Provitamin A carotenoids are independently associated with matrix metalloproteinase-9 in plasma samples from a general population

Abstract. Rydén M, Garvin P, Kristenson M, Leanderson P, Ernerudh J, Jonasson L (Linköping University, Linköping, Sweden; Örebro University Hospital, Örebro, Sweden; University of British Colombia, Vancouver, BC, Canada). Provitamin A carotenoids are independently associated with matrix metalloproteinase‐9 in plasma samples from a general population. J Intern Med 2012; 272: 371–384. Background and aim. Carotenoids in plasma are inversely associated with cardiovascular risk. Low levels can be explained by low dietary intake but also by a number of other factors including inflammatory activity. Given that matrix metalloproteinase (MMP)‐9 has an important role in inflammation and cardiovascular disease, we hypothesized that circulating MMP‐9 levels would be inversely related to total or single carotenoids in a general population cohort. Methods. A well‐characterized population‐based cohort of 285 Swedish men and women (45–69 years) was used for the present study. The intake of carotenoid‐rich fruits and vegetables was estimated from a food frequency questionnaire. Levels of MMP‐9, C‐reactive protein (CRP), interleukin (IL)‐6 and six major carotenoids [β‐cryptoxanthine, α‐carotene, β‐carotene, lutein (+zeaxanthin) and lycopene] were determined in plasma. Results. Lower plasma levels of total and single carotenoids were associated with lower dietary intake of carotenoids, older age, male sex, lower physical activity, higher alcohol consumption, higher body mass index (BMI), higher systolic and diastolic blood pressures, lower levels of total cholesterol and HDL cholesterol and higher levels of CRP, IL‐6 and MMP‐9. After multivariate adjustments, plasma levels of total carotenoids and provitamin A carotenoids (β‐cryptoxanthine, α‐carotene and β‐carotene) remained independently associated with sex, dietary intake of carotenoids, BMI, HDL cholesterol and MMP‐9, whilst associations with CRP and IL‐6 were not maintained. Neither dietary intake of carotenoid‐rich fruits and vegetables, nor vitamin supplement use was associated with MMP‐9, CRP or IL‐6 levels. Conclusion. Plasma carotenoids were associated with a variety of factors including age, sex, dietary intake and metabolic variables. A new finding was the independent relationship in plasma between low provitamin A carotenoids and high MMP‐9, suggesting a link between these carotenoids, matrix turnover and arterial remodelling.     

High plasma levels of alpha- and beta-carotene are associated with a lower risk of atherosclerosis: results from the Bruneck study

BACKGROUND AND PURPOSE: A large number of studies have contributed to the hypothesis that carotenoids, vitamins A and E are protective against atherosclerosis by acting as antioxidants. The aim of this study was to assess the relationship between plasma levels of carotenoids (alpha- and beta- carotene, lutein, lycopene, zeaxanthin, beta-cryptoxanthin), vitamins A and E, and atherosclerosis in the carotid and femoral arteries. METHODS: This prospective and cross sectional study involved a randomly selected population sample of 392 men and women aged 45-65 years. Carotid and femoral artery atherosclerosis was assessed by high-resolution duplex ultrasound. RESULTS: alpha- and beta- carotene plasma levels were inversely associated with the prevalence of atherosclerosis in the carotid and femoral arteries (P=0.004) and with the 5-year incidence of atherosclerotic lesions in the carotid arteries (P=0.04). These findings were obtained after adjustment for other cardiovascular risk factors (sex, age, LDL (low density lipoproteins), ferritin, systolic blood pressure, smoking, categories of alcohol consumption, social status, C-reactive protein). Atherosclerosis risk gradually decreased with increasing plasma alpha- and beta-carotene concentrations (P=0.004). No associations were found between vitamin A and E plasma levels and atherosclerosis. CONCLUSIONS: This study provides further epidemiological evidence of a protective role of high alpha- and beta- carotene in early atherogenesis.     

Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis

Objectives. To examine whether circulating levels of matrix metalloproteinase 9 (MMP‐9) were associated with ultrasound‐assessed intima‐media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP‐9 concentrations related to sampling procedures. Subjects and design. Plasma and serum MMP‐9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross‐sectional study of 61‐year‐old men (n = 473). Preanalytical sources of variability in MMP‐9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP‐9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. Setting. Research unit at university hospital. Results. Plasma concentrations of total and active MMP‐9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP‐9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP‐9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP‐9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP‐9 levels in plasma. Conclusions. Plasma MMP‐9 levels were associated with atherosclerosis in the femoral artery, and total MMP‐9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP‐9 levels.     

