Inflammation and Early Atherosclerosis

Ateroskleroosi on valtimoseinämän sairaus. Pitkälle edennyt ateroskleroosi voi johtaa sydän- ja verisuonitautien, kuten sepelvaltimotaudin, sydäninfarktin ja aivohalvausten syntyyn. Ateroskleroosin alkuvaiheessa valtimon seinämään kertyy kolesterolia ja siinä käynnistyy matala-asteinen tulehdusreaktio. Erityisesti ateroskleroosin tulehdusreaktio on ollut tiiviin tutkimuksen kohteena viime vuosina. Sydän- ja verisuonitautien klassiset riskitekijät ovat ikä, sukurasite, tupakointi, diabetes, korkeat verenpaine- ja kolesterolitasot. Näiden klassisten riskitekijöiden lisäksi korkeita tulehdusmerkkiainepitoisuuksia on yhdistetty sydän- ja verisuonitauteihin, sekä ateroskleroosin. Kuitenkin on epäselvää ovatko tulehdusmerkkiaineiden kohonneet pitoisuudet yhteydessä varhaisiin ateroskleroottisin muutoksiin ja mitkä muut tekijät voivat vaikuttaa näihin pitoisuuksiin. Väitöskirjatutkimuksen tavoitteena oli selvittää näitä kysymyksiä kahdessa laajassa suomalaisessa aineistossa: Lasten ja nuorten sepelvaltimotaudin riskitekijät ja Terveys 2000. Väitöskirjatutkimuksessa selvitettiin C-reaktiivisen proteiinin, seerumin amyloidi A:n, pentraksiini-3:n ja sytomegalovirusvasta-aineiden yhteyttä varhaisiin valtimotaudin muutoksiin ja muihin ateroskleroosin riskitekijöihin. Tutkimuksessa pystyttiin osoittamaan tutkittujen tulehdusmerkkiaineiden olevan yhteydessä moniin ateroskleroosin klassisiin riskitekijöihin, kuten verenpaine- ja kolesterolitasoihin. Lisäksi tulehdusmerkkiaineiden osoitettiin olevan yhteydessä rasva-aineenvaihduntaan ja yhdistelmäehkäisyvalmisteiden käyttöön. Tutkimuksessa osoitettiin myös korkeiden sytomegalovirusvasta-ainepitoisuuksien olevan yhteydessä varhaisiin valtimotaudin muutoksiin nuorilla miehillä.Traditionally atherosclerosis has been considered merely as a lipid storage disease. It has been known that the excess lipid molecules accumulate in the artery walls, which eventually leads to narrowing of the lumen. Nowadays it is also known that atherosclerosis is a chronic inflammatory process that will develop over decades of human life. During that process the artery wall loses its normal function. The feared endpoints of atherosclerosis are cardiovascular diseases, which are the main reasons for disability and mortality in the world. Typical atherosclerotic risk factors have been known for decades: age, male sex, smoking, diabetes, high blood pressure and high cholesterol values. In addition to these traditional risk factors many inflammatory parameters have been shown to be increased in cardiovascular disease patients as well in people who had atherosclerotic changes in the arteries. The Creactive protein (CRP) especially has been shown to be a significant independent biomarker. It has also been shown that preventive treatment for patients with increased CRP values is beneficial. Many other inflammatory markers or immunity mediators have been related to atherosclerosis and cardiovascular disease risk. However, only limited information exists about the role of these factors in healthy people and whether they can be considered as independent risk factors for early atherosclerosis. Data from two large Finnish cohorts were used in this dissertation. The Cardiovascular Risk in Young Finns Study, an ongoing followup study involving participants between 24 and 39 years of age in the 21year followup conducted in 2001 (n=2,283). Inflammatory markers, CRP and serum amyloid A (SAA), as well as cytomegalovirus CMV) antibodies were measured from the participants of the Cardiovascular Risk in Young Finns Study. In the data analysis we found that CRP levels were significantly higher in those women who used combined oral contraceptives. Triglyceride levels were also elevated in combined oral contraceptive users and triglyceride levels were associated with elevated CRP levels. Additionally, the effect of oral contraceptive use on CRP levels was so decisive that it overwhelmed the effect of CRP genetics on CRP values. Increased SAA concentrations were also associated with use of combined oral contraceptives. Interestingly, the use of an intrauterine device was associated with decreased SAA values. SAA levels were also associated directly with body mass index, leptin (a hormone secreted by adipose tissue) and with HDL cholesterol or its surface apoliproteinA1. SAA levels correlated with early vascular changes but these associations were not independent in multivariate models. Decrease in heart rate variability has been shown to be a marker of dysregulation of the autonomic nervous system. We demonstrated that heart rate variability is independently associated with CRP but not with SAA levels. High CMV antibody titers was shown to be related with blood pressure values and inversely with endothelial function in men. These relations were not seen in women. The Health 2000 Study included 1,867 participants between 46 to 76 years of age. PTX3 levels were measured from the participants of the Health 2000 Study. PTX3 levels were associated with atherosclerotic risk factors, including LDL cholesterol levels, pulse pressure and indoleamine 2,3 dioxygenase levels. There was no relation between early vascular changes and PTX3 values. In conclusion, measured inflammatory markers were related to several atherosclerotic risk factors such as metabolic and blood pressure values. However, only high CMV antibody levels were independently associated with unfavourable changes in vascular function

