Exposure to Tobacco Smoke and Markers of Subclinical Atherosclerosis in Children and Adolescents. The STRIP Study.

Background: Measurement of serum cotinine, a major metabolite of nicotine, provides a valid marker for quantifying exposure to tobacco smoke. Exposure to tobacco smoke causes vascular damage by multiple mechanisms, and it has been acknowledged as a risk factor for atherosclerosis. Multifactorial atherosclerosis begins in childhood, but the relationship between exposure to tobacco smoke and arterial changes related to early atherosclerosis have not been studied in children. Aims: The aim of the present study was to evaluate exposure to tobacco smoke with a biomarker, serum cotinine concentration, and its associations with markers of subclinical atherosclerosis and lipid profile in school-aged children and adolescents. Subjects and Methods: Serum cotinine concentration was measured using a gas chromatographic method annually between the ages 8 and 13 years in 538-625 children participating since infancy in a randomized, prospective atherosclerosis prevention trial STRIP (Special Turku coronary Risk factor Intervention Project). Conventional atherosclerosis risk factors were measured repeatedly. Vascular ultrasound studies were performed among 402 healthy 11-year-old children and among 494 adolescents aged 13 years. Results: According to serum cotinine measurements, a notable number of the school aged children and adolescents were exposed to tobacco smoke, but the exposure levels were only moderate. Exposure to tobacco smoke was associated with decreased endothelial function as measured with flow-mediated dilation of the brachial artery, decreased elasticity of the aorta, and increased carotid and aortic intima-media thickness. Longitudinal exposure to tobacco smoke was also related with increased apolipoprotein B and triglyceride levels in 13-year-old adolescents, whose body mass index and nutrient intakes did not differ. Conclusions: These findings suggest that exposure to tobacco smoke in childhood may play a significant role in the development of early atherosclerosis. Key Words: arterial elasticity, atherosclerosis, children, cotinine, endothelial function, environmental tobacco smoke, intima-media thickness, risk factors, ultrasound

Conventional and novel cardiovascular risk factors in young Finns and their associations with structural and functional vascular changes of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study

Background: Atherosclerosis begins in early life progressing from asymptomatic to symptomatic as we age. Although substantial progress has been made in identifying the determinants of atherosclerosis in middle to older age adults at increased cardiovascular risk, there is lack of data examining determinants and prediction of atherosclerosis in young adults. Aims: The current study was designed to investigate levels of cardiovascular risk factors in young adults, subclinical measures of atherosclerosis, and prediction of subclinical arterial changes with conventional risk factor measures and novel metabolic profiling of serum samples. Subjects and Methods: This thesis utilised data from the follow-ups performed in 2001 and 2007 in the Cardiovascular Risk in Young Finns study, a Finnish population-based prospective cohort study that examined 2,204 subjects who were aged 30-45 years in 2007. Subclinical atherosclerosis was studied using noninvasive ultrasound measurements of carotid intima-media thickness (IMT), carotid arterial distensibility (CDist) and brachial flow-mediated dilation (FMD). Measurements included conventional risk factors and metabolic profiling using highthroughput nuclear magnetic resonance (NMR) methods that provided data on 42 lipid markers and 16 circulating metabolites. Results: Trends in lipids were favourable between 2001 and 2007, whereas waist circumference, fasting glucose, and blood pressure levels increased. To study the stability of noninvasive ultrasound markers, 6-year tracking (the likelihood to maintain the original fractile over time) in 6 years was examined. IMT tracked more strongly than CDist and FMD. Cardiovascular risk scores (Framingham, SCORE, Finrisk, Reynolds and PROCAM) predicted subclinical atherosclerosis equally. Lipoprotein subclass testing did not improve the prediction of subclinical atherosclerosis over and above conventional risk factors. However, circulating metabolites improved risk stratification. Tyrosine and docosahexaenoic acid were found to be novel biomarkers of high IMT. Conclusions: Prediction of cardiovascular risk in young Finnish adults can be performed with any of the existing risk scores. The addition of metabonomics to risk stratification improves prediction of subclinical changes and enables more accurate targeting of prevention at an early stage.