Migration at early age from a high to a lower coronary heart disease risk country lowers the risk of subclinical atherosclerosis in middle‐aged men

Background. Study of migrants offers a natural model to assess environmental risk of coronary heart disease (CHD) in countries differing in CHD occurrence. In Sweden, CHD risk has been markedly lower than in Finland from where a large migration occurred in the 1970s. Objectives. To study the structural and functional markers of subclinical atherosclerosis in twin pairs discordant for migration with the main focus on age at migration, length of residence and integration into Swedish society after migration from a high to a lower CHD risk country. Methods. Carotid intima‐media thickness (IMT) and brachial artery endothelial function (EF) were assessed with high‐resolution ultrasound and a set of cardiovascular, socio‐economic and psychosocial risk factors were estimated in 76 middle‐aged male twin pairs discordant for migration from Finland to Sweden. Results. Men who had migrated in adolescence had lower IMT values compared with their co‐twins living in Finland (0.665 ± 0.114 vs. 0.802 ± 0.167 mm, P = 0.009). Also men who integrated well to Swedish society had lower (0.720 ± 0.154 vs. 0.799 ± 0.207 mm, P = 0.013) IMT values than their twin brothers living in Finland. Associations between IMT and migration age and between IMT and integration remained significant in multivariate analyses of several CHD risk factors. The intrapair difference in IMT was significantly associated with immigration age and integration (anova , P = 0.0082), the difference being greatest among pairs where the brother living in Sweden had migrated at early age and integrated well to Swedish society. EF was better in men who had migrated to Sweden before the age of 21 years, but not later, compared with their co‐twins in Finland (6.4 ± 4.6% vs. 3.8 ± 3.6%, P = 0.025). Conclusions. Migration at an early age and good integration are beneficial to vascular health associated with moving from a high to a lower CHD risk country, suggesting that an environment‐sensitive period influences atherogenesis before adulthood.     

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

Abstract. Hamrefors V, Hedblad B, Engström G, Almgren P, Sjögren M, Melander O (Lund University, Malmö, Sweden). A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis. J Intern Med 2012; 271 : 271–281. Objective. To assess whether or not a genetic risk score that was previously shown to be associated with myocardial infarction (MI) and coronary artery disease (CAD) is also associated with markers of carotid atherosclerosis. Design. A total of 4022 middle‐aged subjects from the general Swedish population were genotyped and individually assigned a genetic risk score based on 13 single‐nucleotide polymorphisms (SNPs), previously associated with MI and CAD. The genetic score (Score‐MI) was then related to carotid bulb intima–media thickness (IMT), common carotid artery (CCA) IMT and to the occurrence of carotid plaques in the study population. Results. Score‐MI was associated with IMT of the bulb (P < 0.001) and the CCA (P < 0.001) in unadjusted analyses, and with IMT of the bulb after adjustment for cardiovascular risk factors (P = 0.003). The effect size of Score‐MI on IMT of the bulb was similar to that of LDL cholesterol. After adjustment for cardiovascular risk factors, Score‐MI was also associated with the occurrence of carotid plaques (odds ratio per quintile of Score‐MI = 1.11; 95% confidence interval 1.04–1.18; P = 0.001). In addition to SNPs with known effects on LDL levels, Score‐MI showed nominal associations with increasing systolic blood pressure and decreasing C‐reactive protein levels. Conclusions. This genetic risk score was independently associated with carotid bulb IMT and carotid plaques, providing evidence of an association with early markers of atherosclerosis. This might imply that the genetic MI risk conferred by the score is related to early atherosclerosis and that the risk score may identify at an early stage candidates at risk of developing intermediate phenotypes of atherosclerosis. Further studies should test whether or not assessing the genetic score could be valuable for early treatment decisions in these subjects.     

