% in patients with CKD and concomitant diabetes and by 24% in individuals with neither characteristic. However, the absolute reduction in the risk of the primary outcome as a result of pravastatin use was highest in patients with both CKD and diabetes (6.4%) and lowest in individuals with neither characteristic (3.5%). In conclusion, stage 2 or early stage 3 CKD and diabetes both are associated with higher cardiovascular risk, and pravastatin reduces cardiovascular event rates in people with neither, one, or both characteristics. Given the high absolute benefit of pravastatin in patient with diabetes and stage 2 or early stage 3 CKD, this population in particular should be targeted for widespread use of statins. Additional studies are needed to determine whether these benefits apply to patients with more severe CKD, and recruitment to such studies should be given high priority.

Testing cognitive function in elderly populations: the PROSPER study

Objectives: For large scale follow up studies with non-demented patients in which cognition is an endpoint, there is a need for short, inexpensive, sensitive, and reliable neuropsychological tests that are suitable for repeated measurements. The commonly used Mini-Mental-State-Examination fulfils only the first two requirements. Methods: In the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5804 elderly subjects aged 70 to 82 years were examined using a learning test (memory), a coding test (general speed), and a short version of the Stroop test (attention). Data presented here were collected at dual baseline, before randomisation for active treatment. Results: The tests proved to be reliable (with test/retest reliabilities ranging from acceptable (r=0.63) to high (r=0.88) and sensitive to detect small differences in subjects from different age categories. All tests showed significant practice effects: performance increased from the first measurement to the first follow up after two weeks. Conclusion: Normative data are provided that can be used for one time neuropsychological testing as well as for assessing individual and group change. Methods for analysing cognitive change are proposed.

1.P.153 Influence of pravatatin and plasma lipids on clinical events, in the West of Scotland Coronary Prevention Study (WOSCOPS)

BACKGROUND: The West of Scotland Coronary Prevention Study was a primary prevention trial that demonstrated the effectiveness of pravastatin (40 mg/d) in reducing morbidity and mortality from coronary heart disease (CHD) in moderately hypercholesterolemic men. The present analysis examines the extent to which differences in LDL and other plasma lipids both at baseline and on treatment influenced CHD risk reduction. METHODS AND RESULTS: Relationships between baseline lipid concentrations and incidence of all cardiovascular events and between on-treatment lipid concentrations and risk reduction in patients taking pravastatin were examined by use of Cox regression models and by division of the cohort into quintiles. Variation in plasma lipids at baseline did not influence the relative risk reduction generated by pravastatin therapy. Fall in LDL level in the pravastatin-treated group did not correlate with CHD risk reduction in multivariate regression. Furthermore, maximum benefit of an approximately 45% risk reduction was observed in the middle quintile of LDL reduction (mean 24% fall); further mean decrements in LDL (up to 39%) were not associated with a greater decrease in CHD risk. Comparison of event rates between placebo- and pravastatin-treated subjects with the same LDL cholesterol level provided evidence for an apparent treatment effect that was independent of LDL. CONCLUSIONS: We conclude that the treatment effect of 40 mg/d of pravastatin is proportionally the same regardless of baseline lipid phenotype. There is no CHD risk reduction unless LDL levels are reduced, but a fall in the range of 24% is sufficient to produce the full benefit in patients taking this dose of pravastatin. LDL reduction alone does not appear to account entirely for the benefits of pravastatin therapy.

Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study.

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

The incidence and risk factors for new onset atrial fibrillation in the PROSPER study.

