Pathophysiological mechanisms of microvascular inflammation in the heart and brain

SUMMARY Inflammation of the cardiovascular system plays a crucial role in the pathophysiology of cardiovascular disease. In this thesis, we have analyzed the role of inflammation on the microvasculature of the heart and brain in cardiac disease with special focus on the role of advanced glycation end products (AGEs) herein. In chapter 2 we studied cerebral microvascular inflammation in autopsied patients who died at different time points after myocardial infarction (MI). We found that the proinflammatory factors Nε-(carboxymethyl)lysine (CML) and NADPH oxidase 2 (NOX2) were significantly increased in the microvasculature of the brain in the acute and subacute phases of MI. In Chapter 3 we analyzed the potential beneficial effects of liraglutide on microvascular inflammation of the heart, brain and kidney in a rat model of streptozotocin-induced diabetes mellitus (DM). Liraglutide is a GLP-1 analogue that is used as a drug for type II DM patients, that stimulates insulin production and inhibits glucagon secretion, thereby reducing blood glucose levels and that has been reported to have protective effects on vascular cells in vitro. We found that liraglutide treatment significantly reduced the DM-increased levels of CML, NOXes and the adhesion molecules ICAM-1 and VCAM-1 in the microvasculature of different regions of the heart, the brain and the kidney, without affecting blood glucose levels. These results imply that liraglutide protects the microvasculature against diabetes-induced dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with an increased risk of developing cardiovascular disease, including MI. In chapter 4 we examined the effect of RA on the inflammatory cell densities in the epicardial coronary arteries and the myocardium, as well as the accumulation of cardiac microvascular CML, in autopsied MI patients with and without RA. We found increased inflammatory cell densities in the adventitia of infarct related epicardial coronary arteries. These findings support the hypothesis that RA predisposes towards vulnerable coronary plaque development and increased MI-induced cardiac inflammation, thereby resulting in a higher risk of MI development and worsening its outcome. In the MI-induced cardiac inflammatory response the complement system plays a crucial role, as it aides in the clearance of necrotic tissue, but also exacerbates cardiac damage after MI. In chapter 5 we analyzed the expression of endogenous C1 esterase inhibitor (C1inh), a natural inhibitor of complement, in the hearts of autopsied patients. In MI patients we found C1inh on necrotic cardiomyocytes, colocalizing with complement in the infarct cores of patients who died in the acute inflammatory phase after MI. These results indicate that C1inh is involved in the regulation of complement activity in the infarcted heart and that it is produced locally in the heart after MI. In chapter 6 we compared cardiac inflammation and injury and microvascular inflammation and thrombogenicity between patients who died in the first and second waves of the COVID-19 pandemic. These results show that cardiac inflammation and injury and microvascular inflammation and thrombogenicity were lower in second wave fatal COVID-19 cases compared to the first wave. This may relate to improved treatment strategies in the second wave. In chapter 6 we found increased CML levels in the cardiac microvasculature, along with inflammation of the myocardium (myocarditis) and epicardium (epicarditis) in patients with severe COVID-19, However, it is unknown whether sole epicarditis also impacts the intramyocardial vasculature. Therefore, in Chapter 7 we quantified CML accumulation in the coronary microvasculature of deceased non-COVID patients with sole epicarditis and compared them to control patients. We found increased CML levels in the intramyocardial vasculature of patients with sole epicarditis, which could point to a novel risk factor for further cardiac complications in these patients.