Carotid atherosclerosis,intima media thickness and risk factors--an analysis of 1781 asymptomatic subjects in Taiwan

The aim of this study was to investigate the association of intima media thickness (IMT) and plaque with risk factors for atherosclerosis in asymptomatic subjects in Taiwan. Between 1998 and 2001, the study recruited 1781 asymptomatic subjects (1131 men and 650 women [mean age, 49 years; range 18-85 years]). These were examined by B-mode ultrasound to measure the IMT at the far wall of the common carotid artery (CCA) and the extent of plaque formation. A wide range of vascular risk factors including age, gender, smoking, body mass index, blood chemistry, and previous history were surveyed. The mean (+/-S.D.) IMT observed was 0.68 (+/-0.12) and 0.66 (+/-0.11) mm for men and women, respectively, (P=0.0008). The mean (S.D.) IMT of the CCA was 0.66 (+/-0.12) mm on the right side and 0.68 (+/-0.12) mm on the left side (P=0.0004). IMT increased with aging, according to the equation IMT=(0.005xage in years)+0.403 [corrected]. Higher IMT was associated with male gender, and IMT was greater in the left CCA. About 36.9% of subjects had carotid plaques. The percentage of plaque increased with aging. The plaque prevalence was positively associated with IMT. The value of IMT over the cut point of 0.68 mm correlated with obviously increased risk of carotid atherosclerosis. Age, systolic blood pressure and fasting blood sugar were independent risk factors related to both carotid atherosclerosis and thick IMT.     

Association of carotid atherosclerosis with genetic polymorphisms of the klotho gene in patients with hypertension

Aim: Previous studies suggest that klotho gene polymorphisms may be associated with atherosclerosis, but did not assess the relationship between klotho gene polymorphisms and atherosclerosis parameters such as carotid artery intima‐media thickness (IMT). Here, we studied whether klotho single nucleotide polymorphisms (SNP) were associated with carotid atherosclerosis. Methods: All subjects were Japanese. Eight‐hundred and fifty‐three patients with hypertension (465 men and 388 women) in the outpatient clinic and 1783 subjects from the general population (821 men and 962 women) attending health check‐ups were analyzed in the present study. We measured mean IMT of the common carotid artery to evaluate carotid atherosclerosis. Four single nucleotide polymorphisms (SNP) (rs7323281; intron1, rs5644481; exon4, rs3752472; exon3, rs650439; intron4) of klotho were selected as representative SNP in haplotype blocks. Results: Multivariate logistic regression analysis adjusted by confounding factors showed a significant association of rs650439 with carotid atherosclerosis in hypertensive patients (TT vs TA vs AA, P < 0.01; TT + TA vs AA, P < 0.01). By ancova considering confounding factors, rs650439 was also significantly associated with mean IMT (TT + TA vs AA, P = 0.04) in the hypertensive population. However, there was no significant association between klotho SNP and carotid IMT in the general population. Compared to the general population, the subject group with hypertensive patients clearly had more atherosclerosis risk factors. Conclusion: Only in hypertensive patients was klotho rs650439 strongly associated with mean IMT thickening of the common carotid artery. Therefore, klotho SNP (rs650439) may influence on the progression of carotid atherosclerosis in patients with hypertension. Geriatr Gerontol Int 2010 ; 10: 311–318.     

Antioxidant vitamins and the risk of carotid atherosclerosis : The perth carotid ultrasound disease assessment study (CUDAS)

OBJECTIVES

This study examined whether dietary intake or plasma levels of antioxidant vitamins were independently associated with common carotid artery intima-media (wall) thickness (IMT) or focal plaque, or both, in a large, randomly selected community population.

BACKGROUND

Oxidation of low-density lipoprotein (LDL) cholesterol is thought to be important in early atherogenesis. Antioxidant micronutrients may therefore protect against lipid peroxidation and atherosclerotic vascular disease.

METHODS

We studied 1,111 subjects (558 men and 553 women; age 52 ± 13 years [mean ± SD], range 27 to 77). We measured dietary vitamin intake and fasting plasma levels of vitamins A, C and E, lycopene and alpha- and beta-carotene and performed bilateral carotid artery B-mode ultrasound imaging.

RESULTS

After adjustment for age and conventional risk factors, there was a progressive decrease in mean IMT, with increasing quartiles of dietary vitamin E intake in men (p = 0.02) and a nonsignificant trend in women (p = 0.10). Dietary vitamin E levels accounted for 1% of the variance in measured IMT in men. For plasma antioxidant vitamins, there was an inverse association between carotid artery mean IMT and plasma lycopene in women (p = 0.047), but not in men. None of the other dietary or plasma antioxidant vitamins, nor antioxidant vitamin supplements, were associated with carotid artery IMT or focal carotid artery plaque.