Vascular Function in Chronic Kidney Disease and in Renovascular Disease

Cardiovascular mortality is 15 to 30 times higher in patients with chronic kidney disease than in the age-adjusted general population. Even minor renal dysfunction predicts cardiovascular events and death in the general population. In patients with atherosclerotic renovascular disease the annual cardiovascular event and death rate is even higher. The abnormalities in coronary and peripheral artery function in the different stages of chronic kidney disease and in renovascular disease are still poorly understood, nor have the cardiac effects of renal artery revascularization been well characterized, although considered to be beneficial. This study was conducted to characterize myocardial perfusion and peripheral endothelial function in patients with chronic kidney disease and in patients with atherosclerotic renovascular disease. Myocardial perfusion was measured with positron emission tomography (PET) and peripheral endothelial function with brachial artery flow-mediated dilatation. It has been suggested that the poor renal outcomes after the renal artery revascularization could be due to damage in the stenotic kidney parenchyma; especially the reduction in the microvascular density, changes mainly evident at the cortical level which controls almost 80% of the total renal blood flow. This study was also performed to measure the effect of renal artery stenosis revascularization on renal perfusion in patients with renovascular disease. In order to do that a PET-based method for quantification of renal perfusion was developed. The coronary flow reserve of patients with chronic kidney disease was similar to the coronary flow reserve of healthy controls. In renovascular disease the coronary flow reserve was, however, markedly reduced. Flow-mediated dilatation of brachial artery was decreased in patients with chronic kidney disease compared to healthy controls, and even more so in patients with renovascular disease. After renal artery stenosis revascularization, coronary vascular function and renal perfusion did not improve in patients with atherosclerotic renovascular disease, but in patients with bilateral renal artery stenosis, flow-mediated dilatation improved. Chronic kidney disease does not significantly affect coronary vascular function. On the contrary, coronary vascular function was severely deteriorated in patients with atherosclerotic renovascular disease, possibly because of diffuse coronary artery disease and/or diffuse microvascular disease. The peripheral endothelial function was disturbed in patients with chronic kidney disease and even more so in patient with atherosclerotic renovascular disease. Renal artery stenosis dilatation does not seem to offer any benefits over medical treatment in patients with renovascular disease, since revascularization does not improve coronary vascular function or renal perfusion.

Metabolic syndrome – early cardio-metabolic, vascular and hepatic changes

Background: Metabolic syndrome (MetS) is a combination of several cardio-metabolic risk factors including obesity, hyperglycemia, hypertension and dyslipidemia. MetS has been associated with increased levels of apolipoprotein B (apoB) and low-density lipoprotein oxidation (OxLDL) and with an increased risk of cardiovascular disease and non-alcoholic fatty liver disease. Aims: To establish the relation of apoB and OxLDL with the MetS development and to determine the status of MetS as a risk factor for adverse liver changes and for subclinical atherosclerosis. Subjects and Methods: The present thesis is part of the two large scale population-based, prospective, observational studies. Cardiovascular Risk in Young Finns study was launched in 1980 including 3,596 subjects aged 3-18 years. Thereafter follow-up studies have been conducted regularly. In the latest follow-ups that were performed in 2001 (N=2,283) and 2007 (N=2,204), non-invasive ultrasound studies were introduced to the study protocol to measure subclinical atherosclerosis i.e. carotid intima-media thickness (IMT), carotid artery distensibility (Cdist) and brachial flow-mediated dilatation (FMD). Alanine-aminotransferase (ALT) and gammaglutamyltransferase (GGT) were measured in 2007 to assess liver function. The Bogalusa Heart Study is a long-term epidemiologic study of cardiovascular risk factors launched in 1972 in a biracial community of Bogalusa, Louisiana, USA. Total of 374 youths (aged 9-18 years at baseline in 1984-88) who underwent non-invasive ultrasound studies of the carotid artery as adults, were included in the analyses of the present thesis. Results: The odds ratios (95% confidence intervals) for MetS incidence during a 6-year follow-up by quartiles of apoB were 2.0(1.0-3.8) for the second quartile, 3.1(1.7-5.7) for the third quartile and 4.2(2.3-7.6) for the fourth quartile. OxLDL was not independently associated with incident MetS. Youth (aged 9-18 years) with MetS or with high body mass index were at 2-3 times the risk of having MetS, high IMT, and type 2 diabetes 24-years later as adults. IMT increased 79±7μm (mean±SEM) in subjects with MetS and 42±2μm in subjects without the MetS (P<0.0001) during 6- years. Subjects who lost the MetS diagnosis during 6-year follow-up had reduced IMT progression compared to persistent MetS group (0.036±0.005vs.0.079±0.010 mm, P=0.001) and reduced Cdist change compared to incident MetS group (-0.12±0.05vs.-0.38±0.10 %/mmHg, P=0.03) over 6-year follow-up. MetS predicted elevated ALT (β±SEM=0.380±0.052, P<0.0001 in men and 0.160±0.052, P=0.002 in women) and GGT (β±SEM=0.240±0.058, P<0.0001 in men and 0.262±0.053, P<0.0001 in women) levels after 6-years. Conclusions: These findings suggest that apoB may give additional information on early metabolic disturbances predisposing MetS. MetS may be used to identify individuals at increased risk of developing atherosclerosis and non-alcoholic liver disease. However, recovery from the MetS may have positive effects on liver and vascular properties.

