Ischaemic heart disease, also known as coronary artery disease (CAD), is one of the major causes of morbidity and mortality worldwide, with an estimated death rate of 7.4 million in 2012. The growing incidence of cardiovascular risk factors such as obesity, diabetes, hypertension and physical inactivity warrants an increase in CAD, especially in developing countries. CAD is caused by the accumulation of lipids and inflammatory cells in the arterial walls that form atherosclerotic plaques. Unstable coronary plaques are prone to erosion or rupture, obstructing coronary blood flow and causing an acute myocardial infarction (MI). Despite optimal medical treatment, the risk of recurrent major adverse cardiovascular events in these patients remains substantial, emphasizing the need for additional treatment options.
Although the detection and treatment of MI have improved over the years, still 5% of patients die within the first month after MI. Moreover, approximately one in four patients surviving an MI develops heart failure (HF), with a 5-year survival of less than 50%. HF comes with the largest increase in loss of productivity and direct medical costs in the next 20 years, stressing the need for novel therapies to target both, atherosclerosis and the development of HF after MI. Inflammation has proven to be key in both, which is why the aim of the current thesis was to decrease the burden of IHD by targeting inflammation in atherosclerosis and MI.
To this end, we performed several studies in animal models for atherosclerosis (part 1) and MI (part 2). We show that hematopoietic Toll-like receptor 5 deficiency in mice decreases atherosclerotic plaque burden and increases features of plaque stability through defective macrophage migration and T-cell responsiveness. Moreover, we evaluated the effect of radiofrequency ablation and showed that it is a safe way to reduce vasa vasorum and smooth muscle cell content; however, we were not able to influence plaque size or other features of plaque stability. Also, we show that anti-CD34 capturing technology on coronary stents enhances stent endothelialisation in rabbits, which may be a future application to reduce stent thrombosis.
With respect to MI, we investigated the effect of the inhibitory Leukocyte-associated immunoglobulin-like receptor (LAIR). Although LAIR expression and plasma levels were regulated upon MI in humans, WT and LAIR-1 deficient mice did not differ with respect to infarct size or cardiac function after MI. Also, we provided a protocol for the assessment of primary cardiac outcome measurements in large animal models. We show infarct size and area-at-risk staining, 3-dimensional transesophageal echocardiography and pressure-volume (PV) loop measurements with various standardized measurements. These provide the researcher with a sophisticated way to assess therapeutic efficacy. Using these measurements, we also showed that myeloperoxidase inhibition in a pig model of myocardial infarction did not show decreased infarct size. However, in the evaluation of the inflammasome inhibitor MCC950, we showed a decrease in cardiac damage after MI and preserved cardiac function, a promising option to target inflammation and adverse remodelling after MI.