CONCLUSIONS

This study provides limited support for the hypothesis that increased dietary intake of vitamin E and increased plasma lycopene may decrease the risk of atherosclerosis. No benefit was demonstrated for supplemental antioxidant vitamin use.     

Low plasma lycopene concentration is associated with increased intima-media thickness of the carotid artery wall

Although a number of epidemiological studies have evaluated the association between ss-carotene and the risk of cardiovascular diseases, there has been little research on the role of lycopene, an acyclic form of ss-carotene, with regard to the risk of cardiovascular disease. We investigated the relationship between plasma concentrations of lycopene and intima-media thickness of the common carotid artery wall (CCA-IMT) in 520 middle-aged men and women (aged 45 to 69 years) in eastern Finland. They were examined from 1994 to 1995 at the baseline of the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, a randomized trial concerning the effect of vitamin E and C supplementation on atherosclerotic progression. The subjects were classified into 2 categories according to the median concentration of plasma lycopene (0.12 micromol/L in men and 0.15 micromol/L in women). Mean CCA-IMT of the right and left common carotid arteries was 1.18 mm in men and 0.95 mm in women with plasma lycopene levels lower than the median and 0.97 mm in men (P:<0.001 for difference) and 0.89 mm in women (P:=0.027 for difference) with higher levels of plasma lycopene. In ANCOVA adjusting for cardiovascular risk factors and intake of nutrients, in men, low levels of plasma lycopene were associated with a 17.8% increment in CCA-IMT (P:=0.003 for difference). In women, the difference did not remain significant after the adjustments. We conclude that low plasma lycopene concentrations are associated with early atherosclerosis, manifested as increased CCA-IMT, in middle-aged men living in eastern Finland.     

Plasma leptin is independently associated with the intima-media thickness of the common carotid artery.

OBJECTIVE: To investigate whether intima-media thickness (IMT) of the common carotid artery (CCA), an early marker of asymptomatic atherosclerosis, is significantly and independently associated with plasma concentrations of leptin, an adipose tissue hormone that has recently been proposed as a cardiovascular risk factor in obese patients. DESIGN: Cross-sectional sample of normal-weight and obese men and women. SUBJECTS: One-hundred and twenty healthy subjects (52 men and 68 women), aged 18-45 y and with a wide range of BMI, were recruited for the study. MEASUREMENTS: Fasting plasma leptin concentrations and the IMT of the CCA were measured in all subjects. Leptin concentrations were measured by radioimmunoassay and the IMT of the CCA was quantified by high resolution B-mode ultrasound imaging. Central fat (measured by waist circumference), smoking habits, blood pressure, insulin sensitivity (measured by the insulin tolerance test), and fasting plasma glucose, insulin and lipid pattern (cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol) were also measured. RESULTS: IMT of the CCA was positively correlated with log leptin concentrations (P<0.005 in men and P<0.001 in women), body mass index (P<0.001 in men and women), waist circumference (P<0.001 in men and women), age (P<0.001 in men and P<0.05 in women), and negatively associated with insulin sensitivity in both sexes (P<0.05). IMT was also directly correlated with cholesterol (P<0.05), LDL-cholesterol (P<0.01) and systolic blood pressure in men (P<0.05), and with diastolic blood pressure levels in women (P<0.05). When a multiple linear regression model was used without body mass index (BMI), the correlation between leptin and IMT was maintained in both men (P<0.01) and women (P<0.005), independent of age, insulin sensitivity, smoking habits, systolic blood pressure, fasting glucose, triglycerides, cholesterol, LDL-cholesterol and HDL-cholesterol. By contrast, BMI-adjusted leptin concentrations were not significantly associated with IMT (Pc (partial correlation): 0.41 in men and 0.15 in women). Moreover, when BMI was entered into a multiple linear regression model without leptin, the correlation between BMI and IMT was maintained in both men (P<0.005) and women (P<0.01), independent of the same parameters. CONCLUSION: Plasma leptin concentrations are independently associated with the IMT of the CCA, suggesting that the increase of adipose tissue mass (or leptin per se) may have an unfavourable influence on the development of atherosclerosis. However, the association between IMT and leptin seems to be dependent and/or confounded by the relationship between IMT and obesity.     

