Carotid intima-media thickness (cIMT): a useful clinic tool or research luxury? Another view of the ENHANCE trial.

The ENHANCE trial was the first trial of ezetimibe- simvastatin with a surrogate marker as a primary endpoint. The combination of the 2 drugs is highly effective in reducing total cholesterol and low-density lipoprotein cholesterol levels and with a positive profile on high-density lipoprotein cholesterol. However, there are no data as yet about the clinical effectiveness of the addition of ezetimibe on statin therapy and whether this provides a further reduction of cardiovascular events. The answer to the clinical hard endpoints question will be provided in 2012 by the IMPROVE-IT trial comparing the effectiveness of simvastatin 40 mg plus ezetimibe versus simvastatin 40 mg on 18,000 acute coronary syndrome patients. The ENHANCE study failed in its primary endpoint, carotid intima-media thickness reduction, but has various methodological weaknesses that makes it very difficult to accept the American College of Cardiology statement that ezetimibe should be the last resort after trying all other available treatments.

The controversial role of serum uric acid in essential hypertension: relationships with indices of target organ damage.

The role of serum uric acid (SUA) in the context of adverse cardiovascular events in hypertensive subjects is controversial. Additionally, the relationship between SUA and indices of target organ damage is not well defined in this setting. Towards this end, we studied 842 consecutive nondiabetic patients with stage I-II essential hypertension (office blood pressure=148/95 mmHg, aged 53.4 years), referred to our outpatient hypertensive unit within a period of 4 years. According to the urinary albumin excretion (UAE), the study population was classified into those with microalbuminuria [MA(+), UAE=20-200 mg/24 h, n=222] and those without MA [MA (-), UAE< 20 mg/24 h, n=620]. Moreover, according to the presence of left ventricular hypertrophy (LVH) the participants were subdivided into two additional groups: [LVH (+), n=305 and LVH (-), n=537]. SUA levels were higher by 0.4 mg/dl, (P=0.04) in group MA (+) compared with the group MA (-), while no difference was observed between groups LVH (+) and LVH (-) (P=NS). In the entire population, SUA was correlated with body mass index (BMI) (r=0.17, P<0.001), waist/hip ratio (r=0.3, P<0.001), office systolic blood pressure (SBP) (r=0.14, P<0.05), triglycerides levels (r=0.25, P<0.001), UAE (r=0.35, P<0.001) and HDL (r=-0.26, P<0.001). Multiple regression analysis demonstrated that SUA was significantly related with BMI, office SBP and UAE (P<0.05). In conclusion, increased SUA levels are associated with MA but not with LVH in essential hypertensive subjects. Whether these inter-relationships may elucidate the clinical positioning of augmented SUA in this setting remains to be clarified in future studies.

Effect of angiotensin-converting enzyme inhibitor on collagenolytic enzyme activity in patients with acute myocardial infarction.

Matrix metalloproteinases and their tissue inhibitors are key enzymes degrading myocardial collagen in acute myocardial infarction (AMI). The aim of the present study was to determine whether angiotensin-converting enzyme inhibitors (ACEI) influence collagenase-1 (MMP-1) and their tissue inhibitor (TIMP-1) activity in AMI patients. Plasma levels of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex were measured in 24 patients (aged 58.4 +/- 13.9 years) with AMI. Thirteen patients received perindopril 4 mg/day (group A) and 11 did not (group B). Plasma samples collected on admission and at 0, 3, 6, 9, 12, 18, 24, 36 and 48 hours and on days 3, 4, 5, 7, 15 and 30 thereafter were analyzed by relevant ELISA kits. Ejection fraction (EF) was assessed by ventriculography and end-diastolic diameter (EDD) echo-study on days 6 and 30. Values of collagenolytic enzymes of group A compared with those in group B were on average lower by 34%, 18.3% and 40%, respectively. The difference in values between groups at 0 h, 3 h and 9 h was significant (p < 0.048). ANOVA repeated measurement analysis showed significance within subjects for MMP-1 alone (p < 0.043) and for MMP-1 and ACEI (p < 0.046), while for TIMP-1 and MMP-1/TIMP-1 complex significance was only p < 0.0009. Regarding EDD changes, patients in group A showed minimal or no changes (51.23 +/- 1.8 mm to 51.6 +/- 2.13 mm), their EF was 38.8% and infarct size was medium to large. In contrast, group B showed a trend to increase EDD (41 +/- 0.78 mm to 42.33 +/- 0.59 mm), their EF was 50.5% and infarct size was small to medium. In conclusion, early initiation of ACEI treatment reduces collagenolytic activity. This effect may be considered an alternative mechanism for beneficial effects on postinfarction remodeling.