Influence of early life risk factors and lifestyle on systemic vascular resistance in later adulthood: the cardiovascular risk in young Finns study

Purpose There are limited data available concerning the effects of lifetime risk factors and lifestyle on systemic hemodynamics, especially on systemic vascular resistance. The purpose of the study was to evaluate how lifetime cardiovascular risk factors (body mass index (BMI), high-density lipoprotein, low-density lipoprotein, triglycerides, systolic blood pressure, blood glucose) and lifestyle factors (vegetable consumption, fruit consumption, smoking and physical activity) predict systemic vascular resistance index (SVRI) and cardiac index (CI) assessed in adulthood. Materials and Methods Our study cohort comprised 1635 subjects of the Cardiovascular Risk in Young Finns Study followed up for 27 years since baseline (1980; aged 3-18 years, females 54.3%) who had risk factor and lifestyle data available since childhood. Systemic hemodynamics were measured in 2007 (aged 30-45 years) by whole-body impedance cardiography. Results In the multivariable regression analysis, independent predictors of the adulthood SVRI were childhood BMI, blood glucose, vegetable consumption, smoking, and physical activity (p p p p p p Conclusion Childhood BMI, blood glucose, vegetable consumption, smoking and physical activity independently predict systemic vascular resistance in adulthood. A favourable change in the number of risk factors or BMI from childhood to adulthood was associated with lower vascular resistance in adulthood.</p

Association of lifetime blood pressure with adulthood exercise blood pressure response: the cardiovascular risk in young Finns study

PurposeElevated blood pressure (BP) in childhood has been associated with increased adulthood BP. However, BP and its change from childhood to adulthood and the risk of exaggerated adulthood exercise BP response are largely unknown. Therefore, we studied the association of childhood and adulthood BP with adulthood exercise BP response.Materials and methodsThis investigation consisted of 406 individuals participating in the ongoing Cardiovascular Risk in Young Finns Study (baseline in 1980, at age of 6-18 years; follow-up in adulthood in 27-29 years since baseline). In childhood BP was classified as elevated according to the tables from the International Child Blood Pressure References Establishment Consortium, while in adulthood BP was considered elevated if systolic BP was >= 120 mmHg or diastolic BP was >= 80 mmHg or if use of antihypertensive medications was self-reported. A maximal cardiopulmonary exercise test with BP measurements was performed by participants in 2008-2009, and exercise BP was considered exaggerated (EEBP) if peak systolic blood pressure exceeded 210 mmHg in men and 190 mmHg in women.ResultsParticipants with consistently high BP from childhood to adulthood and individuals with normal childhood but high adulthood BP had an increased risk of EEBP response in adulthood (relative risk [95% confidence interval], 3.32 [2.05-5.40] and 3.03 [1.77-5.17], respectively) in comparison with individuals with normal BP both in childhood and adulthood. Interestingly, individuals with elevated BP in childhood but not in adulthood also had an increased risk of EEBP [relative risk [95% confidence interval], 2.17 [1.35-3.50]).ConclusionsThese findings reinforce the importance of achieving and sustaining normal blood pressure from childhood through adulthood.</p

