Early detection of *silent* myocardial ischemia and cardiac dysfunction in asymptomatic individuals with increased coronary artery calcium scores

Identification of individuals in the general population with high risk of
adverse outcome due to concealed coronary heart disease (CHD), for instance by
acute coronary syndrome (ACS) or sudden cardiac death (SCD), is currently based
on risk scores incorporating traditional risk factors. However, risk scores
have a relatively low predictive accuracy and a substantial proportion of
people suffer from CHD-related adverse outcome while not being recognized as
high-risk or despite being treated for classical risk factors.

The prognostic value of Coronary Artery Calcium (CAC) scoring on computed
tomography (CT) as a measure of coronary atherosclerosis has been extensively
studied. A CAC-score of 0 has been shown to be associated with very low risk of
adverse outcome, whereas a CAC-score >300 has been associated with high risk.
The clinical benefit of CAC-based management decisions with medication is
currently under investigation.

The presence of myocardial ischemia has also been shown to be a strong
predictor of poor clinical outcome. Treatment strategies based on ischemia
detection were shown to improve clinical outcome in symptomatic patients.
Current insights on the implications of ischemia detection are mainly derived
from studies investigating symptomatic patients and less is known for
asymptomatic individuals and smaller areas of ischemia. However, myocardial
perfusion imaging by MRI is expensive. Therefore, selection of asymptomatic
healthy individuals with high risk of adverse outcome is necessary for further
perfusion imaging to be effective in the general asymptomatic public.

An increased CAC-score was associated with the presence of myocardial ischemia
in previous studies, with a high prevalence of ischemia in individuals with
increased CAC-scores. However, these studies investigated patients with a
history of cardiovascular disease by SPECT. MRI was shown to have higher
diagnostic accuracy compared to SPECT.A diagnostic strategy engaging two modern
cardiac imaging techniques to early detect silent myocardial ischemia might be
effective to accurately identify individuals at high risk for adverse outcome.

The aim of this study is to evaluate early silent myocardial ischemia detection
and other parameters of cardiac dysfunction by cardiac MRI in asymptomatic
high-risk individuals. We will study the prevalence and extent of early
detected silent myocardial ischemia by MRI and its association with adverse
clinical outcome during 5 years of follow-up in asymptomatic individuals with
extensive coronary calcification (CAC>300), who are known to have high risk of
CHD-related adverse outcome. MRI findings will only be reported in case of
serious incidental findings that require guideline-based management.

From previous studies, it can be expected that *placebo* interventions might
alter symptom perception. Feedback of only important incidental findings by MRI
might result in the (possibly false) assumption of individuals who receive no
feedback that they have no (heart) disease and influence symptom perception and
medical attention seeking. The group undergoing MRI will be compared to a group
who will not undergo MRI testing, in which the clinical presentation of the
*natural* course of coronary atherosclerosis (occurrence/recognition of
symptoms and medical attention seeking) is assessed, to evaluate the possible
change in perception and medical attention seeking after performing cardiac
MRI.

This is a prospective multi-center observational cohort study. Two cohorts will
be created by randomization to allow the evaluation of the potential change in
perception of symptoms after performing stress CMR perfusion with feedback of
important incidental findings. Participants in cohort 1 will receive stress MRI
perfusion imaging to investigate cardiac function. Participants in cohort 2
will not receive MRI but will be followed to assess the clinical presentation
of the *natural* course of coronary atherosclerosis.1660 individuals will be
randomized to one of the two cohorts. Follow-up will be performed by
questionnaire and reviewing the medical file at 1, 2.5 and 5 years. Prior to
performing the MRI scan, blood from participants in cohort 1 is drawn and
stored to allow evaluation of cardiac blood markers as predictors of MRI
findings.

Participants in the MRI group will undergo MRI and blood will be drawn during 1
visit to the hospital. Furthermore, participants will be asked to fill out 5
questionnaires in total prior to participation (1x), at baseline (1x) and
during follow-up (3x) of approximately 15 minutes per questionnaire.
Participants in the group not undergoing MRI will only be asked to fill out the
questionnaires and do not have to visit the hospital.

MRI is a safe, commonly used diagnostic tool. A small chance of experiencing
mild side effects of the vasodilating agent (adenosine) and contrast medium
(gadolinium) is present. Potential side effects of the vasodilating agent
include dyspnoe or recognizable chest pain or discomfort during infusion. These
side effects are brief (<30 seconds after terminating infusion). Potential side
effects of gadolinium include brief headache, nausea (feeling sick) and
dizziness for a brief time following the injection. Allergic reactions for both
substances are rare. Serious side effects requiring medical care are very rare.
The procedure of drawing blood is also minimally aggravating. A small chance of
hematoma or phlebitis as a consequence of drawing blood exists.