Vascular endothelium and inflammatory process, in patients with combined Type 2 diabetes mellitus and coronary atherosclerosis: the effects of vitamin C.

AIMS: Type 2 diabetes mellitus (DM) and coronary artery disease (CAD) are both associated with endothelial dysfunction and elevated oxidative and inflammatory state. We examined the effect of vitamin C on endothelial function and levels of soluble vascular cell adhesion molecule (sVCAM-1), interleukin-6 (IL-6) and tumour necrosis factor (TNF-alpha), in DM patients with or without CAD and in non-diabetic subjects. METHODS: Thirty-seven patients with DM + CAD, 17 patients with DM without CAD and 21 non-diabetic subjects were divided into groups receiving vitamin C 2 g/day or no anti-oxidant for 4 weeks. Forearm blood flow was determined using venous occlusion gauge-strain plethysmography. Forearm vasodilatory response to reactive hyperemia was considered as index of endothelium-dependent dilation. RESULTS: Baseline levels of IL-6 and TNF-alpha were significantly higher in patients with DM + CAD compared with patients with DM (P < 0.01) or non-diabetic subjects (P < 0.01). IL-6 and TNF-alpha levels were also higher in DM compared with non-diabetic subjects (P < 0.05). sVCAM-1 levels were lower in non-diabetic controls compared with DM + CAD (P < 0.05) or DM (P < 0.05). Reactive hyperaemia was higher in non-diabetic controls compared with DM + CAD (P < 0.001) or DM (P < 0.001). Vitamin C significantly increased reactive hyperaemia only in the DM + CAD group, while it had no effect on serum levels of sVCAM-1, TNF-alpha and IL-6 in any of the groups. CONCLUSIONS: Type 2 diabetes mellitus is associated with impaired endothelial function and increased levels of TNF-alpha, IL-6 and sVCAM-1, especially in patients with DM and CAD. Vitamin C significantly increased forearm vasodilatory response to reactive hyperaemia only in patients with combined DM and CAD.

Obesity in byzantine and in modern era from a public health perspective.

Obesity is one of today's most serious and amplified public health problems. Surprisingly, obesity constituted a health problem through the Byzantine Empire (3rd to 15th century AD) as well; the extent of the problem was then very much alike to that one seen in modem industrialized and developing countries of today. In this report we perform an historical throwback in Byzantine years in order to explore the link regarding the aspects of obesity in these years and in modem era.

FH-Pyrgos: a novel mutation in the promoter (-45delT) of the low-density lipoprotein receptor gene associated with familial hypercholesterolemia.

In a patient with familial hypercholesterolemia (FH), we have identified a new mutation (-45delT) in repeat 3 of the low-density lipoprotein receptor (LDLR) gene promoter. Analysis of a neutral polymorphism in the LDLR mRNA from the patient's white blood cells showed that the expression of one allele was significantly reduced, and cells have only 24% of LDLR activity by binding and uptake of DiI-LDL. Transient transfection studies using a luciferase gene reporter revealed that the -45delT mutation considerably reduces the transcriptional activity of the LDLR promoter and strongly suggest that the mutation is the cause of the FH phenotype.

Inflammatory and thrombotic mechanisms in coronary atherosclerosis.

Many molecular and cellular mechanisms link inflammation and haemostatic mechanisms. Inflammation, and perhaps chronic infection, may play important roles in the initiation and progression of atherosclerosis. Atherosclerotic lesions are heavily infiltrated by cellular components associated with inflammation (macrophages and T lymphocytes), and acute plaque rupture is also associated with inflammatory components. Several markers of systemic inflammation may predict future cardiovascular events in apparently healthy subjects as well as in patients with chronic and acute syndromes. There may thus be therapeutic potential in modifying the atherosclerotic, vasomotor, and thrombotic components of ischaemic heart disease.