Determinants of femoral and carotid artery atherosclerosis

Abstract. Objectives . The aim of the study was to find the most important determinants of early atherosclerosis in the carotid and femoral arteries. Design . Carotid and femoral maximal intima media thickness (IMT) was measured 19 months after the first of 4 risk factor measurements. Setting . Department of Community Health and General Practice, University of Kuopio, and Occupational Health Care in Pyhäsalmi Mine, Finland. Subjects . The subjects comprised 60 male volunteers aged from 32 to 65 years from amongst 277 workers at the Pyhäsalmi Mine, Finland. Subjects were invited for an ultrasound examination, in order of serum total cholesterol content, until the required figure of 60 cases was achieved. Main outcome measures . Carotid and femoral maximal intima media thickness. Results . Systolic blood pressure (P < 0.01), serum total cholesterol (P < 0.01), age (P = 0.01) and pack-years smoked (P = 0.02) were independent determinants of maximal carotid artery IMT, and total cholesterol (P = 0.01), age (P = 0.03) and pack-years smoked (P = 0.01) for maximal femoral artery IMT. For the latter, plasma fibrinogen concentration (P = 0.10) was the next factor to enter the multiple regression model. Body mass index, heart rate, serum HDL cholesterol, triglycerides, urate, apolipoprotein A,*** antithrombin III, lipid peroxides, vitamin E and plasma vitamin C had no significant association with either maximal carotid or femoral IMT or the mean of the carotid and femoral IMT. Conclusions . Systolic blood pressure, serum total cholesterol, age and pack-years smoked are the most important determinants of early atherosclerosis in the carotid artery and total cholesterol, age and pack-years smoked in the femoral artery. Prevention should take into consideration these findings. The role of plasma fibrinogen and oxidized low density lipoprotein would require re-evaluation in larger populations studied longitudinally.     

Serum amyloid A is independently associated with metabolic risk factors but not with early atherosclerosis: the Cardiovascular Risk in Young Finns Study

Background. Serum amyloid A (SAA) is a sensitive marker of inflammation and its elevation has been implicated in obesity and in cardiovascular disease, yet data on its regulation in young adults or on its role in early atherosclerosis is scarce. We investigated which factors explain the variation in SAA and analysed whether SAA could be associated with preclinical atherosclerosis. Methods. Serum amyloid A levels were measured in participants of the Cardiovascular Risk in Young Finns Study (n = 2280, n = 1254 women, n = 1026 men). Correlates and determinants of SAA were analysed and the effect of SAA on subclinical atherosclerosis, measured as intima‐media thickness (IMT) and carotid artery compliance, was evaluated with risk‐factor adjusted models. Results. Serum amyloid A correlated directly and independently of BMI with C‐reactive protein (CRP), waist circumference and leptin in both sexes, with total cholesterol, LDL cholesterol and ApolipoproteinA1 (ApoA1) in women and with triglycerides, insulin levels and insulin resistance in men. Use of combined oral contraceptives and intrauterine device was also associated with SAA levels. Determinants for SAA included CRP, leptin and ApoA1 in women, and CRP, leptin and HDL cholesterol in men. SAA levels correlated with carotid compliance in both sexes and with IMT in men, yet SAA had no independent effect on IMT or carotid compliance in multivariable analysis. Conclusions. Serum amyloid A was associated with several metabolic risk factors but was not an independent predictor of IMT or carotid artery compliance. Further longitudinal studies will show whether SAA holds a prognostic value as a risk marker, analogously to CRP.     

Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes

Aims/hypothesis Intima media thickness (IMT) of the common carotid artery (CCA) is a validated surrogate marker of early atherosclerosis. The aim of our study was to assess the association between IMT in CCA and long-term mean HbA₁c in type 1 diabetes. We also elucidated the association between carotid IMT and preclinical coronary atherosclerosis.Methods In 39 individuals with type 1 diabetes, HbA₁c was measured prospectively over 18 years. The IMT examinations were performed with high-resolution ultrasound. The association between carotid IMT and preclinical coronary atherosclerosis (assessed by intravascular ultrasound [IVUS]) was tested in 29 of the patients.Results Mean HbA₁c over 18 years was 8.2% (range: 6.6–11.3%). Mean age at follow-up after 18 years was 43 years and mean duration of diabetes was 30 years. IMT was significantly higher in diabetic patients than in an age- and sex-matched reference population. The IMT values were at the same level as for controls who were 20 years older. In women, HbA₁c was significantly associated with mean average CCA IMT (r²=0.77, p<0.0001 when adjusted for age), whereas there was no significant association for men. Among women, a significant association was also found between carotid IMT and the percentage of coronary vessel area stenosis (r=0.65, p=0.03).Conclusions/interpretation The present findings suggest an important role of long-term hyperglycaemia in the development of atherosclerosis, especially in women with type 1 diabetes.Type 1 diabetes patients have earlier development of, and more advanced, atherosclerosis compared with an age- and sex-matched reference population. In women, carotid IMT reflects preclinical coronary atherosclerosis.     

