Aortic Intima-Media Thickness and Mean Platelet Volume in Children With Type 1 Diabetes Mellitus

Background: Diabetes mellitus type 1 is the most common endocrine metabolic disorder occurring in childhood and adolescence due to the autoimmune destruction of pancreatic beta cells as a result of various environmental factors interacting with an underlying genetic predisposition. Diabetes is a risk factor for early onset atherosclerosis, and the high mortality rate seen in these patients is partially related to cardiovascular diseases. Objectives: This study was conducted to compare mean platelet volume as a marker of early atherosclerosis with aortic intima-media thickness in children with type 1 diabetes and to identify its correlation with known cardiovascular risk factors. Patients and Methods: The study included 27 patients between age range of 6 and 17 years that were diagnosed with type 1 diabetes and 30 healthy children of the same age range who did not have any chronic disease. In both groups, we used the color Doppler ultrasound to measure children’s aortic intima-media thickness and identify their mean platelet volumes. Results: There was no significant difference between the groups regarding gender distribution, age, High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL) cholesterol levels (P > 0.05). Also no significant difference could be documented between the patient and control groups regarding the aortic intima-media thickness and mean platelet volume (P > 0.05). However, there was a significant correlation between aortic intima-media thickness and mean platelet volume (r = 0.351; P < 0.05). Conclusions: In the present study, there was no evidence of early atherosclerosis in children with type 1 diabetes. However, mean platelet volume having a significant correlation with aortic intima-media thickness may be useful as an early marker of atherosclerosis.

Valutazione dello spessore intima-media carotideo come fattore di rischio cardiovascolare nei pazienti affetti da psoriasi moderato-severa

Evaluation of carotid artery intima-media thickness in patients affected by psoriasis Psoriasis is associated with an increased risk of atherosclerosis. This study compared subclinical atherosclerosis, evaluating intima-media thickness the of the carotid in psoriasis vulgaris patients and healthy controls using high-resolution ultrasonography and the correlation of this parameter with other cardiovascular risk factors, like insulin resistance and dyslipidemia, METHODS: We will study 40 psoriasis patients, asymptomatic for cardiovascular diseases, and 40 healthy controls matched for age and sex. Intima-media thickness of the common carotid arteries will be measured ultrasonographically. Diabetes mellitus, hypertension, renal failure, a history of cardiovascular or cerebrovascular disease will be exclusion criteria. Subjects who are receiving lipid-lowering therapy, antihypertensive or anti-aggregant drugs, nitrates or long-term systemic steroids will be also excluded. Objective of this study is the evaluation of carotid artery intima-media thickness and its correlation with other blood cardiovascular risk factors in patients affected by psoriasis but asinptomatic for coronary comparing this data with the healthy control subjects. Considering that the presence of psoriasis is an independent risk factor for subclinical atherosclerosis, we want to consider this method of evaluation of cardiovascular risk and to control this risk to prevent IMA.

Relação entre biomarcadores inflamatórios e espessamento da intima-média carotídea em crianças obesas pré-púberes

