Untersuchung des Einflusses von Angiotensin-Rezeptor-Neprilysin-Inhibitoren (ARNI) auf das kollaterale Arterienwachstum im koronaren Arteriogenesemodell in der Ratte

Investigation of the effect of angiotensin receptor neprilysin inhibitors (ARNI) on collateral artery growth in the coronary arteriogenesis model of the rat

Heart failure triggered by myocardial ischemia is one of the leading causes of human death worldwide. Research into preventive measures to avoid the development of heart failure after myocardial infarction and ultimately the event of sudden cardiac death has been ongoing for many years. Studies have shown that patients with high-grade occlusions of large coronary arteries with a distinct coronary collateral vascular network have a better prognosis to survive myocardial infarction, since collateral arteries can restore blood flow in the ischemic area in the case of myocardial infarction.
Arteriogenesis describes the growth of small collateral blood vessels into larger conducting blood vessels. Current research aims to stimulate natural arteriogenesis by various therapeutic measures. Therapeutic arteriogenesis serves as an important compensatory mechanism for the prevention of vascular ischemia through the growth of biological bypasses. Previous studies showed that increasing bradykinin concentration and reducing kinin degradation positively stimulate arteriogenesis in the periphery and brain. The aim of the dissertation at hand was to investigate whether the angiotensin receptor/ neprilysin inhibitor Entresto®, consisting of the pharmacological combination preparation sacubitril and valsartan, therapeutically stimulates protective myocardial arteriogenesis in a rat heart arteriogenesis model by enhancing bradykinin.
At the start of the study, the repetitive-occluding program (ROP) was established to stimulate coronary collateral growth in the heart of the Sprague-Dawley rat. To achieve this, a balloon catheter was surgically implanted on the ramus interventricularis paraconalis of the coronary sinistra artery. Over the next seven days, the catheter was repeatedly inflated with air following a tightly controlled schedule, each time triggering the short-term occlusion of the artery. This procedure was monitored by a standardized computer program. After seven days, myocardial infarction was triggered by the permanent inflation of the occluder during the final surgery, which was followed by the removal of the heart. The study included four experimental groups. All groups received the initial operation. One group (Rop) was then connected to the repetitiveoccluding program. One group served as a control group and was not connected to the ROP. The other two experimental groups also used the ROP, and in addition, the groups received different drug therapies. One of these experimental groups was treated with the combined angiotensin receptor-neprilysin inhibitor Entresto®, whereas the other group was treated with the angiotensin receptor blocker valsartan. The primary end-point measurement was performed by determining the collateral perfusion using isotope-labeled microspheres injected during both the initial and final surgery.
After using the repetitive-occluding program for seven days, the mean collateral perfusion was found to be significantly higher in the ROP group than in the control group. In the experimental group treated with valsartan, no additional improvement in coronary arteriogenesis could be detected compared with the group treated with ROP alone. The group additionally treated with the angiotensin receptor/neprilysin inhibitor Entresto® showed a significantly improved collateral perfusion compared with the other experimental groups.
Thus, the study at hand proves for the first time that treatment with the angiotensin receptor/neprilysin inhibitor Entresto® leads to a marked improvement in collateral perfusion by accelerating the stimulation of collateral vessel growth. Crucial to the effect of Entresto® may be the increase or stabilization of bradykinin levels. This occurs due to the inhibition of neprilysin, the enzyme responsible for bradykinin degradation. At the same time, valsartan serves as a modulator of blood pressure regulation to counteract possible exaggerated effects of a neprilysin inhibitor. The demonstrated pharmacological mechanism triggered by Entresto® treatment may have a high clinical benefit as a preventive drug treatment option in heart failure and myocardial infarction.