Systemic vascular resistance predicts the development of hypertension: the cardiovascular risk in young Finns study

Purpose: To study whether systemic hemodynamics, especially systemic vascular resistance, predicts the development of hypertension and improves the risk prediction of incident hypertension beyond common risk factors in the risk models in young adults. Materials and methods: Typical risk factors for hypertension in the risk prediction models (systolic and diastolic blood pressure, parental history of hypertension, age, sex, body-mass index, smoking), laboratory values (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, C-reactive protein), heart rate (HR), stroke index (SI), and systemic vascular resistance index (SVRI) calculated by whole-body impedance cardiography were evaluated in 2007 and blood pressure in 2011 in 1293 Finnish adults (aged 30-45 years; females 56%;n = 1058 normotensive in 2007). Results: Of hemodynamic variables, SVRI and HR evaluated in 2007 were independently associated with systolic blood pressure (p Conclusions: These findings suggest that systemic vascular resistance index predicts the incidence of hypertension in young adults and that the evaluation of systemic hemodynamics could provide an additional tool for hypertension risk prediction.</div

Inflammation and Early Atherosclerosis

Ateroskleroosi on valtimoseinämän sairaus. Pitkälle edennyt ateroskleroosi voi johtaa sydän- ja verisuonitautien, kuten sepelvaltimotaudin, sydäninfarktin ja aivohalvausten syntyyn. Ateroskleroosin alkuvaiheessa valtimon seinämään kertyy kolesterolia ja siinä käynnistyy matala-asteinen tulehdusreaktio. Erityisesti ateroskleroosin tulehdusreaktio on ollut tiiviin tutkimuksen kohteena viime vuosina. Sydän- ja verisuonitautien klassiset riskitekijät ovat ikä, sukurasite, tupakointi, diabetes, korkeat verenpaine- ja kolesterolitasot. Näiden klassisten riskitekijöiden lisäksi korkeita tulehdusmerkkiainepitoisuuksia on yhdistetty sydän- ja verisuonitauteihin, sekä ateroskleroosin. Kuitenkin on epäselvää ovatko tulehdusmerkkiaineiden kohonneet pitoisuudet yhteydessä varhaisiin ateroskleroottisin muutoksiin ja mitkä muut tekijät voivat vaikuttaa näihin pitoisuuksiin. Väitöskirjatutkimuksen tavoitteena oli selvittää näitä kysymyksiä kahdessa laajassa suomalaisessa aineistossa: Lasten ja nuorten sepelvaltimotaudin riskitekijät ja Terveys 2000. Väitöskirjatutkimuksessa selvitettiin C-reaktiivisen proteiinin, seerumin amyloidi A:n, pentraksiini-3:n ja sytomegalovirusvasta-aineiden yhteyttä varhaisiin valtimotaudin muutoksiin ja muihin ateroskleroosin riskitekijöihin. Tutkimuksessa pystyttiin osoittamaan tutkittujen tulehdusmerkkiaineiden olevan yhteydessä moniin ateroskleroosin klassisiin riskitekijöihin, kuten verenpaine- ja kolesterolitasoihin. Lisäksi tulehdusmerkkiaineiden osoitettiin olevan yhteydessä rasva-aineenvaihduntaan ja yhdistelmäehkäisyvalmisteiden käyttöön. Tutkimuksessa osoitettiin myös korkeiden sytomegalovirusvasta-ainepitoisuuksien olevan yhteydessä varhaisiin valtimotaudin muutoksiin nuorilla miehillä.Traditionally atherosclerosis has been considered merely as a lipid storage disease. It has been known that the excess lipid molecules accumulate in the artery walls, which eventually leads to narrowing of the lumen. Nowadays it is also known that atherosclerosis is a chronic inflammatory process that will develop over decades of human life. During that process the artery wall loses its normal function. The feared endpoints of atherosclerosis are cardiovascular diseases, which are the main reasons for disability and mortality in the world. Typical atherosclerotic risk factors have been known for decades: age, male sex, smoking, diabetes, high blood pressure and high cholesterol values. In addition to these traditional risk factors many inflammatory parameters have been shown to be increased in cardiovascular disease patients as well in people who had atherosclerotic changes in the arteries. The Creactive protein (CRP) especially has been shown to be a significant independent biomarker. It has also been shown that preventive treatment for patients with increased CRP values is beneficial. Many other inflammatory markers or immunity mediators have been related to atherosclerosis and cardiovascular disease risk. However, only limited information exists about the role of these factors in healthy people and whether they can be considered as independent risk factors for early atherosclerosis. Data from two large Finnish cohorts were used in this dissertation. The Cardiovascular Risk in Young Finns Study, an ongoing followup study involving participants between 24 and 39 years of age in the 21year followup conducted in 2001 (n=2,283). Inflammatory markers, CRP and serum amyloid A (SAA), as well as cytomegalovirus CMV) antibodies were measured from the participants of the Cardiovascular Risk in Young Finns Study. In the data analysis we found that CRP levels were significantly higher in those women who used combined oral contraceptives. Triglyceride levels were also elevated in combined oral contraceptive users and triglyceride levels were associated with elevated CRP levels. Additionally, the effect of oral contraceptive use on CRP levels was so decisive that it overwhelmed the effect of CRP genetics on CRP values. Increased SAA concentrations were also associated with use of combined oral contraceptives. Interestingly, the use of an intrauterine device was associated with decreased SAA values. SAA levels were also associated directly with body mass index, leptin (a hormone secreted by adipose tissue) and with HDL cholesterol or its surface apoliproteinA1. SAA levels correlated with early vascular changes but these associations were not independent in multivariate models. Decrease in heart rate variability has been shown to be a marker of dysregulation of the autonomic nervous system. We demonstrated that heart rate variability is independently associated with CRP but not with SAA levels. High CMV antibody titers was shown to be related with blood pressure values and inversely with endothelial function in men. These relations were not seen in women. The Health 2000 Study included 1,867 participants between 46 to 76 years of age. PTX3 levels were measured from the participants of the Health 2000 Study. PTX3 levels were associated with atherosclerotic risk factors, including LDL cholesterol levels, pulse pressure and indoleamine 2,3 dioxygenase levels. There was no relation between early vascular changes and PTX3 values. In conclusion, measured inflammatory markers were related to several atherosclerotic risk factors such as metabolic and blood pressure values. However, only high CMV antibody levels were independently associated with unfavourable changes in vascular function

