Physical activity, C-reactive protein levels and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study.

BACKGROUND: Physical activity is inversely associated with the risk of future coronary artery disease. Whether this relationship is in part mediated by lower levels of systemic inflammation, as indicated by C-reactive protein concentrations, is unknown. METHODS: We performed a nested case-control study among apparently healthy men and women enrolled in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study, to investigate the relationship among habitual (work-related and leisure time) physical activity, cardiovascular risk factors and the risk of future coronary artery disease. RESULTS: Among men, those with an active lifestyle had a significantly lower risk of future coronary artery disease than those with an inactive lifestyle [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.47-0.90; P for linearity, 0.008], after adjustment for smoking, systolic blood pressure, diabetes, body mass index and low-density lipoprotein and high-density lipoprotein cholesterol. Additional adjustment for C-reactive protein levels attenuated this relationship only slightly (OR 0.68; 95%CI 0.49-0.93; P for linearity, 0.02). Similarly, active women had an adjusted odds ratio of 0.48 (0.28-0.82; P for linearity <0.001) for future coronary artery disease compared with inactive women. Additional adjustment for C-reactive protein levels attenuated this relationship slightly (OR 0.51; 0.30-0.87; P for linearity, 0.003). CONCLUSIONS: We observed that people with an active lifestyle had a substantially lower risk of future coronary artery disease than people with an inactive lifestyle, and that this relationship was partly mediated through lower levels of established cardiovascular risk factors and in addition, C-reactive protein. This observation suggests that reduced systemic inflammation may be one of the mechanisms through which physical activity leads to reduced cardiovascular risk.     

Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study

Aims/hypothesis The aim of this study was to examine the association between baseline body iron stores and new-onset diabetes. Subjects and methods We studied the association between baseline serum ferritin concentration and type 2 diabetes in 360 clinically incident diabetes cases and 758 controls nested within the EPIC (European Prospective Investigation of Cancer)-Norfolk Cohort Study. Serum ferritin levels were categorised into five groups: sex-specific quartiles of the normal range of ferritin and a group with clinically raised ferritin below levels indicative of haemochromatosis. Results Baseline serum ferritin was higher among cases than control participants (geometric mean: men 96.6 vs 67.8 ng/ml, respectively, p < 0.001; women 45.9 vs 34.8 ng/ml, respectively, p = 0.005). In analyses adjusted for known risk factors (age, BMI, sex, family history, physical activity, smoking habit) and dietary factors measured by 7-day food diary, the risk of diabetes was markedly elevated in participants with clinically raised ferritin compared with the lowest quartile (odds ratio [OR] 7.4, 95% CI 3.5–15.4). Further adjustment for potential confounding by inflammation (C-reactive protein, IL-6 and fibrinogen) had no material impact on the observed association, while adjustment for hepatic enzymes (alanine aminotransferase and γ glutamyl transferase) and adiponectin attenuated the magnitude of association, but it remained statistically significant (OR 3.2 [1.3–7.6]). Conclusions/interpretation Serum ferritin is an important and independent predictor of the development of diabetes. This finding may have important implications for understanding the aetiology of diabetes.     

C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993-2003

INTRODUCTION: Measurement of C-reactive protein (CRP) levels has been proposed as a useful marker to improve the prediction of future coronary artery disease (CAD) risk, but this notion has been challenged recently. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women. The odds ratio (OR) for future CAD incidence was 2.49 (95% CI=2.02-3.08, p for linearity <0.0001) unadjusted, and 1.66 (95% CI=1.31-2.12, p for linearity <0.0001), after adjustment for classical cardiovascular risk factors, for top versus bottom quartile of the CRP distribution. Notably, the risk factor adjusted predictive value was substantially stronger for fatal CAD (OR=2.92, 95% CI=1.83-4.67, p for linearity <0.0001) than for non-fatal CAD (OR=1.25, 95% CI=0.93-1.66, p for linearity=0.06). CRP levels were among the strongest predictors of CAD incidence and mortality. CRP levels remained a statistically significant predictor of future CAD, even after adjustment for the Framingham risk score. CONCLUSIONS: In this British cohort with risk factor levels representative of a contemporary Western population, CRP concentration was among the strongest predictors of CAD incidence and mortality. We suggest that current guidelines on CRP measurement in clinical practice should be based on contemporary and representative populations.     

