Cardiovascular disease remains the commonest cause of death worldwide. The
majority of deaths are caused by atherosclerotic plaque rupture with resultant
myocardial infarction or stroke, or rupture of abdominal aortic aneurysms.
Conventional imaging modalities have consistently failed to identify atherosclerotic
plaques or aneurysms with high-risk pathological features that are at highest risk of
rupture or progression. The development of modern molecular imaging techniques
targeted at these features could lead to the identification of such high-risk plaques
and aneurysms in vivo and guide the development of novel treatment strategies. The
aim of this thesis was to evaluate whether novel molecular modalities have a role in
providing new insights into biological disease processes, and identify high-risk
plaques and aneurysms. Using positron emission tomography-computed tomography
(PET-CT), 18F-fluorodeoxyglucose and 18F-fluoride were utilised as markers of
metabolic inflammation and active calcification. Cellular inflammation was assessed
using ultrasmall superparamagnetic particles of iron oxide (USPIO) enhanced
magnetic resonance imaging (MRI).
In a prospective trial, 80 patients with myocardial infarction (n=40) and stable angina
(n=40) underwent 18F-fluoride and 18F-fluorodeoxyglucose PET-CT, and invasive
coronary angiography (Chapter 3). Intense 18F-fluoride uptake localised to recently
ruptured plaque in patients with acute myocardial infarction. In patients with stable
coronary artery disease, 18F-fluoride uptake identified coronary plaques with high-risk features on intravascular ultrasound. 18F-fluoride PET-CT is the first noninvasive
imaging method to identify and localise ruptured and high-risk coronary
plaques.
Aortic vascular uptake of 18F- fluorodeoxyglucose was studied in patients with
myocardial infarction and stable angina (Chapter 4). In a separate outcome of 1,003
patients enrolled in the Global Registry of Acute Coronary Events, we further
evaluated whether infarct size predicted recurrent coronary events. Patients with
myocardial infarction had higher remote atherosclerotic tracer uptake that correlated
with the degree of myocardial necrosis, and exceeded that observed in patients with
stable coronary disease. The outcome cohort demonstrated that patients with higher
degree of myocardial necrosis had the highest risk of early recurrent myocardial
infarction. This supports the hypothesis that acute myocardial infarction exacerbates
systemic atherosclerotic inflammation and remote plaque destabilization: myocardial
infarction begets myocardial infarction.
In a prospective imaging cohort, the role inflammation and calcification was assessed
in 63 patients with abdominal aortic aneurysms and 19 age and sex matched patients
with atherosclerosis (Chapter 5). Compared to non-aneurysmal segments, enhanced
inflammation and calcification was observed within the wall of aortic aneurysmal
segments. In comparison to matched controls with atherosclerosis, the entire aorta in
those with aortic aneurysm appears more highly inflamed, suggesting presence of a global aortopathy rather than a disease confined only to the abdominal region of the
aorta. Aortic aneurysms have greater active inflammation and calcification than
atherosclerotic controls suggesting a more intense, destructive and transmural
pathological process. A subgroup of fifteen patients with aortic aneurysms
underwent imaging with both PET-CT with 18F-fluorodeoxyglucose, and T2*-
weighted MRI before and 24 h after administration of USPIO (Chapter 6). Whilst
there was a moderate correlation between the two tracers, there were distinct
differences in the pattern and distribution of uptake suggesting a differential
detection of macrophage glycolytic and phagocytic activity respectively.
These studies provide novel insights into vascular biological processes involved in
the initiation, progression and rupture of atherosclerotic plaques and aortic
aneurysms. Future longitudinal studies are needed to establish whether these
techniques have a role in improving the clinical management and treatment of
patients with coronary artery disease and aortic aneurysms