A exposição precoce a fatores de risco cardiovascular gera estado inflamatório crônico, podendo causar dano da função endotelial, seguido de espessamento da íntima-média carotídea. O objetivo desta pesquisa foi estudar a espessura íntima-média carotídea e seu comportamento em relação aos fatores e biomarcadores de risco cardiovascular em crianças com excesso de peso pré-púberes. Realizou-se estudo transversal com 80 obesos, 18 com sobrepeso e 31 eutróficos do Ambulatório de Pediatria do Hospital Universitário Pedro Ernesto da Universidade do Estado do Rio de Janeiro. Avaliou-se, através de comparação de médias, medianas e frequências, o comportamento dos fatores de risco e da espessura íntima-média carotídea entre os sexos; entre obesos, com sobrepeso e eutróficos; entre resistentes e não resistentes à insulina. Avaliou-se, através de análise de regressão logística bivariada e multivariada, associação entre os fatores de risco e espessamento de íntima-média carotídea. Houve diferença estatisticamente significativa das médias e medianas de escore Z de índice de massa corpórea (p-valor=0,02), pressão arterial sistólica (p-valor=0,04) e adiponectina (p-valor=0,02) entre sexos; de circunferência da cintura (p-valor=0,0001), pressão arterial sistólica (p-valor=0,0001), diastólica (p-valor=0,001), homeostaticmodelacessment for insulinresitance (p-valor=0,0001), colesterol total (p-valor=0,02), HDL (p-valor=0,01), LDL (p-valor=0,03), triglicerídeos (p-valor=0,01), proteína C reativa (p-valor=0,0001), interleucina 6 (p-valor=0,02), leptina (p-valor=0,0001), espessura da íntima-média carotídea esquerda (p-valor=0,03) entre obesos, com sobrepeso e eutróficos; de escore Z de índice de massa corpórea (p-valor=0,0009), circunferência da cintura (p-valor=0,0001), pressão arterial sistólica (p-valor=0,0001), diastólica (p-valor=0,0006), colesterol total (p-valor=0,0004), triglicerídeos (p-valor=0,0002), leptina (p-valor=0,004) entre resistentes e não resistentes à insulina. Na regressão logística bivariada, escore Z de índice de massa corpórea, circunferência da cintura e pressão arterial sistólica associaram-se positivamente (p-valor<0,05) com o espessamento das carótidas direita, esquerda e com média dos valores de ambas. Na regressão logística multivariada, escore Z de índice de massa corpórea (p-valor=0,02) e pressão arterial sistólica (p-valor=0,04), associaram-se positivamente com íntima-média carotídea espessada à esquerda; níveis tensionais sistólicos (p-valor=0,01) se associaram com a média dos valores da íntima média carotídea de ambos os lados.Os achados mostram nas crianças pré-púberes com excesso de peso: que os fatores e biomarcadores de risco cardiovascular já se encontram presentes; influência de escore Z de índice de massa corpórea e níveis tensionais sistólicos sobre espessura íntima-média carotídea. A prevenção de aterosclerose deve iniciar precocemente, identificando-se e controlando-se fatores de risco cardiovascular. O pediatra deve procurar promover saúde cardiovascular da criança, prevenindo e/ou controlando obesidade, orientado prática regular de exercícios físicos e hábitos alimentares saudáveis.

The mediating role of physical inactivity on the relationship between inflammation and artery thickness in prepubertal adolescents

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Urinary albumin levels in the normal range determine arterial wall thickness in adults with Type 2 diabetes: a FIELD substudy

Aim Cardiovascular disease (CVD) rates are substantially higher among patients with Type 2 diabetes than in the general population. The objective of this study was to identify the determinants of carotid intima media thickness (IMT) in patients with Type 2 diabetes. Methods We measured the thickness of the intima media layer of the carotid artery, a strong predictor of the risk of future vascular events, in 397 Type 2 diabetic patients drawn from the Fenofibrate Intervention and Event Lowering in Diabetes study, prior to treatment allocation. Results The mean IMT was 0.78 mm [interquartile range (IQR) 0.23 mm], and the maximum IMT was 1.17 mm (IQR 0.36 mm). By multivariate analysis, age, sex, duration of diabetes, triglycerides, and total cholesterol were independently correlated with IMT, as was urine albumin-creatinine ratio (ACR) (P < 0.001). The effect of ACR on IMT was further examined by tertile. Clinically significant differences in IMT were associated with ACR > 0.65 mg/mmol, approximately one-fifth the standard clinical threshold for microalbuminuria (P < 0.01). Long-term diabetes, independent of other parameters, was associated with a 50% increase in age-related thickening. Conclusions IMT in people with Type 2 diabetes is independently and continuously related to urine albumin levels and to the duration of diabetes. These results support previous data linking urine albumin measurements within the normal range with increased ischaemic cardiac mortality in the setting of Type 2 diabetes, and strongly suggest that urine albumin levels within this range should trigger a formal evaluation for CVD.