Cholesterol and coronary heart disease. The importance of patient-specific attributable risk

The value of treating hypercholesterolemia remains controversial despite extensive investigation, in part because of the research orientation of much of the relevant literature. Most published studies report relative measures of risks such as the risk ratio. However, clinicians are concerned with the magnitude of risk, or attributable risk, the difference in risk in those with highest and lowest serum cholesterol levels. Since maximum risk modification is rarely achieved, the attributable risk often overstates the potential benefit of risk factor reduction. A variant of the attributable risk, the practical attributable risk, gives a more realistic estimate of potential benefit. Since clinicians treat individuals and not populations, these measures of risk are most useful if reported for subgroups of patients (eg, men and women, as well as those of varying age). To illustrate these concepts, we review the literature on hypercholesterolemia, report the risk ratio, attributable risk, and practical attributable risk for important patient populations, and discuss the implications for clinical practice.     

LDL/apo B ratio predict coronary heart disease in Type 2 diabetes independent of ASCVD risk score: A case-cohort study

Background and aimsCoronary heart disease (CHD) is a major mortality risk factor in patients with diabetes. LDL cholesterol (LDL-C) is a major risk factor for the development of atherosclerosis. There is one apolipoprotein B (ApoB) molecule in each LDL particle. We aimed to evaluate the predictive value of the LDL-C/ApoB ratio for CHD in patients with type 2 diabetes (T2D).Methods and resultsIn this case-cohort study (apo)lipoproteins and glycemic indices were measured in 1058 individuals with T2D from February 2002 to March 2019, with a median duration of follow up of 10 years. Of 1058 patients with T2D, coronary heart disease occurred in 242 patients. Increased waist circumference, waist-to-hip ratio, and hemoglobin A1c, low-density lipoprotein cholesterol (LDL-C)/Apolipoprotein B (ApoB) ratio, presence of hypertension and metabolic syndrome, and insulin and statin use were more prevalent among patients with CHD (P < 0.001). Logistic regression analysis showed that an LDL-C/ApoB ratio equal or lower than 1.2 could predict CHD independent of ASCVD risk score [adjusted OR:1.841, CI:1.257–2.698, P < 0.001] when adjusted for multiple confounders. The atherogenic index of plasma (AIP) did not predict CHD.ConclusionThis study showed that LDL-C/ApoB ratio, but not the atherogenic index of plasma, may be considered as an indicator of CHD independent of the ASCVD risk score in patients with T2D. This finding merits further clarification to optimize preventive strategies for CHD.     

The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects.

More than decade ago, several cross-sectional studies have reported differences in LDL particle size, density and composition between coronary heart disease (CHD) patients and healthy controls. Three recent prospective, nested case-control studies have since confirmed that the presence of small, dense LDL particles was associated with more than a three-fold increase in the risk of CHD. The small, dense LDL phenotype rarely occurs as an isolated disorder. It is most frequently accompanied by hypertriglyceridemia, reduced HDL cholesterol levels, abdominal obesity, insulin resistance and by a series of other metabolic alterations predictive of an impaired endothelial function and increased susceptibility to thrombosis. Whether or not the small, dense LDL phenotype should be considered an independent CHD risk factor remains to be clearly established. The cluster of metabolic abnormalities associated with small, dense LDL particles has been referred to as the insulin resistance-dyslipidemic phenotype of abdominal obesity. Results from the Québec Cardiovascular Study have indicated that individuals displaying three of the numerous features of insulin resistance (elevated plasma insulin and apolipoprotein B concentrations and small, dense LDL particles) showed a remarkable increase in CHD risk. Our data suggest that the increased risk of CHD associated with having small, dense LDL particles may be modulated to a significant extent by the presence/absence of insulin resistance, abdominal obesity and increased LDL particle concentration. We suggest that the complex interactions among the metabolic alterations of the insulin resistance syndrome should be considered when evaluating the risk of CHD associated with the small, dense LDL phenotype. From a therapeutic standpoint, the treatment of this condition should not only aim at reducing plasma triglyceride levels, but also at improving all features of the insulin resistance syndrome, for which body weight loss and mobilization of abdominal fat appear as key elements. Finally, interventions leading to reduction in fasting triglyceride levels will increase LDL particle size and contribute to reduce CHD risk, particularly if plasma apolipoprotein B concentration (as a surrogate of the number of atherogenic particles) is also reduced.     