Common pathways for primary hypertrophic and dilated cardiomyopathy.

Testing the hypothesis that hypertrophic and dilated cardiomyopathy as well as viral myocarditis share a common mitogenic growth response pathway with mitotically competent cell types are the aims of this study. The expression of the c-fos, H-ras and c-myc genes was immunohistochemically determined in biopsies from 12 patients with dilated cardiomyopathy, 24 patients with hypertrophic cardiomyopathy, and 4 patients with myocarditis. Normal myocardium from 9 subjects was used as the control group. Staining results were correlated with patient's demographic data. C-fos, H-ras and c-myc protein overexpression was seen in 15 patients (62.5%) with primary hypertrophic and 4 patients (33.3%) with dilated cardiomyopathy. The majority of hypertrophic and dilated cardiomyopathy patients expressed at least one of the genes studied compared with the control group (p = 0.006). Primary cardiomyopathy patients also showed a statistically significant difference in the gene co-expression compared with the control group (p = 0.042). C-fos, H-ras, and C-myc protein expression did not differ substantially between patients with hypertrophic and dilated cardiomyopathy. Patients with myocarditis expressed only the C-fos protein (n = 2, 50%). C-fos, h-ras and c-myc genes are overexpressed in patients with cardiac hypertrophy and cardiac dilation. Cardiac myocytes respond to biomechanical stress by initiating several different processes. One of them is oncogene expression. This results in a hypertrophy of the myocytes proportional in length and width (hypertrophic cardiomyopathy or with a relatively greater increase in length than in the width (dilated cardiomyopathy).

Effects of L-arginine on flow mediated dilatation induced by atrial pacing in diseased epicardial coronary arteries.

OBJECTIVE: To examine the effects of L-arginine on basal coronary tone and flow mediated dilatation induced by atrial pacing in patients with coronary artery disease and stable angina. DESIGN: Atrial pacing was performed during intracoronary infusions of normal saline and L-arginine (150 micromol/min) in 8 patients with coronary artery disease and stable angina. The luminal diameter of epicardial coronary arteries was assessed by quantitative angiography. RESULTS: L-arginine administration significantly increased the diameter of all the coronary segments and stenoses. During atrial pacing with saline infusion, luminal diameter of the proximal, distal, and stenosis reference segments increased significantly (p < 0.01 versus saline) but stenosis diameter did not change. L-arginine administration did not change the magnitude (NS) of atrial pacing induced dilatation in proximal and distal segments and in coronary stenoses and their reference segments. CONCLUSIONS: Non-stenotic segments of diseased coronary arteries dilate in response to atrial pacing but stenoses do not. L-arginine dilates coronary segments and stenoses but does not increase the magnitude of the response to atrial pacing in proximal and distal segments and in coronary stenoses and their reference segments. These findings provide evidence that the shear stress responsive mechanism is absent at stenoses but present in non-stenotic segments of diseased coronary arteries. They also indicate a relative deficiency of L-arginine, except in the shear response mechanism.

The association between occupational stress and the risk of developing acute coronary syndromes: the CARDIO2000 Study.

OBJECTIVE: The aim of this study was to investigate the association between occupational stress and the risk of developing acute coronary syndromes, in a population-based sample of patients and controls. METHODOLOGY: During 2000-01, a case-control study was conducted (CARDIO2000). A random and stratified sample of 848 middle aged patients with a first of an acute coronary syndrome and 1078 cardiovascular disease free participants, matched with the patients by gender, age and region, was selected from all regions of Greece. In addition to the common cardiovascular risk factors, the effect of occupational stress on coronary risk was evaluated, after taking into account income, marital status, educational and occupational level of the participants. The levels of occupational stress were measured by administering to the individuals a self-reported questionnaire. RESULTS: After controlling for age, gender and region, by design, and the presence of smoking, hypertension, hypercholesterolaemia, diabetes mellitus, physical activity status, educational and financial status and nutritional habits, multivariate analysis showed that the levels of occupational stress are positively associated with the risk of developing acute coronary syndromes in the investigated sample (Odds Ratio = 2.2, p < 0.01). Moreover, the presence of occupational stress seems to affect more significantly males than females, smokers than non-smokers, hypertensives than normotensives and high alcohol consumers compared to low alcohol consumers. CONCLUSIONS: Although the design of the present study does not provide evidence of causality, a strong positive association between occupational stress and acute coronary syndromes seems to exist. Thus, public health policies should take into account lifestyle conditions related to work in the design of preventive strategies at the primary level.