Metabolic syndrome in young adults – prevalence, childhood predictors and association with subclinical atherosclerosis

Background: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, insulin resistance, impaired glucose tolerance, hypertension and dyslipidemia. The prevalence of MetS is increasing worldwide in all age groups. MetS is associated with increased risk of cardiovascular disease and type 2 diabetes mellitus. Aims: The aim of the present study was to investigate the prevalence, secular trends and childhood predictors of MetS in young adults. Furthermore, the relations between MetS and subclinical atherosclerosis were studied and whether apolipoproteins (apo) B and A-I, C-reactive protein (CRP) and type II secretory phospholipase A2 (sPLA2) were associated with MetS, and to what extent the atherogenicity of MetS was explained by these factors. Participants and Methods: The present thesis is part of the large scale population-based, prospective study, the Cardiovascular Risk in Young Finns Study. The first cross-sectional study was conducted in 1980 and included 3,596 participants aged 3-18 years. Carotid and brachial ultrasound studies were performed for 2,283 of these participants in 2001 and 2,200 of these participants in 2007. Results: The overall prevalence of MetS in young adults aged 24-39 years in 2001 was 10-15 % and 6 years later in 30-45 year-old adults it was 15-23 % depending on the MetS definition used. Between the years 1986 and 2001, MetS prevalence increased from 1.0 % to 7.5 % (p<0.0001) in 24-year-old participants that was mostly driven by the increased central obesity. Participants with MetS had increased carotid intima-media thickness (cIMT) and decreased carotid elasticity compared to those without the syndrome. Impaired brachial flow-mediated dilatation (FMD) was not related to MetS but it modified the relationship between MetS and cIMT (P for interaction 0.023). High levels of apoB, CRP, sPLA2 and low levels of apoA-I associated with MetS in young adults. In prospective analysis both MetS and high apoB predicted (P<0.0001) incident high cIMT, defined as cIMT>90th percentile and/or plaque. The association between MetS and incident high cIMT was attenuated by ~40 % after adjustment with apoB. Conclusions: MetS is common in young adults and increases with age. Screening for risk factors, especially obesity, at an early life stage could help identify children and adolescents at increased risk of developing MetS and cardiovascular disease later in life. MetS identifies a population of young adults with evidence of increased subclinical atherosclerosis. Impaired brachial endothelial response is not a hallmark of MetS in young adults, but the status of endothelial function modifies the association between metabolic risk factors and atherosclerosis. In addition, the atherogenicity of MetS in this population assessed by incident high cIMT appears to be substantially mediated by elevated apoB.

Common dyslipidemias, high lipoprotein(a) concentrations and endothelial function in the children of the STRIP study families

Extreme lipid values predisposing on illnesses are dyslipidemias. Dyslipidemias evolve in early childhood, but their significance or persistency is not well known. Common dyslipidemias may aggregate in the same families. This thesis is a part of the longitudinal randomized Special Turku coronary Risk factor Intervention Project STRIP, in which 1054 families with six months old children were randomized to a control or to an intervention group. The family lipid data from the first 11 years was used. Fasting samples at the age of five years defined the lipid phenotypes. The dyslipidemias coexisting in the parent and the child were studied. At the age of 11 years 402 children participated artery ultrasound studies. The significance of the childhood dyslipidemias and lipoprotein(a) concentration on endothelial function was evaluated with the flow mediated arterial dilatation test. Frequently elevated non-HDL cholesterol concentration from one to seven-year-old children associated to similar parental dyslipidemia that improved the predictive value of the childhood sample. The familial combinations were hypercholesterolemia (2.3%), hypertriglyceridemia (2.0%), familial combined hyperlipidemia (1.8%), and isolated low HDL-cholesterol concentration (1.4%). Combined hyperlipidemia in a parent predicted most frequently the child’s hyperlipidemia. High lipoprotein(a) concentration aggregated in some families and associated to childhood attenuated brachial artery dilatation. Hypercholesterolemia and high lipoprotein(a) concentration at five years of age predicted attenuated dilatation. This study demonstrated that parental dyslipidemias and high lipoprotein(a) concentration help to find early childhood dyslipidemias. The association of hypercholesterolemia and lipoprotein(a) concentration with endothelial function emphasizes the importance of the early recognition of the dyslipidemias.

