Inflammation and Early Atherosclerosis

Abstract

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.