Plasma levels of active extracellular matrix metalloproteinases 2 and 9 in patients with essential hypertension before and after antihypertensive treatment.

This study was designed to test the hypothesis that plasma concentrations of matrix metallo-proteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two enzymes that share similar substrate specificity (collagen type IV and V), possibly related to vascular remodelling, are altered in essential hypertension. The second aim of the study was to assess whether chronic antihypertensive treatment with the calcium channel blocker amlodipine would normalize these alterations. To test this hypothesis, we measured plasma concentrations of active MMP-2 and MMP-9 in 42 patients with never-treated essential hypertension and in 25 normotensive control subjects. Measurements were repeated after 6 months of treatment with the calcium channel blocker amlodipine. Baseline values of MMP-2 and MMP-9 were decreased (P=0.01 and 0.002, respectively) in hypertensive patients compared with normotensives. Hypertensive patients with systemic vascular resistances <1440 dyn s/cm(5) exhibited higher values of MMP-2 (P=0.005) and MMP-9 (P=0.001) than hypertensive patients with systemic vascular resistances >1440 dyn s/cm(5). Treated patients attained a nonsignificant increase in MMP-2 plasma concentrations, but a significant increase in MMP-9 plasma concentrations (P=0.01) compared to respective values before treatment. In conclusion, these findings suggest that plasma concentrations of active MMP-2 and MMP-9, mainly related to vascular extracellular matrix metabolism, are depressed in patients with essential hypertension. A 6 month treatment with amlodipine can normalize MMP-9 but not MMP-2 plasma concentrations. The hypothesis that antihypertensive treatment may modulate collagen metabolism remains to be determined by further studies.

Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques.

AIMS: Heat released from atherosclerotic plaques as a result of the local inflammatory process, may be measured in vivo by a thermography catheter. Statins seem to have an antiinflammatory effect which results in plaque stabilization. The aim of this study was to investigate the effect of statins on plaque temperature. METHODS AND RESULTS: The study population included 72 patients: 21 with effort angina, 32 with unstable angina and 19 with acute myocardial infarction. In the study group, 37 patients received statins for more than 4 weeks and 35 were not receiving statins. We measured the temperature difference (deltaT) between the atherosclerotic plaque and the proximal vessel wall (background temperature) using a thermography catheter. The statistical analysis showed that the mean value of deltaT was higher in the untreated group compared to the treated-with-statin, group (0.56+/-0.41 vs 0.29+/-0.33 degrees C, P<0.01). Moreover, a progressive increase in deltaT by type of clinical syndrome was observed in both groups (statin group; effort angina: 0.24+/-0.15, unstable angina: 0.26+/-0.26, acute myocardial infarction: 0.40+/-0.28, vs untreated group; effort angina: 0.41+/-0.26, unstable angina: 0.44+/-0.28, acute myocardial infarction: 0.84+/-0.52, P<0.05). Multivariate analysis showed that treatment with statins was an independent factor in temperature variation, after taking into account the effect of the clinical syndrome (P<0.05). CONCLUSIONS: Patients on statin treatment produce less heat from the culprit coronary lesion than those not treated. Thus, statins seem to have a favourable effect on heat release from atherosclerotic plaques, and whether this effect has an impact on plaque stabilization needs to be investigated in future studies.

Association between exposure to environmental tobacco smoke and the development of acute coronary syndromes: the CARDIO2000 case-control study.