Marqueurs de risque cardiovasculaire et intima-media carotidienne chez les patients diabétiques de type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Marqueurs de risque cardiovasculaire et intima-media carotidienne chez les patients diabétiques de type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Work Stress and Early Atherosclerosis: Do Genetic Background and Pre-Employment Risk Factors Explain Conflicting Findings?

According to the models conceptualizing work stress, increased risk of health problems arise when high job demands co-occur with low job control (the demand-control model) or the efforts invested by the employee are disproportionately high compared to the rewards received (effort-reward imbalance model). This study examined the association between work stress and early atherosclerosis with particular attention to the role of pre-employment risk factors and genetic background in this association. The subjects were young healthy adults aged 24-39 who were participating in the 21-year follow-up of the ongoing prospective "Cardiovascular Risk in Young Finns" study in 2001-2002. Work stress was evaluated with questionnaires on demand-control model and on effort-reward model. Atherosclerosis was assessed with ultrasound of carotid artery intima-media thickness (IMT). In addition, risk for enhanced atherosclerotic process was assessed by measuring with heart rate variability and heart rate. Pre-employment risk factors, measured at age 12 to 18, included such as body mass index, blood lipids, family history of coronary heart disease, and parental socioeconomic position. Variants of the neuregulin-1 were determined using genomic DNA. The results showed that higher work stress was associated with higher IMT in men. This association was not attenuated by traditional risk factors of atherosclerosis and coronary heart disease or by pre-employment risk factors measured in adolescence. Neuregulin-1 gene moderated the association between work stress and IMT in men. A significant association between work stress and IMT was found only for the T/T genotype of the neuregulin-1 gene but not for other genotypes. Among women an association was found between higher work stress and lower heart rate variability, suggesting higher risk for developing atherosclerosis. These associations could not be explained by demographic characteristics or coronary risk factors. The present findings provide evidence for an association between work stress and atherosclerosis in relatively young population. This association seems to be modified by genetic influences but it does not appear to be confounded by pre-employment adolescent risk factors.

Childhood and adolescent antecedents of work stress and early atherosclerosis

Work stress is after musculoskeletal disorders the second most common work-related health problem in the European Union, affecting 28% of EU employees. Furthermore, a 50% excessive cardiovascular disease risk among employees with work stress is reported. High job demands combined with low job control according to the Job Demands-Job Control model, or high effort combined with low rewards according to Effort-Reward Imbalance model, are likely to produce work stress in the majority of employees. Atherosclerotic wall thickening is a validated marker of an increased risk of cardiovascular disease. This study examined the role of childhood and adolescent factors as antecedents of work stress and early atherosclerosis, and in the relationship between them. The Cardiovascular Risk in Young Finns Study, (the CRYF project) started in 1980 when the participants were at the age of three to 18 years. Follow-ups have been conducted every three years until 1992, after that in 1997 and 2001, and the latest is ongoing in 2008. The participants parents reported their socioeconomic position in 1980 and 1983, and their life satisfaction in 1983. Biological risk factors were measured in 1980 and 2001. Type A behaviour was reported in 1986, 1989 and 2001. In the 2001 follow-up when the participants were aged 24 to 39, work stress was assessed from responses to questionnaires on job demands-job control and effort-reward imbalance, and education. Ultrasound measurement of the carotid intima-media thickness (CIMT) was used to assess atherosclerosis. There were 755, 746, 1014 and 494 participants in studies I-IV, respectively. The results showed that low parental socioeconomic position and parental life dissatisfaction during childhood and adolescence predicted higher levels of job strain 18 years later, and that education mediated the relationship between parental socioeconomic position and job strain. Childhood and adolescent family factors were not related to the effort-reward imbalance. Parental life satisfaction was associated with high rewards at work among the men, and high parental socioeconomic position was associated with high reward among the women. Among the men, the eagerness-energy component of Type A behaviour across different developmental periods predicted increased CIMT. Among the women, hard-driving component of Type A behaviour predicted decreased CIMT. Low leadership characteristic in adolescence and early adulthood was associated with both high job strain and increased CIMT, and attenuated the relationship between job strain and CIMT to non-significance in men. The current findings add to the literature on the relationship between job strain and health literature in adopting a developmental perspective. The results imply that work stress does not completely originate from work. There are childhood and adolescent environmental and dispositional effects on work stress and CIMT several years later, and these partly seem to operate through educational attainment.

