Ankle-brachial index, high-sensitivity C-reactive protein and endothelial function in a cardiovascular risk population

Atherosclerotic vascular disease is the leading cause of death in the Western world. Its main three manifestations are coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Asymptomatic peripheral arterial disease is usually diagnosed using the ankle brachial index, and values ≤ 0.90 are used to determine the diagnosis. The classical risk factors of peripheral arterial disease, such as smoking and diabetes, are well known and early interventions are mandatory to improve the prognosis. What is not well known is the role of inflammation as a risk factor. Yet, a novel approach to cardiovascular diseases is the measurement of endothelial function. In this thesis, we studied the ankle-brachial index, C-reactive protein and endothelial function in a cardiovascular risk population. A total of 2856 subjects were invited to the study and 2085 (73%) responded. From these subjects, a cohort of 1756 risk persons was screened. We excluded the subjects with previously known cardiovascular disease or diabetes, because they were already under systematic follow-up. Out of the study subjects, 983 (56%) were women and 773 (44%) men. The ankle brachial index and high-sensitivity C-reactive protein were measured from 1047 subjects. Endothelial function was assessed by measuring reactive hyperemia pulse amplitude tonometry from 66 subjects with borderline peripheral arterial disease. In this study, smoking was a crucial risk factor for peripheral arterial disease. Subclinical peripheral arterial disease seems to be more common in hypertensive patients even without comorbidities. The measurement of the ankle brachial index is an efficient method to identify patients at an increased cardiovascular risk. High-sensitivity C-reactive protein did not correlate with the ankle brachial index or peripheral arterial disease. Instead, it correlated with measures of obesity. In a cardiovascular risk population with borderline peripheral arterial disease, nearly every fourth subject had endothelial dysfunction. This might point out a subgroup of individuals in need of more intensive treatment for their risk factors.

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.

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.

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

Physical activity in adolescence - with special reference to cardiovascular health

Liikunta ja sydän- ja verisuoniterveys nuorilla Aikuisiällä ilmenevien sydän- ja verisuonisairauksien kehitys alkaa lapsuudessa. Vähäinen liikunta lisää vaaraa sairastua sydän- ja verisuonisairauksiin sekä vaikuttaa haitallisesti näiden sairauksien riskitekijöihin läpi elämän. Tämän tutkimuksen tavoitteena oli tutkia nuorten liikuntaa ja sen yhteyttä sydän- ja verisuoniterveyteen. Sydän- ja verisuoniterveyttä tutkittiin riskitekijöiden sekä valtimon laajentumiskyvyn avulla. Tutkittavat koostuivat nuorista, jotka osallistuivat pitkäaikaisen sepelvaltimotaudin ehkäisytutkimuksen (STRIP) 13-vuotistutkimuskäynnille ja jotka raportoivat vapaa-ajan liikuntatottumuksensa (n=560). Liikunnan lisäksi nuorten pituus, paino, verenpaine ja olkavaltimon laajentumiskyky mitattiin sekä analysoitiin laboratorionäytteitä (otettiin verinäyte) ja selvitettiin ruoankäyttöä. Vähäinen vapaa-ajan liikunta oli yleistä etenkin tytöillä. Vapaa-ajallaan vähän liikkuvat pojat viettivät enemmän aikaa televisio- ja tietokoneruudun ääressä kuin vapaa-ajallaan paljon liikkuvat pojat. Äidin, toisin kuin isän, vapaa-ajan liikunta ja paino olivat yhteydessä lapsen vapaa-ajan liikuntaan. Vähän liikkuvat tytöt olivat olleet jo kahden vuoden iästä saakka useammin ylipainoisia kuin runsaammin liikkuvat ikätoverinsa. Sydän- ja verisuonisairauksien riskitekijöiden kasautuminen oli tavallisempaa vähän kuin paljon liikkuvilla nuorilla. Vähän liikkuvilla pojilla oli lisäksi huonompi olkavaltimon laajentumiskyky kuin paljon liikkuvilla pojilla. Tämä on tärkeä löydös, koska valtimon laajentumiskyky kuvannee sydän- ja verisuoniterveyttä jo ennen rakenteellisten muutosten ilmaantumista. Useat nuoret, etenkin tytöt, liikkuivat vähän vapaa-ajallaan. Vähäisellä vapaa-ajan liikunnalla oli haitallinen yhteys sydän- ja verisuonisairauksien riskitekijöihin sekä valtimon laajentumiskykyyn. Nuorten kannustaminen liikunnalliseen elämäntapaan on erittäin tärkeää sydän- ja verisuoniterveyden edistämiseksi sekä nuoren että kansanterveyden kannalta.

