Adipose tissue pro-inflammatory gene expression is associated with cardiovascular disease.

BACKGROUND: Obese patients are at high risk of developing cardiovascular disease. Several studies suggest obesity as an independent risk factor. Adipose tissue is now accepted as an endocrine organ that produces and secretes a variety of cytokines, hormones and other metabolic players involved in the pathogenesis of atherosclerosis. Among this versatile group of mediators and effectors of inflammation and atherothrombosis, we have studied the expression of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), plasminogen activator inhibitor-1 (PAI-1), interleukin-18 (IL-18) and interleukin-6 (IL-6). All these markers, in their circulatory form, have been associated with cardiovascular disease. However, there is no much data available on their expression in adipose tissue in human subjects with and without cardiovascular disease. MATERIAL AND METHODS: We successfully isolated RNA from subcutaneous fat biopsies of 61 patients with or without cardiovascular disease. We then measured the RNA expression of MMP-9, TIMP-1, PAI-1, IL-18 and IL-6 with Real-Time PCR, using relative quantification. RESULTS: Albeit not statistically significant, all inflammatory mediators - except IL-18 - were highly expressed in patients with cardiovascular disease (n = 16) compared with those without (n = 45). Pooling the gene expression data, trying to capture the overall inflammatory activity in adipose tissue in a score system, we observed a highly significant association with CVD. CONCLUSIONS: Trying to capture the overall inflammatory activity, in addition to the mass of adipose tissue, could provide useful hints towards a pathogenetic link between obesity and presence of cardiovascular disease.

Consumption of fruit and berries is inversely associated with carotid atherosclerosis in elderly men.

Epidemiological data suggest that fruit and vegetable consumption is associated with a lowered risk of CVD. We assessed the association between the intima-media thickness (IMT) of the carotid artery and dietary intake of vegetables, fruit and berries in elderly men with a high risk of CVD. Subjects (age 70 +/- 5 years) were survivors from a cohort of 1232 men that participated in the Oslo Diet and Antismoking Study in 1972-3. Measurements of the carotid IMT by high resolution B-mode ultrasound, risk factor assessment and dietary data based on an FFQ were collected in 1997-9. Complete dietary and ultrasound data were available for 547 subjects. The carotid IMT in the highest quartile of dietary intake of fruit and berries was 0.89 (SE 0.18) mm compared with 0.96 (SE 0.25) mm in the lowest quartile, giving a mean difference of 0.075 (SE 0.027) mm (P = 0.033). In multivariate regression analysis increased intake of fruit and berries remained inversely associated with IMT after adjustment for age, cigarette smoking, dietary cholesterol and saturated fat, consumption of milk, cream and ice cream and energy intake (multivariate regression coefficient 0.257; R(2) 0.066; SE 0.209; P < 0.001). The difference of 348 g of fruit and berries per d between the lowest and highest quartile of intake was associated with a 5.5 % adjusted difference in mean IMT. These findings suggest that consumption of fruit and berries may be protective against carotid atherosclerosis in elderly men at high risk of CVD.

Long-term influence of diet and/or omega-3 fatty acids on matrix metalloproteinase-9 and pregnancy-associated plasma protein-A in men at high risk of coronary heart disease.

BACKGROUND: Matrix metalloproteinases (MMPs) are important in the atherosclerotic process. The relationship between MMPs and traditional risk factors for cardiovascular disease (CVD) and any influence of lifestyle changes are largely unknown. OBJECTIVES: In a factorial design, we studied the effects of 3 years of dietary counselling and/or n-3 PUFA supplementation (2.4 g/d) on the levels of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1) and pregnancy-associated plasma protein (PAPP-A) in a population of elderly men at high risk of CVD (n = 563, age 70+/-6 years). We further explored the association between these markers and different disease entities, carotid intima media thickness (IMT) and traditional risk factors for CVD. RESULTS: Smokers had significantly higher levels of MMP-9 (p<0.0001), and TIMP-1 levels were lower in subjects with previous AMI (p = 0.021). MMP-9 was significantly correlated with LDL-C and inversely with HDL-C (both p<0.0001). There were no significant correlations between the measured variables and IMT. Significant reductions in MMP-9 and PAPP-A levels after 36 months were found in all study groups, however, with no between-group differences. CONCLUSIONS: The elevated levels of MMP-9 in smokers and the reduced levels of TIMP-1 in patients with previous AMI reflect an importance of MMPs in the development of CVD. Intervention with diet and/or n-3 PUFA supplementation did not influence the levels of MMP-9, TIMP-1 or PAPP-A in the present population.

Comparison of biochemical, functional and structural aspects of arterial wall properties in elderly men.