Chronic and acute stress in atherosclerosis : the role of endothelial function and arterial elasticity

Atherosclerosis is the main underlying pathology of coronary heart disease. Coronary heart disease is a serious health problem in Finland, and it is the leading cause of morbidity and mortality in industrialized countries. Psychological stress correlates with coronary heart disease events – myocardial infarction and sudden death, which are the most common clinical syndromes of atherosclerotic narrowing of arteries. The present series of studies examines the interaction between stress and endothelial function in relation to atherosclerosis. The study also aims to give new information on the mechanisms through which stress has its effect on atherosclerosis progression, focusing on possible relations between psychological stress and the functioning of the endothelium. Our project is based on data from one of the largest national epidemiological studies, the Cardiovascular Risk in Young Finns study, which has monitored the development of risk factors for coronary heart disease in 3596 young adults since 1980. The present study combines experimental stress research with epidemiology and uses an advanced method for examining atherosclerosis development in healthy subjects (intima-media thickness ultrasound measurement). The physiological parameters used were heart rate, respiratory sinus arrhythmia and pre-ejection period. Chronic stress was assessed by vital exhaustion. The ultrasound measurements that served as the indexes of preclinical atherosclerosis were carotid intima-media thickness, brachial flow-mediated dilatation and carotid artery compliance. The effects of cardiovascular risk factors found to be important were taken into account: serum cholesterols level, triglyceride level, serum insulin level and systolic and diastolic blood pressure. There were 69, 1596, 81 and 1721 participants in studies I-IV, respectively. The results showed that both chronic and acute stress may exert an effect on atherosclerosis in subjects with impaired endothelial responses. The findings are consistent with the idea that risk factors are more harmful if the endothelium is not working properly. Chronic stress was found to be a risk if it has resulted in ineffective cardiac stress reactivity or delayed recovery. Men were shown to be at increased risk for atherosclerotic progression in early life, which suggests men’s decreased stress coping ability in relation to stressful psychosocial coronary risk factors. Autonomic imbalance may be the common mechanism of the stress influence on atherosclerosis development. The results of the present study contain background information for the identification the first stages of atherosclerosis, and they may be useful for preventive medicine programs for young adults and could help to improve cardiovascular health in Finland as well as in other countries.

Inflammation-induced atherogenesis, liver alterations, and cardiovascular outcome