Measuring Effects on Intima Media Thickness: An Evaluation of Rosuvastatin in Subclinical Atherosclerosis—The Rationale and Methodology of the METEOR Study

BACKGROUND: Increased carotid intima media thickness (IMT) is associated with established coronary heart disease (CHD) and is a marker of atherosclerosis. Statins are an effective treatment for dyslipidaemia, and have been shown to retard progression or promote carotid IMT regression in patients at high risk of CHD. Rosuvastatin is a highly efficacious statin, and the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) study is designed to assess the impact of rosuvastatin on carotid IMT progression in low risk subjects with signs of subclinical atherosclerosis. METHODS: In this randomised, parallel-group study, asymptomatic subjects at low risk of cardiovascular disease, but with evidence of atherosclerosis (defined as carotid IMT >or=1.2 mm and <3.5 mm), will receive rosuvastatin (40 mg/day) or placebo for 104 weeks. The study will enrol 840 European and US subjects randomised 5:2 between rosuvastatin and placebo. The primary end point will be the change in carotid IMT from baseline to study end, measured using B-mode ultrasonography. Other efficacy end points include changes in the serum lipid profile and C-reactive protein. Safety parameters will also be assessed. CONCLUSION: The METEOR study will evaluate whether long-term rosuvastatin treatment promotes regression, or slows progression, of subclinical atherosclerosis in asymptomatic subjects at low risk of cardiovascular disease.     

Ultrasound screening of multifocal atherosclerosis: markers for coronary heart disease

Background and Objective The frequency of multifocal atherosclerosis (MFA) in patients with coronary heart disease (CHD) has not been thoroughly studied. The purpose of our study was to perform ultrasound screening for MFA in patients with coronary atherosclerosis and make evaluation of the sensitivity and significance of different atherosclerosis markers. Methods Using Color Dupplex Ultrasound (CDU), we studied 32 clinically healthy persons and 87 patients of the city of B with clinical data for CHD where we also performed coronarography. Results In patients with coronary atherosclerosis we found high frequency of carotid atherosclerosis (93%) and peripheral artery disease (PAD) (81%). We established verifiable thickening of the intima-media (IMT) of the common carotid artery (CCA) and common femoral artery (CFA) in patients with CHD. There is a correlation between the frequency of carotid and femoral stenoses and CHD proven by coronarography. Patients with CHD had a high relative risk to develop carotid (RR = 5) and peripheral atherosclerosis (RR=3.5) and high frequency of asymptomatic stenoses and thromboses of the internal carotid artery (86.9%) and femoral artery (78.3%), as well as aneurisms of the abdominal aorta (8.1%). Markers for CAD with high sensitivity were the atherosclerotic plaques of ICA (0.93) and CFA (0.81) as well as IMT of the CFA (0.84). Conclusions MFA are common among patients with CHD. Ultrasound diagnosis is the method of choice for simultaneous non-invasive screening of carotid, peripheral and MFA and provides sensitive markers for coronary atherosclerosis. The most sensitive and specific markers for CHD are the combination of the IMT and atherosclerotic plaques of CCA, ICA and CFA (100% sensitivity and 0.92 specificity).     

Relation between insulin resistance and carotid intima‐media thickness and stenosis in non‐diabetic subjects. Results from a cross‐sectional study in Malmö, Sweden