Influence of early life risk factors and lifestyle on systemic vascular resistance in later adulthood : the cardiovascular risk in young Finns study

Purpose: There are limited data available concerning the effects of lifetime risk factors and lifestyle on systemic hemodynamics, especially on systemic vascular resistance. The purpose of the study was to evaluate how lifetime cardiovascular risk factors (body mass index (BMI), high-density lipoprotein, low-density lipoprotein, triglycerides, systolic blood pressure, blood glucose) and lifestyle factors (vegetable consumption, fruit consumption, smoking and physical activity) predict systemic vascular resistance index (SVRI) and cardiac index (CI) assessed in adulthood. Materials and Methods: Our study cohort comprised 1635 subjects of the Cardiovascular Risk in Young Finns Study followed up for 27 years since baseline (1980; aged 3–18 years, females 54.3%) who had risk factor and lifestyle data available since childhood. Systemic hemodynamics were measured in 2007 (aged 30–45 years) by whole-body impedance cardiography. Results: In the multivariable regression analysis, independent predictors of the adulthood SVRI were childhood BMI, blood glucose, vegetable consumption, smoking, and physical activity (p ≤.046 for all). Vegetable consumption, smoking, and physical activity remained significant when adjusted for corresponding adult data (p ≤.036 for all). For the CI, independent predictors in childhood were BMI, systolic blood pressure, vegetable consumption, and physical activity (p ≤.044 for all), and the findings remained significant after adjusting for corresponding adult data (p ≤.046 for all). The number of childhood and adulthood risk factors and unfavourable lifestyle factors was directly associated with the SVRI (p <.001) in adulthood. A reduction in the number of risk factors and unfavourable lifestyle factors or a favourable change in BMI status from childhood to adulthood was associated with a lower SVRI in adulthood (p <.001). Conclusion: Childhood BMI, blood glucose, vegetable consumption, smoking and physical activity independently predict systemic vascular resistance in adulthood. A favourable change in the number of risk factors or BMI from childhood to adulthood was associated with lower vascular resistance in adulthood.publishedVersionPeer reviewe