Serum parathyroid hormone levels predict coronary heart disease: the Troms? Study.

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with hypertension, coronary atherosclerosis and other cardiovascular diseases. We aimed to evaluate serum parathyroid hormone (PTH) levels as an independent risk factor for coronary heart disease (CHD) in subjects with serum calcium within the reference range. DESIGN: Population-based cross-sectional study. METHODS: The Troms? Study was attended by 27159 subjects aged 25-79 years. Serum PTH was measured in 3570 subjects. They all completed a questionnaire on medical history, including questions on angina pectoris and myocardial infarction along with a food-frequency questionnaire. A total of 1459 men and 1753 women with serum calcium 2.20-2.60 mmol/l, serum creatinine<121 micromol/l and who did not use diuretics were included in the present study. Linear regression was used to reveal associations between PTH, age, body mass index, serum calcium, calcium intake, cholesterol, blood pressure, glycosylated haemoglobin (HbA1c) and smoking status. A logistic regression model was used to find the independent predictors of CHD. RESULTS: When stratified for age the rate of CHD was higher in the subjects with serum PTH > 6.8 pmol/l than in those with normal or low serum PTH levels [relative risk 1.67, 95% confidence interval (CI) 1.26-2.23 in men and 1.78, 95% CI 1.22-2.57 in women]. The highest PTH quartile (> 3.50 pmol/l in men and > 3.30 pmol/l in women) predicted CHD, with odds ratios of 1.70 (95% CI 1.08-2.70) for men and 1.73 (95% CI 1.04-2.88) for women, versus the lowest PTH quartile (< 1.90 pmol/l for men and <1.80 pmol/l for women). CONCLUSIONS: Serum PTH predicts CHD in subjects with calcium levels within the reference range. This may indicate a role for PTH in the development of CHD.     

Serum adiponectin levels predict the risk of coronary heart disease in Japanese patients with type 2 diabetes

Aims/Introduction

An inverse association between adiponectin and coronary heart disease (CHD) has been found in Caucasians, but it is uncertain whether this association can be extrapolated to the East Asian population. The present study aimed to investigate whether serum adiponectin levels can predict CHD in Japanese patients with type 2 diabetes as observed in Caucasians.

Materials and Methods

This longitudinal study included 504 patients with type 2 diabetes (342 men and 162 women) who were admitted to Sumitomo Hospital between July 2005 and December 2006. We used Cox proportional hazard analysis to estimate the hazard ratio (HR) of CHD associated with serum adiponectin levels at baseline.

Results

During a median follow up of 5.7 years (2177 person‐years), 40 participants had new CHD and 10 had recurrent CHD. After multivariate adjustment, the highest compared with the lowest quartile of serum adiponectin levels had a significantly reduced risk of CHD (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.13–0.94; P = 0.017). The multivariate adjusted HR for the risk of CHD according to a doubling of adiponectin at baseline was 0.61 (95% CI 0.39–0.97; P = 0.037).

