Towards understanding the interplay of inflammation, immunity and circulating cells in atherosclerosis development in young adulthood: a magnetic resonance study

Atherosclerosis is a chronic inflammatory condition that causes detectable
changes in the arterial wall prior to clinical symptoms in end organs. The
disease affects all vascular beds, including the coronary, carotid, aorta and
peripheral arteries and is present years before symptoms arise. Although
classical risk factors such as age, sex, hypertension, cholesterol levels,
smoking and diabetes mellitus have been conclusively linked to induction and
promotion of atherosclerosis they do not fully account for clinically manifest
disease later in life. This problem presents a diagnostic dilemma: we know
there are (asymptomatic) subjects with (rapidly progressing) atherosclerosis,
but they cannot be conclusively identified by using traditional risk factor
profiling alone. Conversely, there are also subjects with elevated levels of
traditional risk factors who do not harbor atherosclerotic disease, or whose
atherosclerotic disease progresses at a much slower pace. When considering the
long asymptomatic latent period before symptoms develop, and that there are
highly effective preventive therapies available, it is clear there is a need to
identify markers that reliably predict the presence and extent of
atherosclerosis in individual patients. In fact, the most recent American
College of Cardiology / American Heart Association (ACC/AHA) guideline for
assessment of cardiovascular risk in asymptomatic adults (published in November
2010) acknowledges this problem and states: "the problem is immense, but the
preventive opportunity is also great".

A further problem is the fact that the association between traditional risk
factors and clinical symptoms of atherosclerotic occlusive disease in various
beds have been established primarily in people older than 40 years of age.
Consequently, the ACC/AHA guideline further states that: "with regard to global
risk scores...it is important to note that there are limited data from
Framingham and other long-term observational studies on 10-year risk in young
adults; consequently, it is difficult to estimate 10-year risk in young
adults", and "to direct attention to the lifetime significance of coronary risk
factors in younger adults, the writing committee considered measurement of a
global risk score possibly worthwhile even in persons as young as age 20"

The relevance of the proposed study lies in clarification of the
interrelationship between these markers and the presence of early
atherosclerosis. The young adult is an especially relevant study subject as the
potential gain in quality adjusted life years by early intervention - in the
form of both lifestyle changes and pharmacological intervention - is largest
(i.e. will lead to the largest gain in quality adjusted life years). Also,
young adults are more amenable to life style changes compared to older
subjects. The insights obtained in this study will therefore pave the way for
initiation of preventive treatment in young patients at highest risk for
developing clinically manifest atherosclerosis. Insight into which biomarkers
best predict presence and (accelerated) progression of atherosclerosis in the
young allows for the most cost-effective use of the inherently limited funds to
develop strategies to prevent future cardiovascular events.

In other words, the results of this study will yield improved tools to identify
individuals at highest risk of developing clinically manifest atherosclerosis.
The most intensive preventive measures can then be directed at these
individuals. This is likely to be a more (cost-) effective approach compared
targeting preventive measures to subjects based on traditional risk factors
alone.

The overall objective of this project is to assess the interplay between
classical risk factors (including lifestyle factors), plasma markers, markers
of activated circulating cells and atherosclerosis burden at MR imaging
(expressed as aortic vessel wall thickness and presence of plaques) in the
development of atherosclerosis in young adulthood to further elucidate key
drivers of clinically manifest atherosclerosis later in life.

The 4 objectives of this project are to assess:

1. Which markers of circulating cells relate to presence and rate of change in
atherosclerosis over time in young adulthood?
2. Which plasma markers of systemic inflammation (including micro-particles)
relate to (a) presence and (b) rate of change in atherosclerosis over time in
young adulthood?
3. Which plasma markers of systemic inflammation and markers of circulating
cells can best identify individuals in young adulthood that are at high risk of
developing advanced atherosclerosis, over classical cardiovascular risk factors
(including lifestyle factors)?
4. What are the factors that affect change over time in plasma markers of
systemic inflammation and markers of circulating cells in young adulthood?

Atherosclerosis burden is measured with MR imaging (expressed as aortic vessel
wall thickness and presence of plaques)

This is a prospective, single center study. It will be a collaboration
between the Departments of Experimental Cardiology, the Julius Center for
Health Sciences and Primary care and the department of Radiology at the
University Medical Center Utrecht, The Netherlands. The cooperating study
subjects will sign an informed consent prior to any study related procedure.
The study subjects will be included and examined. Subsequently, these
individuals will be re-examined 3 years after the first examination. In total
520 patients will be included.

Permission to use the Utrecht Health Project as a sampling frame for our study
has been permitted by the Julius Huisartsen Netwerk (JHN). Invitations will be
sent to the potential participants on behalf of the project group and with
consent from the JHN. If this method would not lead to enough participants, we
will furthermore recruit participants via advertising. When participants are
willing to participate, a visit at the UMC Utrecht will be planned. Before that
visit, all participants have to give written informed consent . During the
visit at the UMC Utrecht, participants will undergo a physical examination,
blood sampling and MR imaging. All these tests will be performed within 2
hours. Afterwards, participants will receive a questionnaire at home that they
have to complete.

The risks of this study are minimal. The infusion, the blood withdrawal, the
infusion of contrast agent and the MR Imaging are procedures that are safe,
innocent, without (long term) side effects and do no potential harm to the
subject. Gadovist is a safe and innocent contrast agent that is routinely used
daily in usual patient care. Side effects of Gadovist are very rare, if a side
effect (i.e. an allergic reaction) occurs, this reaction is easy to treat,
health risks are minimal. The most prevalent side effects of Gadovist contrast
are headache, nausea, a warm feeling and local reactions at the injection site
(i.e. swelling and pain). However, the frequency of these side effects is very
low. Adjacent to that, the study population consists of an ongoing cohort of
healthy young adults in whom it is very unlikely that adverse events will
occur. However, this study has the potential to have enormous benefits as well
for its participants as for the general population. This multidisciplinary
proposal is aimed at decreasing cardiovascular disease burden. A highly
innovative element of this proposal is assessment of the presence and extent of
atherosclerosis in the young, including changes over time, which is an area
where very little data is available. The project may open horizons by enhancing
insight in development of atherosclerosis in humans at a young age (25-35
years) and its determinants. Furthermore, it may open opportunities to find
specific markers for identification of those at high risk of development of
atherosclerosis and opens ways for evaluation of interventions targeted to
these markers. Serial magnetic resonance imaging will boost opportunities for
studying the rate of aortic atherosclerosis over time in response to both non-
pharmacological and pharmacological interventions. The young adult is an
especially relevant study subject as the potential gain in quality adjusted
life years by early intervention - in the form of both lifestyle changes and
pharmacological intervention - is largest (i.e., will lead to the largest gain
in quality adjusted life years). Also, young adults are more amenable to life
style changes compared to older subjects. The insights obtained in this study
may therefore pave the way for initiation of preventive treatment in young
patients at highest risk for developing clinically manifest atherosclerosis.
Insight into which biomarkers best predict presence and (accelerated)
progression of atherosclerosis in the young may allow for the most
cost-effective use of the inherently limited funds to develop strategies to
prevent future cardiovascular events.
Hence, the results of this study potentially may yield improved tools to
identify individuals at highest risk of developing clinically manifest
atherosclerosis. The most intensive preventive measures can then be directed at
these individuals. This is likely to be a more (cost-)effective approach
compared targeting preventive measures to subjects based on traditional risk
factors alone.