OBJECTIVE: A variety of methods are available to assess arterial wall properties. The aim of this study was to investigate the relationship between some of the biochemical, functional and structural measurements of arterial wall characteristics. MATERIAL AND METHODS: The study comprised 563 elderly men at high risk of coronary heart disease. Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, von Willebrand factor (vWF) and tissue-type plasminogen activator antigen (tPAag) were compared with pulse wave velocity (PWV) measured by finger photoplethysmography and intima-media thickness (IMT) and plaque score of the common carotid artery. RESULTS: Levels of ICAM-1 were significantly correlated with plaque score (r = 0.17, p<0.001). Levels of vWF were significantly correlated with plaque score (r = 0.11, p = 0.009) and PWV (r = 0.12, p = 0.007), and levels of tPAag were significantly correlated with PWV (r = 0.16, p<0.001). These associations, although generally weak, remained statistically significant after adjustment for relevant cardiovascular risk factors. PWV did not correlate significantly with IMT or plaque score. CONCLUSIONS: The limited intercorrelation between biochemical, functional and structural measurements of arterial wall properties observed in the present population indicate that the various methods reflect different aspects of the atherosclerotic process.

Follow-up of diet and cardiovascular risk factors 20 years after cessation of intervention in the Oslo Diet and Antismoking Study.

OBJECTIVE: The Oslo Diet and Antismoking study was a 5-year randomised trial initiated in 1972-1973, which studied the effect of dietary change and smoking cessation for the prevention of coronary heart disease among high-risk middle-aged men. To test the long-term maintenance of lifestyle change, we examined diet and cardiovascular risk factors in subjects initially randomised to the control and intervention groups 20 years after cessation of the intervention. SUBJECTS AND DESIGN: Of the original cohort that included 1232 participants, 910 survivors were identified in 1997 and cardiovascular risk factors were measured in 563 (62%) in 1997-1999. Of these, 558 (99%) also completed questionnaires about their food intake and attitudes to health and diet. RESULTS: Cigarette smoking was nearly halved between baseline and 20-year follow-up in each of the intervention and control groups (P<0.001 within groups), but did not differ between the intervention group (39%) versus the control group (34%); P=0.07. Body mass index increased by 1.4+/-2.6 and 1.6+/-2.6 kg/m(2) between baseline and 20-year follow-up in the intervention and control groups, respectively (P<0.001 within groups; NS between groups). Serum total cholesterol and triglyceride concentrations decreased substantially in subjects treated or untreated with statins (P<0.001 within the intervention and control groups) but did not differ between the groups (total cholesterol change of -1.4+/-1.3 and -1.3+/-1.2 mmol/l, respectively, and triglyceride change of -0.5+/-1.0 mmol/l in both groups). Men in the intervention group reported a less atherogenic fat quality score and lower intakes of fat, saturated fat and cholesterol, higher intakes of long chain polyunsaturated fatty acids, protein and beta-carotene and greater attention to lifestyle and change of diet than the control group (all P<0.05). The fatty acid concentrations did not differ, however, between the intervention and control groups (P>0.05). CONCLUSIONS: No long-term differences in smoking rates or lipid concentrations between the intervention and control groups were observed in the surviving attendees two decades after the end of the trial. Lifestyle intervention still influenced the dietary intake, though modestly.

Markers of endothelial cell activation in elderly men at high risk for coronary heart disease.

OBJECTIVE: Circulating cell adhesion molecules (CAMS) are regarded as inflammatory markers related to the process of atherosclerosis and cardiovascular disease (CVD). In the haemostatic system, elevated levels of thrombomodulin (TM), von Willebrand factor (vWF) and tissue-type plasminogen activator antigen (tPAag) have likewise been associated with atherothrombotic cardiovascular disease states. MATERIAL AND METHODS: Levels of these circulating markers were investigated in a cross-sectional study including 563 men aged 70 (64-76) years characterized as hypercholesterolaemic in 1972, as related to the following clinical entities: cardiovascular morbidity (28%), diabetes (15%), hypertension (70%) and smoking habits (34%) after 24 years. RESULTS: In patients presenting with CVD, significantly higher levels of tPAag were encountered (12.9 versus 12.0 ng/ml, p = 0.02). In smokers, levels of sICAM-1 were significantly higher (331 versus 298 ng/ml, p < 0.001), whereas levels of sVCAM-1 and sTM were lower compared with those in non-smokers (543 versus 582 ng/ml, p = 0.01, 40.6 versus 44.5 ng/ml, p < 0.01, respectively). In diabetics, levels of sE-selectin and tPAag were significantly higher than those in non-diabetics (55.9 versus 45.7 ng/ml, p < 0.001, 13.6 versus 12.0, p = 0.001, respectively). In subjects with hypertension, levels of TM were elevated (44.0 versus 40.8 ng/ml, p = 0.03). In multivariate regression analyses, tPAag remained significantly associated with the presence of CVD (p = 0.03), sE-selectin with diabetes (p=0.004), sTM with hypertension (p = 0.02) and sVCAM-1, sICAM-1 and sTM with smoking, (p = 0.01, p < 0.001, p < 0.001, respectively). CONCLUSIONS: The present results may contribute to the understanding of the multitude of factors influencing these endothelial markers and their evaluation in various disease entities.

Effect of diet intervention on long-term mortality in healthy middle-aged men with combined hyperlipidaemia.