Cardiovascular diseases, which presently are considered inflammatory diseases, affect millions of people worldwide. Chronic infections may contribute to the systemic inflammation suggested to increase the risk for cardiovascular diseases. Such chronic infections are periodontitis and Chlamydia pneumoniae infection. They are highly prevalent as approximately 10% of adult population and 30% of people over 50 years old are affected by severe periodontitis and 70-80% of elderly people are seropositive for C. pneumoniae. Our general aim was to investigate the role of infection and inflammation in atherosclerosis both in animal and human studies. We aimed to determine how the two pathogens alter the atherosclerosis-associated parameters, and how they affect the liver inflammation and lipid composition. Furthermore, we evaluated the association between matrix metalloproteinase-8 (MMP-8), a proteinase playing a major role in inflammation, and the future cardiovascular diseases (CVD) events in a population-based cohort. For the animal experiments, we used atherosclerosis-susceptible apolipoprotein E deficient (apoE-/-) mice. They were kept in germ free conditions and fed with a normal chow diet. The bacteria were administered either intravenously (A. actinomycetemcomitans) or intranasally (C. pneumoniae). Several factors were determined from serum as well as from aortic and hepatic tissues. We also determined how cholesterol efflux, a major event in the removal of excess cholesterol from the tissues, and endothelial function were affected by these pathogens. In the human study, serum MMP-8 and its tissue inhibitor (TIMP-1) concentrations were measured and their associations during the follow-up time of 10 years with CVD events were determined. An infection with A. actinomycetemcomitans increased concentrations of inflammatory mediators, MMP production, and cholesterol deposit in macrophages, decreased lipoprotein particle size, and induced liver inflammation. C. pneumoniae infection also elicited an inflammatory response and endothelial dysfunction, as well as induced liver inflammation, microvesicular appearance and altered fatty acid profile. In the population-based cohort, men with increased serum MMP-8 concentration together with subclinical atherosclerosis (carotid artery intima media thickness > 1mm) had a three-fold increased risk for CVD death during the follow-up. The results show that infections with A. actinomycetemcomitans and C. pneumoniae induce proatherogenic changes, as well as affect the liver. These data therefore support the concept that common infections have systemic effects and could be considered as cardiovascular risk factors. Furthermore, our data indicate that, as an independent predictor of fatal CVD event, serum MMP-8 could have a clinical significance in diagnosing cardiovascular diseases.

Diet and the development of atherosclerosis: a whole-diet approach from childhood to adulthood

Cardiovascular diseases (CVDs) are the leading cause of mortality in the world. Studies of the impact of single nutrients on the risk for CVD have often provided inconclusive results, and recent research in nutritional epidemiology with a more holistic whole-diet approach has proven fruitful. Moreover, dietary habits in childhood and adolescence may play a role in later health and disease, either independently or by tracking into adulthood. The main aims of this study were to find childhood and adulthood determinants of adulthood diet, to identify dietary patterns present among the study population and to study the associations between long-term food choices and cardiovascular health in young Finnish adults. The study is a part of the multidisciplinary Cardiovascular Risk in Young Finns study, which is an ongoing, prospective cohort study with a 21-year follow-up. At baseline in 1980, the subjects were children and adolescents aged 3 to 18 years (n included in this study = 1768), and young adults aged 24 to 39 years at the latest follow-up study in 2001 (n = 1037). Food consumption and nutrient intakes were assessed with repeated 48-hour dietary recalls. Other determinations have included comprehensive risk factor assessments using blood tests, physical measurements and questionnaires. In the latest follow-up, ultrasound examinations were performed to study early atherosclerotic vascular changes. The average intakes showed substantial changes since 1980. Intakes of fat and saturated fat had decreased, whereas the consumption of fruits and vegetables had increased. Intake of fat and consumption of vegetables in childhood and physical activity in adulthood were important health behavioural determinants of adult diet. Additionally, a principal component analysis was conducted to identify major dietary patterns at each study point. A similar set of two major patterns was recognised throughout the study. The traditional dietary pattern positively correlated with the consumption of traditional Finnish foods, such as rye, potatoes, milk, butter, sausages and coffee, and negatively correlated with fruit, berries and dairy products other than milk. This type of diet was independently associated with several risk factors of CVD, such as total and low-density lipoprotein cholesterol, apolipoprotein B and C-reactive protein concentrations among both genders, as well as with systolic blood pressure and insulin levels among women. The traditional pattern was also independently associated with intima media thickness (IMT), a subclinical predictor of CVD, in men but not in women. The health-conscious pattern, predominant among female subjects, non-smokers and urbanites, was characterised by more health-conscious food choices such as vegetables, legumes and nuts, tea, rye, fish, cheese and other dairy products, as well as by the consumption of alcoholic beverages. This pattern was inversely, but less strongly, associated with cardiovascular risk factors. Tracking of the dietary pattern scores was observed, particularly among subjects who were adolescents at baseline. Moreover, a long-term high intake of protein concurrent with a low intake of fat was positively associated with IMT. These findings suggest that food behaviour and food choices are to some extent established as early as in childhood or adolescence and may significantly track into adulthood. Long-term adherence to traditional food choices seems to increase the risk for developing CVD, especially among men. Those with intentional or unintentional low fat diets, but with high intake of protein may also be at increased risk for CVD. The findings offer practical, food-based information on the relationship between diet and CVD and encourage further use of the whole-diet approach in epidemiological research. The results support earlier findings that long-term food choices play a role in the development of CVD. The apparent influence of childhood habits is important to bear in mind when planning educational strategies for the primary prevention of CVD. Further studies on food choices over the entire lifespan are needed.

