Neural regulation of inflammatory processes in the heart and in large arteries.

The immune system is essential for the maintenance of the body and in this function inflammation is a powerful tool. Since underperformance as well as excessive inflammation are a serious threat to physical health a strict regulation is vital. The autonomic nervous system plays an important role in this regulation in which activity of the parasympathetic part decreases the inflammatory response while sympathetic nerve activity can act pro- as well as anti-inflammatory. Inflammatory processes play a serious role in cardiovascular diseases (CVD). In atherosclerosis, aneurysms and myocardial infarctions they are a determining factor for the level of final damage and function loss. Understanding of these processes is not fully clear. The studies in this thesis aim to: 1- assess a beneficial effect of vagal stimulation in different manifestations of CVD. 2- investigate associations of innervation and local inflammation in the diseased arterial wall. An additional chapter presents the development of an implantable vagus nerve stimulator for small laboratory animals. The study in chapter 2 shows that tail blood sampling and femoral arterial injury lead to an identical parasympathetic effect that causes a serious decrease of inflammatory responsiveness and this is irrespective of the used anesthetic and the time under anesthesia. The arterial wall is quite sensitive and even gentle manipulation of the femoral artery generates an inhibitory effect on inflammatory cytokine production. It is important to take account of these effects in surgical and experimental procedures since they may be of influence on the experimental and therapeutic outcome. Chapters 3 and 4 present studies in mice on the inflammation attenuating effect of vagus nerve stimulation (VS) after myocardial infarction (MI) or ischemia-reperfusion (IR). In groups receiving VS with MI or IR, infarct size over area at risk ratio was significantly decreased and a non-significant decrease was found for ejection fraction and infarct size. However, the evidence was not strong enough to prove a VS-related reduction of final cardiac damage and function loss 48 hours after experimental MI or cardiac IR. In chapter 5 a study on density of innervation and present inflammatory cells in human abdominal artery wall in developing stages of atherosclerosis is presented. Results indicate that a decrease in total and sympathetic innervation precedes a decline in inflammatory activity. Cholinergic innervation did not show significant differences but comparison with inflammatory cells and sympathetic patterns are indicative for autonomic balance. Little is known about the development of aneurysms. Innervation in aneurysmal carotid and popliteal artery samples were therefore investigated in chapter 6. Carotid arteries show denser innervation than popliteal arteries, which applies for both aneurysmal and control samples. A non-significant increase of sympathetic fibers in carotid aneurysms as compared to control arteries may indicate that outgrowth of these fibers may be associated with development of aneurysms. With the development of an implantable device that enables intermittent stress less vagus nerve stimulation we can now study inflammatory related conditions in small laboratory animals over an extended period (Ch.7)