Nocturnal Transcutaneous Carbon Dioxide and Early Changes in Atherosclerosis in Pre- and Postmenopausal Women

The risk of cardiovascular diseases and sleep-disordered breathing increases after menopause. This cross-sectional study focuses on overnight transcutaneous carbon dioxide (TcCO₂) measurements and their power to predict changes in the early markers of cardiovascular and metabolic diseases. The endothelial function of the brachial artery, the intima-media thickness of the carotid artery, blood pressure, glycosylated hemoglobin A1C and plasma levels of cholesterols and triglycerides were used as markers of cardiovascular and metabolic diseases. The study subjects consisted of healthy premenopausal women of 46 years of age and postmenopausal women of 56 years of age. From wakefulness to sleep, the TcCO₂ levels increased more in postmenopausal women than in premenopausal women. In estrogen-users the increase in TcCO₂ levels was even more pronounced than in other postmenopausal women. From the dynamic behaviour of the nocturnal TcCO₂ signal, several important features were detected. These TcCO₂ features had a remarkable role in the prediction of endothelial dysfunction and thickening of the carotid wall in healthy premenopausal women. In addition, these TcCO₂ features were linked with blood pressure, lipid profile and glucose balance in postmenopausal women. The nocturnal TcCO₂ profile seems to contain significant information, which is associated with early changes in cardiovascular diseases in middle-aged women. TcCO₂ might not only measure the tissue carbon dioxide levels, but the TcCO₂ signal variation may also reflect peripheral vasodynamic events caused by increased sympathetic activity during sleep.

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.

Cardiovascular health and fitness after childhood acute lymphoblastic leukaemia

The last few decades have turned childhood acute lymphoblastic leukaemia (ALL) from a virtually incurable disease to a disease with 80–90% survival rates. However, this has not come without a cost. Various late effects of the treatment are nowadays well acknowledged, and the survivors have increased cardiovascular (CV) morbidity and mortality. While the treatment of ALL may have direct toxic effects on various organ systems, lifestyle factors affect the CV risk of the survivors as well. Data on CV health and fitness after treatment with common Nordic protocols since 1986 has been scarce. This thesis aimed to study CV health and fitness and the effects of a 3-month exercise intervention in 16–30-year-old long-term survivors of childhood ALL. Fitness was poor especially in female survivors. One third reported ≤1h of moderate physical activity (PA) weekly. While the levels of other CV risk factors were similar in survivors and controls, attenuations in vascular endothelium and cardiac function were found when using advanced echocardiographic methods. The exercise programme improved fitness, insulin resistance, endothelial function as well as measures of cardiac function. While the results do not allow definite conclusions on whether the subclinical signs of cardiac and vascular endothelial dysfunction are due to the treatment of ALL or sedentary lifestyle/poor fitness after treatment, the results are interesting and emphasize the effects of PA in this population. The results indicate beneficial effects of PA on the heart health in ALL survivors and suggest that they should be encouraged to physically active lifestyle.

The role of endothelial enzymes NOS, VAP-1 and CD73 in acute lung injury

Acute lung injury (ALI) is a syndrome of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that is not caused by left atrial hypertension. Since there is no effective treatment available, this frequent clinical syndrome significantly contributes to mortality of both medical and surgical patients. Great majority of the patients with the syndrome suffers from indirect ALI caused by systemic inflammatory response syndrome (SIRS). Sepsis, trauma, major surgery and severe burns, which represent the most common triggers of SIRS, often induce an overwhelming inflammatory reaction leading to dysfunction of several vital organs. Studies of indirect ALI due to SIRS revealed that respiratory dysfunction results from increased permeability of endothelium. Disruption of endothelial barrier allows extravasation of protein-rich liquid and neutrophils to pulmonary parenchyma. Both under normal conditions and in inflammation, endothelial barrier function is regulated by numerous mechanisms. Endothelial enzymes represent one of the critical control points of vascular permeability and leukocyte trafficking. Some endothelial enzymes prevent disruption of endothelial barrier by production of anti-inflammatory substances. For instance, nitric oxide synthase (NOS) down-regulates leukocyte extravasation in inflammation by generation of nitric oxide. CD73 decreases vascular leakage and neutrophil emigration to inflamed tissues by generation of adenosine. On the other hand, vascular adhesion protein-1 (VAP-1) mediates leukocyte trafficking to the sites of inflammation both by generation of pro-inflammatory substances and by physically acting as an adhesion molecule. The aims of this study were to define the role of endothelial enzymes NOS, CD73 and VAP-1 in acute lung injury. Our data suggest that increasing substrate availability for NOS reduces both lung edema and neutrophil infiltration and this effect is not enhanced by concomitant administration of antioxidants. CD73 protects from vascular leakage in ALI and its up-regulation by interferon-β represents a novel therapeutic strategy for treatment of this syndrome. Enzymatic activity of VAP-1 mediates neutrophil infiltration in ALI and its inhibition represents an attractive approach to treat ALI.