Association of lifetime blood pressure with adulthood exercise blood pressure response : the cardiovascular risk in young Finns study

Purpose: Elevated blood pressure (BP) in childhood has been associated with increased adulthood BP. However, BP and its change from childhood to adulthood and the risk of exaggerated adulthood exercise BP response are largely unknown. Therefore, we studied the association of childhood and adulthood BP with adulthood exercise BP response. Materials and methods: This investigation consisted of 406 individuals participating in the ongoing Cardiovascular Risk in Young Finns Study (baseline in 1980, at age of 6–18 years; follow-up in adulthood in 27–29 years since baseline). In childhood BP was classified as elevated according to the tables from the International Child Blood Pressure References Establishment Consortium, while in adulthood BP was considered elevated if systolic BP was ≥120 mmHg or diastolic BP was ≥80 mmHg or if use of antihypertensive medications was self-reported. A maximal cardiopulmonary exercise test with BP measurements was performed by participants in 2008–2009, and exercise BP was considered exaggerated (EEBP) if peak systolic blood pressure exceeded 210 mmHg in men and 190 mmHg in women. Results: Participants with consistently high BP from childhood to adulthood and individuals with normal childhood but high adulthood BP had an increased risk of EEBP response in adulthood (relative risk [95% confidence interval], 3.32 [2.05–5.40] and 3.03 [1.77–5.17], respectively) in comparison with individuals with normal BP both in childhood and adulthood. Interestingly, individuals with elevated BP in childhood but not in adulthood also had an increased risk of EEBP [relative risk [95% confidence interval], 2.17 [1.35–3.50]). Conclusions: These findings reinforce the importance of achieving and sustaining normal blood pressure from childhood through adulthood.publishedVersionPeer reviewe

Systemic vascular resistance predicts the development of hypertension : the cardiovascular risk in young Finns study

Purpose To study whether systemic hemodynamics, especially systemic vascular resistance, predicts the development of hypertension and improves the risk prediction of incident hypertension beyond common risk factors in the risk models in young adults. Materials and methods Typical risk factors for hypertension in the risk prediction models (systolic and diastolic blood pressure, parental history of hypertension, age, sex, body-mass index, smoking), laboratory values (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, C-reactive protein), heart rate (HR), stroke index (SI), and systemic vascular resistance index (SVRI) calculated by whole-body impedance cardiography were evaluated in 2007 and blood pressure in 2011 in 1293 Finnish adults (aged 30–45 years; females 56%; n = 1058 normotensive in 2007). Results Of hemodynamic variables, SVRI and HR evaluated in 2007 were independently associated with systolic blood pressure (p < 0.001 and p = 0.047, respectively) and SVRI with diastolic blood pressure measured in 2011 (p = 0.014), and SVRI and HR were independent predictors of incident hypertension (p < 0.001 and p = 0.024, respectively). SVRI was the most significant predictor of incident hypertension independently of other risk factors (odds ratio 2.73 per 1 standard deviation increase, 95% confidence interval 1.93–3.94, p < 0.001). The extended prediction model (including SVRI) improved the incident hypertension risk prediction beyond other risk factors, with an area under the receiver operating characteristic curve of 0.846 versus 0.817 (p = 0.042) and a continuous net reclassification improvement of 0.734 (p < 0.001). Conclusions These findings suggest that systemic vascular resistance index predicts the incidence of hypertension in young adults and that the evaluation of systemic hemodynamics could provide an additional tool for hypertension risk prediction