Aims To assess whether there is an association between insulin resistance and carotid intima‐media thickness and stenosis in non‐diabetic subjects free from symptomatic cardiovascular disease. Methods A cross‐sectional population‐based study in Malmö, Sweden, of 4816 (40% men) subjects, born 1926–1945. The prevalence of insulin resistance was established by the homeostasis model assessment (HOMA) and defined as values above the 75th percentile. Criteria issued by the European Group for the Study of Insulin Resistance (EGIR) were used for the definition of the insulin resistance syndrome. Common carotid artery intima‐media thickness (IMT) and carotid stenosis (> 15%) were measured by B‐mode ultrasonography. Results Age and sex‐adjusted common carotid IMT among subjects with the insulin resistance syndrome (12.7%) and controls was 0.812 mm, respectively, 0.778 mm (P < 0.001). The prevalence of stenosis in the two groups was 22.9 and 19.2% (P = 0.040). Insulin resistance per se was after adjustment for age and sex associated with increased IMT (0.780 mm vs. 0.754 mm, P < 0.001). This association disappeared, however, when other factors included in the insulin resistance syndrome were taken into account. Conclusions Fasting serum insulin covaries with a number of factors and conditions known to influence the development of atherosclerosis. It is concluded that the association between insulin resistance, as assessed by the HOMA method in non‐diabetic subjects, and atherosclerosis is explained by its covariance with established risk factors for cardiovascular disease of which hypertension seems to be the most significant.     

Dissociation between microalbuminuria and common carotid thickness in essential hypertensive men

BACKGROUND: The reasons why microalbuminuria (albuminuria > or = 15 microg/min), an expression of a renal microcirculatory abnormality, predicts cardiovascular disease in essential hypertension are unsettled. To test the hypothesis that microalbuminuria represents a marker of subclinical atherosclerosis, we evaluated its association with common carotid artery (CCA) intima media thickness (IMT), a measure of preclinical atherosclerosis and an independent predictor of cardiac and cerebrovascular events, in uncomplicated essential hypertensive individuals. MATERIALS AND METHODS: Albuminuria, ultrasonographic CCA IMT (the mean of six bilateral far wall measurements within 1.5 cm proximally to the flow divider), brachial blood pressure (BP), smoking habits and lipids were evaluated in 136 stage 1-3 untreated essential hypertensive men free of cardiovascular disease. RESULTS: CCA IMT did not differ between normo- (n = 99) and microalbuminuric (n = 37) patients. The correlation between CCA IMT and albuminuria was not significant, and the prevalence of microalbuminuria across IMT quartiles was not different. Microalbuminuric patients showed higher systolic BP and that parameter was the only independent correlate in a multivariate logistic regression model including also age, CCA IMT, diastolic BP, lipids and smoking habits as independent variables and microalbuminuria as the dependent one. CONCLUSION: This cross-sectional study in hypertensive subjects free of cardiovascular disease has shown a dissociation between microalbuminuria and CCA IMT, a surrogate measure of subclinical atherosclerosis, and a parameter linearly related to cardiovascular events. The data do not support the theory of microalbuminuria as a surrogate measure of subclinical atherosclerosis, while confirming the importance of systolic BP levels as an independent correlate of increased albuminuria in essential hypertension. Journal of Human Hypertension (2000) 14, 831-835     

Rosiglitazone and carotid IMT progression rate in a mixed cohort of patients with type 2 diabetes and the insulin resistance syndrome: main results from the Rosiglitazone Atherosclerosis Study

Objective. Insulin resistance is associated with progression of atherosclerosis. We assessed the effect of 12 months of treatment with rosiglitazone (RSG) on the progression of carotid intima–media thickness (IMT) in people with type 2 diabetes mellitus (T2DM) or the insulin resistance syndrome (IRS). Design. Randomized, double-blind, placebo-controlled trial. Setting. Malmö University Hospital, Malmö, Sweden. Subjects. 555 subjects (200 with T2DM and 355 nondiabetics with IRS according to EGIR criteria), aged 35–80 years. 447 subjects (165 T2DM and 282 IRS) completed the study. Intervention. Participants were allocated to placebo or RSG 4 mg for 2 months and then 8 mg daily. Main outcome measure. Change in composite IMT [mean IMT in the common carotid artery (CCA) and maximal IMT in the bulb] was the primary and various other IMT measures were secondary outcome variables. Results. There was no effect of RSG treatment in the mixed population. In T2DM patients there was a reduced progression of the composite IMT (mean change: 0.041 vs. 0.070 mm, P = 0.07), and of the mean IMT CCA (mean change: −0.005 mm vs. 0.021 mm, P = 0.007). RSG treatment led to significant reductions of HOMA-IR, fasting plasma glucose, HbA1c, PAI-1 activity, fibrinogen, C-reactive protein and matrix metalloproteinase-9. Conclusions. In a mixed study population of patients with T2DM and IRS RSG treatment was not associated with a statistically significant reduction of carotid IMT progression rate. Separate analyses of these two patient groups indicated, however, a significant beneficial effect on CCA IMT in T2DM patients but no similar effect in subjects with IRS.     