Conclusions

High serum adiponectin levels are significantly associated with a lower risk of CHD in Japanese patients with type 2 diabetes. This association is independent of other well‐known CHD risk factors.     

Cholesterol and coronary heart disease. The attributable risk reduction of diet and drugs

The efficacy of treating hypercholesterolemia is often expressed in relative terms as the ratio of risk in treated vs untreated populations. However, the clinical impact of treatment is best measured by the difference in risk, which is called the attributable risk reduction. Attributable risk reduction is most useful clinically if it is reported for specific subgroups of patients according to age, sex, and other risk factors. To illustrate this concept, its applications and limitations, we review the literature on the primary and secondary treatment of hypercholesterolemia, present the attributable risk reduction, and describe its implications for clinical practice.     

Cholesterol in patients with coronary heart disease

CLINICAL PROBLEM: To examine the evidence supporting the recent National Cholesterol Education Program (NCEP) recommendation that low to moderate levels of cholesterol should be aggressively managed in patients with coronary heart disease (CHD). METHODS: Cohort studies and clinical trials with angiographic or clinical endpoints, that included CHD patients with low to moderate levels of cholesterol, were systematically identified through a MEDLINE search and critically reviewed. SYNOPSIS: None of the cohort studies show that a moderate level of cholesterol confers significantly increased risk of CHD death, although a pooled relative risk of 1.14 (95% CI 1.08 to 1.4) suggests that there may be a slight excess risk. Of five angiographic trials of CHD patients with moderate levels of cholesterol, two demonstrated no improvement in angiographic endpoints with intensive lipid-lowering therapy and the other three are difficult to interpret since they included other interventions in addition to the cholesterol-lowering regimen. No large clinical trial with clinical endpoints has been reported for CHD patients with low to moderate levels of cholesterol. RECOMMENDATIONS: The recommendation to treat CHD patients who have low to moderate levels of cholesterol with diet or drugs is not based on convincing evidence of efficacy. This is in clear contrast to the recommendation for CHD patients with high levels of cholesterol, for whom there is definitive clinical trial evidence of benefit from cholesterol-lowering therapy. While we await clinical trial results for CHD patients with low to moderate levels of cholesterol, clinicians and patients must consider the possible disadvantages of therapy in relation to the uncertain benefit. Received from the Section of General Internal Medicine, Department of Medicine, Veterans Affairs Medical Center, and the University of Minnesota School of Medicine, Minneapolis, Minnesota.     

LDL size and risk of coronary heart disease in elderly men and women

A predominance of small, dense, low density lipoprotein (LDL) particles has consistently been associated with coronary heart disease (CHD) in young and middle-aged subjects in cross-sectional studies. Recently, 3 prospective, case-control studies showed that decreased LDL size is a predictor of CHD in middle-aged subjects. However, it is not known whether decreased LDL size is mainly associated with premature CHD or whether it continues to play a role in CHD risk at older ages also. We performed a prospective, nested case-control study in 86 subjects (58 nondiabetic and 28 type 2 diabetic) aged 65 to 74 years who were free of myocardial infarction at baseline and who then had a myocardial infarction or CHD death during a 3.5-year follow-up (cases) and in 172 controls matched for sex and diabetes status but who remained free of CHD during follow-up. LDL particle size determined by gradient gel electrophoresis (268.2+/-0.9 versus 268.5+/-0.7 A, P=0.782) and the proportion of subjects with LDL subclass phenotype B (20.9 versus 21. 5, P=0.914) were similar among cases and controls. Furthermore, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A(1), fasting glucose, fasting insulin, waist-to-hip ratio, and body mass index were not associated with CHD risk. However, smoking and increased systolic blood pressure, apolipoprotein B levels, and the total cholesterol-high density lipoprotein cholesterol ratio were significant predictors of CHD events both in univariate and multivariate analyses. Our findings indicate that LDL size is not a predictor of CHD events in elderly white subjects after controlling for diabetes status.