Determinants of Coronary and Carotid Atherosclerosis in Finnish Patients with Clinically Suspected Coronary Artery Disease. A Quantitative Angiography and Ultrasound Study

Background. Cardiovascular disease (CVD) remains the most serious threat to life and health in industrialized countries. Atherosclerosis is the main underlying pathology associated with CVD, in particular coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease. Risk factors play an important role in initiating and accelerating the complex process of atherosclerosis. Most studies of risk factors have focused on the presence or absence of clinically defined CVD. Less is known about the determinants of the severity and extent of atherosclerosis in symptomatic patients. Aims. To clarify the association between coronary and carotid artery atherosclerosis, and to study the determinants associated with these abnormalities with special regard to novel cardiovascular risk factors. Subjects and methods. Quantitative coronary angiography (QCA) and B-mode ultrasound were used to assess coronary and carotid artery atherosclerosis in 108 patients with clinically suspected CAD referred for elective coronary angiography. To evaluate anatomic severity and extent of CAD, several QCA parameters were incorporated into indexes. These measurements reflected CAD severity, extent, and overall atheroma burden and were calculated for the entire coronary tree and separately for different coronary segments (i.e., left main, proximal, mid, and distal segments). Maximum and mean intima-media thickness (IMT) values of carotid arteries were measured and expressed as mean aggregate values. Furthermore, the study design included extensive fasting blood samples, oral glucose tolerance test, and an oral fat-load test to be performed in each participant. Results. Maximum and mean IMT values were significantly correlated with CAD severity, extent, and atheroma burden. There was heterogeneity in associations between IMT and CAD indexes according to anatomical location of CAD. Maximum and mean IMT values, respectively, were correlated with QCA indexes for mid and distal segments but not with the proximal segments of coronary vessels. The values of paraoxonase-1 (PON1) activity and concentration, respectively, were lower in subjects with significant CAD and there was a significant relationship between PON1 activity and concentration and coronary atherosclerosis assessed by QCA. PON1 activity was a significant determinant of severity of CAD independently of HDL cholesterol. Neither PON1 activity nor concentration was associated with carotid IMT. The concentration of triglycerides (TGs), triglyceride-rich lipoproteins (TRLs), oxidized LDL (oxLDL), and the cholesterol content of remnant lipoprotein particle (RLP-C) were significantly increased at 6 hours after intake of an oral fatty meal as compared with fasting values. The mean peak size of LDL remained unchanged 6 hours after the test meal. The correlations between total TGs, TRLs, and RLP-C in fasting and postprandial state were highly significant. RLP-C correlated with oxLDL both in fasting and in fed state and inversely with LDL size. In multivariate analysis oxLDL was a determinant of severity and extent of CAD. Neither total TGs, TRLs, oxLDL, nor LDL size were linked to carotid atherosclerosis. Insulin resistance (IR) was associated with an increased severity and extent of coronary atherosclerosis and seemed to be a stronger predictor of coronary atherosclerosis in the distal parts of the coronary tree than in the proximal and mid parts. In the multivariate analysis IR was a significant predictor of the severity of CAD. IR did not correlate with carotid IMT. Maximum and mean carotid IMT were higher in patients with the apoE4 phenotype compared with subjects with the apoE3 phenotype. Likewise, patients with the apoE4 phenotype had a more severe and extensive CAD than individuals with the apoE3 phenotype. Conclusions. 1) There is an association between carotid IMT and the severity and extent of CAD. Carotid IMT seems to be a weaker predictor of coronary atherosclerosis in the proximal parts of the coronary tree than in the mid and distal parts. 2) PON1 activity has an important role in the pathogenesis of coronary atherosclerosis. More importantly, the study illustrates how the protective role of HDL could be modulated by its components such that equivalent serum concentrations of HDL cholesterol may not equate with an equivalent, potential protective capacity. 3) RLP-C in the fasting state is a good marker of postprandial TRLs. Circulating oxLDL increases in CAD patients postprandially. The highly significant positive correlation between postprandial TRLs and postprandial oxLDL suggests that the postprandial state creates oxidative stress. Our findings emphasize the fundamental role of LDL oxidation in the development of atherosclerosis even after inclusion of conventional CAD risk factors. 4) Disturbances in glucose metabolism are crucial in the pathogenesis of coronary atherosclerosis. In fact, subjects with IR are comparable with diabetic subjects in terms of severity and extent of CAD. 5) ApoE polymorphism is involved in the susceptibility to both carotid and coronary atherosclerosis.