OBJECTIVE: To investigate the association between environmental tobacco smoke (ETS) exposure (at least 30 minutes a day) and the risk of developing acute coronary syndromes (ACS). DESIGN AND SETTING: The CARDIO2000 is a case-control study which was conducted in Greece from 2000 to 2001. Cases included 847 individuals with a first event of ACS and 1078 cardiovascular disease-free controls. Cases and controls were frequency matched on age (within three years of age), sex, and region. MAIN OUTCOME MEASURES: ACS was defined as a diagnosis of first acute myocardial infarction or unstable angina. Main independent variable: Exposure to ETS was measured by self report as follows: after the second day of hospitalisation for the cases, and at the entry for the controls, participants were asked whether they were currently exposed to tobacco smoke from other people (home and/or work) for more than 30 minutes a day. The responses were categorised into three levels: no exposure, occasional exposure (< 3 times per week), and regular exposure. In addition participants were asked how many years they had been exposed. Because these were self reported assessments and prone to bias, the results were compared to reports obtained from subjects' relatives or friends, using the Kendal's tau coefficient that showed high agreement. RESULTS: 731 (86%) of the patients and 605 (56%) of the controls reported current exposure of 30 minutes per day or more to ETS. Among current non-smokers, cases were 47% more likely to report regular exposure to ETS (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.26 to 1.80) compared to controls. Exposure to ETS at work was associated with a greater risk of ACS compared to home exposure (+97% v +33%). The risk of ACS was also raised in active smokers (OR 2.83, 95% CI 2.07 to 3.31) regularly exposed to ETS. CONCLUSIONS: This study supports the hypothesis that exposure to ETS increases the risk of developing ACS. The consistency of these findings with the existing totality of evidence presented in the literature supports the role of ETS in the aetiology of ACS.

The role of traditional mediterranean type of diet and lifestyle, in the development of acute coronary syndromes: preliminary results from CARDIO 2000 study.

The traditional Mediterranean type of diet is inversely associated with the risk of developing coronary heart disease. Aim of this study is to investigate the relationships between Mediterranean type of diet, various lifestyle factors and their contribution to the risk of developing acute coronary syndromes. During 2000, a case-control study was conducted (CARDIO2000) and food items as well as olive oil consumption were recorded in addition to various cardiovascular risk factors. Based on the estimated risk model we found that the Mediterranean type of diet reduces significantly the risk of developing acute coronary syndromes even in the presence of unfavorable lifestyle situations, such as sedentary life, smoking habit, as well as hypertension, hypercholesterolemia and diabetes mellitus.

The effect of the combination of Mediterranean diet and leisure time physical activity on the risk of developing acute coronary syndromes, in hypertensive subjects.

The World Health Organization reports that the number of hypertensives, worldwide, is estimated to be 600 million people. In addition a considerable proportion of hypertensive subjects remains untreated or uncontrolled. In this work we investigated the combined effect of physical activity and Mediterranean diet on coronary risk, in hypertensives. Thus we randomly selected, from all Greek regions, 848 hospitalised patients (695 males, 58 +/- 10 years old and 153 females, 65 +/- 9 years old) with a first event of coronary heart disease (CHD) and 1078 paired, by sex, age, region controls, without any suspicions for CHD. Physically active were those who reported non-occupational physical activity more than once per week. Subjects 'closer' to the Mediterranean diet were assessed through a special nutrient questionnaire. A total of 418 (49%) of the patients and 303 (28%) of the controls were hypertensive. Of these, 115 (27%) patients and 70 (23%) controls were untreated, 148 (35%)-111 (36%) were uncontrolled and 155 (38%)-122 (41%) were controlled (P-value <0.01). One hundred and sixty-two (19%) of the patients and 265 (25%) of the controls (P < 0.01) were 'closer' to the combination of Mediterranean type of diet and physical activity. The analysis showed that the previous combination is related to a 25% reduction of the coronary risk in controlled hypertensive subjects (OR = 0.75, P < 0.01), a 11% reduction in untreated (OR = 0.89, P < 0.05) and 17% reduction (OR = 0.83, P < 0.05) in uncontrolled, after adjusting for age, sex, educational and financial level and the conventional cardiovascular risk factors. Consequently, the adoption of Mediterranean diet by physically active subjects seems to reduce significantly the coronary risk and prevent, approximately, the one-third of acute CHD, in controlled hypertensive subjects.