IDEAS for Strategic Technology Management: Design of an electronically mediated scenario method

The age-old adage goes that nothing in this world lasts but change, and this generation has indeed seen changes that are unprecedented. Business managers do not have the luxury of going with the flow: they have to plan ahead, to think strategies that will meet the changing conditions, however stormy the weather seems to be. This demand raises the question of whether there is something a manager or planner can do to circumvent the eye of the storm in the future? Intuitively, one can either run on the risk of something happening without preparing, or one can try to prepare oneself. Preparing by planning for each eventuality and contingency would be impractical and prohibitively expensive, so one needs to develop foreknowledge, or foresight past the horizon of the present and the immediate future. The research mission in this study is to support strategic technology management by designing an effective and efficient scenario method to induce foresight to practicing managers. The design science framework guides this study in developing and evaluating the IDEAS method. The IDEAS method is an electronically mediated scenario method that is specifically designed to be an effective and accessible. The design is based on the state-of-the-art in scenario planning, and the product is a technology-based artifact to solve the foresight problem. This study demonstrates the utility, quality and efficacy of the artifact through a multi-method empirical evaluation study, first by experimental testing and secondly through two case studies. The construction of the artifact is rigorously documented as justification knowledge as well as the principles of form and function on the general level, and later through the description and evaluation of instantiations. This design contributes both to practice and foundation of the design. The IDEAS method contributes to the state-of-the-art in scenario planning by offering a light-weight and intuitive scenario method for resource constrained applications. Additionally, the study contributes to the foundations and methods of design by forging a clear design science framework which is followed rigorously. To summarize, the IDEAS method is offered for strategic technology management, with a confident belief that it will enable gaining foresight and aid the users to choose trajectories past the gales of creative destruction and off to a brighter future.

Alpha2-Adrenoceptor-mediated vascular responses induced by dexmedetomidine

Alpha2-Adrenoceptors are cell-surface G protein coupled receptors that mediate many of the effects of the catecholamines noradrenaline and adrenaline. The three human α2-adrenoceptor subtypes are widely expressed in different tissues and organs, and they mediate many different physiological and pharmacological effects in the central and peripheral nervous system and as postsynaptic receptors in target organs. Previous studies have demonstrated that α2-adrenoceptors mediate both vascular constriction and dilatation in humans. Large inter-individual variation has been observed in the vascular responses to α2-adrenoceptor activation in clinical studies. All three receptor subtypes are potential drug targets. It was therefore considered important to further elucidate the details of adrenergic vascular regulation and its genetic variation, since such knowledge may help to improve the development of future cardiovascular drugs and intensive care therapies. Dexmedetomidine is the most selective and potent α2-adrenoceptor agonist currently available for clinical use. When given systemically, dexmedetomidine induces nearly complete sympatholysis already at low concentrations, and postsynaptic effects, such vasoconstriction, can be observed with increasing concentrations. Thus, local infusions of small doses of dexmedetomidine into dorsal hand veins and the application of pharmacological sympathectomy with brachial plexus block provide a means to assess drug-induced peripheral vascular responses without interference from systemic pharmacological effects and autonomic nervous system regulation. Dexmedetomidine was observed to have biphasic effects on haemodynamics, with an initial decrease in blood pressure at low concentrations followed by substantial increases in blood pressure and coronary vascular resistance at high concentrations. Plasma concentrations of dexmedetomidine that significantly exceeded the recommended therapeutic level did not reduce myocardial blood flow below the level that is observed with the usual therapeutic concentrations and did not induce any evident myocardial ischaemia in healthy subjects. Further, it was demonstrated that dexmedetomidine also had significant vasodilatory effects through activation of endothelial nitric oxide synthesis, and thus when the endothelial component of the blood vessel response to dexmedetomidine was inhibited, peripheral vasoconstriction was augmented. Hand vein constriction responses to α2-adrenoceptor activation by dexmedetomidine were only weakly associated with the constriction responses to α1-adrenoceptor activation, pointing to independent cellular regulation by these two adrenoceptor classes. Substantial inter-individual variation was noted in the venous constriction elicited by activation of α2-adrenoceptors by dexmedetomidine. In two study populations from two different continents, a single nucleotide polymorphism in the PRKCB gene was found to be associated with the dorsal hand vein constriction response to dexmedetomidine, suggesting that protein kinase C beta may have an important role in the vascular α2-adrenoceptor signalling pathways activated by dexmedetomidine.