Long-term effects of fenofibrate on lipoproteins and surrogate markers of macrovascular and microvascular disease in people with type 2 diabetes

Background and aims. Diabetic dyslipidemia is a highly atherogenic triad of increased triglycerides, decreased HDL cholesterol, and small dense LDL. Fibrates have a beneficial effect on diabetic dyslipidemia, and they have reduced cardiovascular events in randomized trials. Fenofibrate has reduced albuminuria and markers of low-grade inflammation and endothelial dysfunction. The present studies were undertaken to characterize the alterations of VLDL and LDL subclasses and to investigate the binding of LDL to arterial wall in type 2 diabetes. Further purpose was to elucidate the effects of fenofibrate on several lipoprotein subclasses, augmentation index (AIx), carotid intima-media thickness (IMT), and renal function. Subjects. 239 type 2 diabetic subjects were recruited among participants of the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study at the Helsinki centre. The patients were randomized to fenofibrate (200mg/d) or placebo for 5 years. Additionally, a healthy control group (N = 93) was recruited. Results. VLDL1 triglycerides increased in similar proportion to total triglycerides in type 2 diabetic patients and control subjects. Despite the increase in total apoCIII levels, VLDL apoCIII was decreased in diabetic patients. Enrichment of LDL with apoCIII induced a small increase in binding of LDL to arterial wall proteoglycan. Intrinsic characteristics of diabetic LDL, rather than levels of apoCIII, were responsible for increased proteoglycan binding of diabetic LDL with high apoCIII. Fenofibrate reduced triglycerides, increased LDL size, and shifted HDL subclasses towards smaller particles with no change in levels of HDL cholesterol. High levels of homocysteine were associated with lower increase of HDL cholesterol and apoA-I during fenofibrate treatment. Long-term fenofibrate treatment did not improve IMT, AIx, inflammation, or endothelial function. Fenofibrate decreased creatinine clearance and estimated glomerular filtration rate. No effect on albuminuria was seen with fenofibrate. Instead, Cystatin C was increased during fenofibrate treatment. Conclusions. 1) Elevation of VLDL 1 triglycerides was the major determinant of plasma triglyceride concentration in control subjects and type 2 diabetic patients. 2) LDL with high apoCIII showed multiple atherogenic properties, that were only partially mediated by apoCIII per se in type 2 diabetes 3) Fenofibrate demonstrated no effect on surrogate markers of atherosclerosis. 4) Fenofibrate had no effect on albuminuria and the observed decrease in markers of renal function could complicate the clinical surveillance of the patients. 5) Fenofibrate can be used to treat severe hypertriglyceridemia or in combination therapy with statins, but not to increase HDL levels.

Preterm birth and risk factors for chronic disease : Helsinki Study of Very Low Birth Weight Adults

Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (< 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.