AIMS Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for its development. METHODS AND RESULTS The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a randomized, double-blind controlled trial that recruited 5804 individuals aged 70-82 years with a history of, or risk factors for, vascular disease. A total of 2891 were allocated to pravastatin and 2913 to placebo; mean follow-up was 3.2 years. Electrocardiograms (ECGs), which were recorded at baseline, annually thereafter, and at run-out, were processed by computer and reviewed manually. In all, 264 of 2912 (9.1%) of the placebo group and 283 of 2888 (9.8%) of the pravastatin-treated group developed AF [hazard ratio 1.08 (0.92,1.28), P= 0.35)]. Multivariate analysis showed that PR and QTc intervals, age, left ventricular hypertrophy, and ST-T abnormalities were related to development of AF after adjustment for many variables including alcohol consumption, which itself was univariately predictive of developing AF. Previous myocardial infarction on the ECG was not a risk factor. A history of vascular disease was strongly linked with developing AF but not diabetes and hypertension. CONCLUSION Pravastatin does not reduce the incidence of AF in older people at risk of vascular disease, at least in the short-medium term. Risk factors for AF include older age, prolongation of PR or QTc intervals, left ventricular hypertrophy, and ST-T abnormalities on the ECG.

Biogerontology: Mechanisms and Interventions

Abstract:  Proinflammatory cytokines, like interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α), are implicated in the development of atherosclerosis. The role of anti‐inflammatory cytokines, like IL‐10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL‐10 gene (4259AG, −1082GA, −592CA, and −2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the −592A variant allele) and risk of coronary events (P= 0.019). Moreover, analysis of separate SNPs found a significant association between −2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04–2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti‐inflammatory cytokines may play an important role.

Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation

Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known to be associated with circulating concentrations, thereby utilising these variants as proxies for circulating CRP levels. By analysing data from several studies examining the association between relevant CRP polymorphisms and CHD risk, the present collaboration will undertake a Mendelian randomisation analysis to help assess the likelihood of any causal relevance of CRP levels to CHD risk. A central database is being established containing individual data on CRP polymorphisms, circulating CRP levels, and major coronary outcomes as well as age, sex and other relevant characteristics. Associations between CRP polymorphisms or haplotypes and CHD will be evaluated under different circumstances. This collaboration comprises, at present, about 37,000 CHD outcomes and about 120,000 controls, which should yield suitably precise findings to help judge causality. This work should advance understanding of the relevance of low-grade inflammation to CHD and indicate whether or not CRP itself is involved in long-term pathogenesis.

Influence of etofibrate on low density lipoprotein metabolism.

This study examined the effect of single dose etofibrate (1.0 g/day) on plasma lipids and lipoproteins in a group of eleven hypercholesterolemic individuals. The drug lowered plasma triglyceride and cholesterol by 32% and 14%, respectively (P less than 0.005). The cholesterol reduction came from a decrement in both VLDL and LDL. The cholesterol content of HDL did not change although its mass as determined by analytical ultracentrifugation rose by 29%. LDL metabolism was followed before and during drug therapy. Treatment increased catabolism of this lipoprotein by 14%, without affecting synthesis. The increased clearance resulted from activation (64%) of the LDL receptor pathway. There was a reciprocal decrease in the amount of lipoprotein channelled into the receptor-independent route.

Genetic variation in PCAF, a key mediator in epigenetics, is associated with reduced vascular morbidity and mortality: evidence for a new concept from three independent prospective studies

Aims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality. Methods and results The association of genetic variation in the PCAF-gene with CHD, restenosis and mortality was investigated in three large cohorts. The results were combined to examine overall effects on CHD mortality and on restenosis risk. Compared with the homozygous −2481G allele in the PCAF promoter, a significant reduction in CHD mortality risk with the homozygous −2481C PCAF promoter allele was observed. A combined risk reduction for CHD death for the three studies was 21% (15–26%; p=8.1×10–4). In elderly patients (>58 years) the effects were stronger. Furthermore, this PCAF allele was significantly associated with all-cause mortality (p=0.001). Functional analysis showed that nuclear factors interact in vitro with the oligonucleotides encompassing the −2481G/C polymorphism and that this interaction might be influenced by this polymorphism in the PCAF promoter. Moreover, modulation of PCAF gene expression was detectable upon cuff-placement in an animal model of reactive stenosis. Conclusion We showed in three large prospective studies that the −2481C allele in the PCAF promoter is associated with a significant survival advantage in elderly patients. Our observations promote the concept that epigenetic processes are under genetic control and that, other than environment, variation in genes encoding KATs may also determine susceptibility to CHD outcomes and mortality.