Genesis and Evolution of Brittle Structures In Southwestern Finland and Western South Africa. Insights into Fault Reactivation, Fluid Flow and Structural Maturity in Precambrian Cratons

The bedrock of old crystalline cratons is characteristically saturated with brittle structures formed during successive superimposed episodes of deformation and under varying stress regimes. As a result, the crust effectively deforms through the reactivation of pre-existing structures rather than by through the activation, or generation, of new ones, and is said to be in a state of 'structural maturity'. By combining data from Olkiluoto Island, southwestern Finland, which has been investigated as the potential site of a deep geological repository for high-level nuclear waste, with observations from southern Sweden, it can be concluded that the southern part of the Svecofennian shield had already attained structural maturity during the Mesoproterozoic era. This indicates that the phase of activation of the crust, i.e. the time interval during which new fractures were generated, was brief in comparison to the subsequent reactivation phase. Structural maturity of the bedrock was also attained relatively rapidly in Namaqualand, western South Africa, after the formation of first brittle structures during Neoproterozoic time. Subsequent brittle deformation in Namaqualand was controlled by the reactivation of pre-existing strike-slip faults.In such settings, seismic events are likely to occur through reactivation of pre-existing zones that are favourably oriented with respect to prevailing stresses. In Namaqualand, this is shown for present day seismicity by slip tendency analysis, and at Olkiluoto, for a Neoproterozoic earthquake reactivating a Mesoproterozoic fault. By combining detailed field observations with the results of paleostress inversions and relative and absolute time constraints, seven distinctm superimposed paleostress regimes have been recognized in the Olkiluoto region. From oldest to youngest these are: (1) NW-SE to NNW-SSE transpression, which prevailed soon after 1.75 Ga, when the crust had sufficiently cooled down to allow brittle deformation to occur. During this phase conjugate NNW-SSE and NE-SW striking strike-slip faults were active simultaneous with reactivation of SE-dipping low-angle shear zones and foliation planes. This was followed by (2) N-S to NE-SW transpression, which caused partial reactivation of structures formed in the first event; (3) NW-SE extension during the Gothian orogeny and at the time of rapakivi magmatism and intrusion of diabase dikes; (4) NE-SW transtension that occurred between 1.60 and 1.30 Ga and which also formed the NW-SE-trending Satakunta graben located some 20 km north of Olkiluoto. Greisen-type veins also formed during this phase. (5) NE-SW compression that postdates both the formation of the 1.56 Ga rapakivi granites and 1.27 Ga olivine diabases of the region; (6) E-W transpression during the early stages of the Mesoproterozoic Sveconorwegian orogeny and which also predated (7) almost coaxial E-W extension attributed to the collapse of the Sveconorwegian orogeny. The kinematic analysis of fracture systems in crystalline bedrock also provides a robust framework for evaluating fluid-rock interaction in the brittle regime; this is essential in assessment of bedrock integrity for numerous geo-engineering applications, including groundwater management, transient or permanent CO2 storage and site investigations for permanent waste disposal. Investigations at Olkiluoto revealed that fluid flow along fractures is coupled with low normal tractions due to in-situ stresses and thus deviates from the generally accepted critically stressed fracture concept, where fluid flow is concentrated on fractures on the verge of failure. The difference is linked to the shallow conditions of Olkiluoto - due to the low differential stresses inherent at shallow depths, fracture activation and fluid flow is controlled by dilation due to low normal tractions. At deeper settings, however, fluid flow is controlled by fracture criticality caused by large differential stress, which drives shear deformation instead of dilation.