OBJECTIVES: The aim was to study the effect of a 5-year diet intervention on 24-year mortality in middle aged men with combined hyperlipidaemia. SETTING: We studied 104 initially healthy men (in 1972) aged 40-49 years with baseline values of total serum cholesterol >6.45 mmol L-1 and fasting triglycerides >2.55 mmol L-1, within the randomized diet and smoking cessation trial of the Oslo study (n = 1232). METHODS: The participants were randomized to a 5-year diet intervention or a control group. The diet consisted of a traditional lipid-lowering diet with emphasis on reduction of saturated fat, total caloric intake and body weight. The groups were initially well balanced with regard to traditional risk factors for mortality. RESULTS: Thirty-three subjects died during the 24-year observation period [17 of cardiovascular disease (CVD) and 12 of cancer]. In the diet intervention group, mortality was 51% lower (RR = 0.49, 95% CI 0.22-0.91, P = 0.022) as compared with the control group. This difference remained significant in a Cox regression analysis after adjusting for age and smoking status (RR = 0.47, 95% CI 0.23-0.96, P = 0.038). CONCLUSION: This study indicates that the investigated 5-year diet intervention significantly reduces late mortality in healthy middle-aged men with combined hyperlipidaemia.

Fasting triglycerides as a predictor of long-term mortality in middle-aged men with combined hyperlipidaemia.

OBJECTIVE: To study cholesterol, triglycerides, smoking and blood pressure as potential predictors of long-term mortality in middle-aged males with combined hyperlipidaemia. METHODS: The study included 104 healthy men aged 40-49 years with total serum cholesterol >6.45 mmol/L and fasting triglycerides >2.55 mmol/L within the randomized diet and smoking cessation trial of the Oslo study (n=1232). RESULTS: Thirty-three subjects died during the 24-year observation period. Univariate analysis showed that only age, fasting triglycerides and smoking were significantly related to mortality. An analysis for trend through quartiles of triglycerides showed a statistically significant association with mortality (p=0.049). Subjects in the lowest triglyceride quartile (2.55-2.75 mmol/L) had a 70%, reduction in mortality compared with the remaining subjects (>2.75 mmol/L) (RR=0.30, 95% CI 0.10-0.90, p=0.014). Non-smokers had a 60% reduced mortality compared with smokers (RR=0.40, 95% CI 0.17-0.94, p=0.019). When studied in a Cox regression analysis, with age, triglycerides and smoking as independent variables, triglycerides were significantly related to mortality, 1st quartile vs. 2nd, 3rd and 4th quartiles: risk rate=0.24, (95% CI 0.07-0.77, p=0.02). For non-smokers vs. smokers, the Cox analysis showed a risk rate=0.39, (95% CI 0.15-1.02, p=0.054). CONCLUSION: This study indicates that high levels of fasting triglycerides (>2.75 mmol) are independently associated with increased late mortality in healthy middle-aged men with combined hyperlipidaemia.

Are left ventricular mass, geometry and function related to vascular changes and/or insulin resistance in long-standing hypertension? ICARUS: a LIFE substudy.

Vascular hypertrophy and insulin resistance have been associated with abnormal left ventricular (LV) geometry in population studies. We wanted to investigate the influence of vascular hypertrophy and insulin resistance on LV hypertrophy and its function in patients with hypertension. In 89 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured blood pressure; insulin sensitivity by hyperinsulinaemic euglucaemic clamp; minimal forearm vascular resistance (MFVR) by plethysmography; intima-media cross-sectional area of the common carotid arteries (IMA) by ultrasound; and LV mass, relative wall thickness (RWT), systolic function and diastolic filling by echocardiography after two weeks of placebo treatment. LV mass index correlated to IMA/height (r=0.36, P=0.001), serum insulin (r=-0.25, P<0.05), plasma glucose (r=-0.34, P<0.01), and showed a tendency towards a correlation to insulin sensitivity (r=0.21, P=0.051), but was unrelated to MFVR. Deceleration time of early diastolic transmitral flow positively correlated to IMA/height (r=0.30, P<0.01). The ratio between early and atrial LV filling peak flow velocity negatively correlated to MFVR(men) (r=-0.30, P<0.05). Endocardial and midwall systolic LV function were not related to vascular hypertrophy, plasma glucose, serum insulin or insulin sensitivity. In conclusion, insulin resistance was not related to LV hypertrophy or reduced LV function. However, high thickness of the common carotid arteries was associated with LV hypertrophy and high deceleration time of early diastolic transmitral flow. High MFVR was associated with low ratio between early and atrial LV filling peak flow velocity. This may suggest that systemic vascular hypertrophy contributes to abnormal diastolic LV relaxation in patients with hypertension and electrocardiographic LV hypertrophy.

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study. Insulin Carotids US Scandinavia.

BACKGROUND: Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. METHODS: In 88 unmedicated patients with stage II-III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima-media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. RESULTS: IMT was positively correlated to systolic blood pressure (r= 0.26, P < 0.05), whole body glucose uptake index (M/IG; r= 0.22, P< 0.05), age (r= 0.24, P< 0.05) and negatively correlated to body mass index (r= -0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r= -0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = -0.40, P< 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). CONCLUSIONS: High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.