Relationship of QT interval duration with carotid intima media thickness in a clinically healthy population undergoing cardiovascular risk screening

OBJECTIVES: To investigate the relationship between cardiac repolarization (QT interval duration) and intima media thickness (IMT) of the carotid arteries as surrogate measures of subclinical atherosclerosis. DESIGN: Prospective study with consecutive subjects enrolled in the SAPHIR program (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk). SETTING: The analysis of the material was performed at the departments of medicine and neurology of a university hospital. SUBJECTS: The study cohort comprises a population-based sample of 1199 clinically healthy subjects (851 men and 348 women; age 39-66 years). Exclusion criteria were cardiovascular disease, diabetes, atrial fibrillation, bundle branch block and use of medication affecting QT interval duration. MAIN OUTCOME MEASURES: IMT of common (CCA) and internal carotid arteries (ICA) was measured by B-mode ultrasound. QT interval duration was determined in the resting 12-lead electrocardiogram by an automatic analysis program. The QT intervals were corrected for heart rate with five standard equations (QTc-Bazett, -Fridericia, -Framingham, -Hodges and -Rautaharju) and tested for their relationship with carotid IMT after adjustment for clinical and metabolic variables. Results. Females had higher heart rates than males (64 +/- 10 b min(-1) vs. 60 +/- 9 b min(-1), P <0.0005), with longer mean QT (410 +/- 28 ms vs. 404 +/- 28 ms, P=0.003) and QTc intervals in all correction formulae (P <0.0005). Significant correlations between QT/QTc and ICA IMT (r=0.14-0.16) were found in males. In the general linear model the association between QTc (except for Bazett) and ICA IMT remained significant after adjusting for age, BMI and further cardiovascular risk factors. In females the crude correlations between QT/QTc and ICA IMT were lower than those with CCA IMT. Only the correlation between uncorrected QT and CCA IMT (r=0.15, P=0.006) remained significant after adjustment for covariates. CONCLUSIONS: The results of the present study demonstrate that QT and QTc prolongation are in part associated with IMT of carotid arteries, which is an established risk marker of subclinical atherosclerosis. In men the data support the hypothesis of an association between QTc and ICA IMT. In women a statistically significant relationship was found between the uncorrected QT interval and CCA IMT. These findings suggest that differences in carotid IMT and ventricular repolarization between genders might be related to hormonal and nonhormonal effects.     

Cardiorespiratory fitness and the progression of carotid atherosclerosis in middle-aged men

BACKGROUND: Good cardiorespiratory fitness has been associated with reduced risk for clinical events of atherosclerotic vascular diseases, but whether it is related to slower progression of early atherosclerosis is unclear. OBJECTIVE: To study the association between cardiorespiratory fitness and the progression of early carotid atherosclerosis. DESIGN: 4-year follow-up study. SETTING: Eastem Finland. PARTICIPANTS: Population-based sample of 854 men 42 to 60 years of age. MEASUREMENTS: Maximal oxygen uptake (VO2max [mL/kg per minute]) was measured directly by using respiratory gas exchange in a cycle ergometer exercise test. Carotid atherosclerosis was assessed by using B-mode ultrasonography. RESULTS: After adjustments for age, technical covariates, and cigarette smoking, VO2max had strong, inverse, and graded associations with 4-year increases in maximal intima-media thickness (IMT) (standardized regression coefficient beta = -0.120; P = 0.002), plaque height (beta = -0.140; P < 0.001), surface roughness (beta = -0.147; P < 0.001), and mean IMT (beta = -0.080; P = 0.035). These associations weakened but remained statistically significant after additional adjustment for systolic blood pressure, serum levels of apolipoprotein B, diabetes, and plasma fibrinogen levels. The increases in maximal IMT, surface roughness, and mean IMT (23%, 31%, and 100%, respectively) were larger among men in the lowest quartile of VO2max (<26.1 mL/kg per minute) than among those in the highest quartile (>36.2 mL/kg per minute). CONCLUSIONS: Good cardiorespiratory fitness is associated with slower progression of early atherosclerosis in middle-aged men. These findings are important because they emphasize that middle-aged men can be evaluated for cardiorespiratory fitness to estimate their future risk for atherosclerotic vascular diseases. Additional research is warranted to investigate a possible causal relationship between cardiorespiratory fitness and atherosclerosis.