Renin-Angiotensin System Inhibitors Can Prevent Intravenous Lipid Infusion-Induced Myocardial Microvascular Dysfunction and Leukocyte Activation

Abstract

Background: Levels of triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to endothelial dysfunction through renin-angiotensin system (RAS) activation and oxidative stress. The present study investigated how systemic FFA loading affected myocardial microcirculation during hyperemia via RAS. Methods and Results:Eight healthy men received candesartan, perindopril, or a placebo for 2 days in a double-blind crossover design, and then myocardial microcirculation during hyperemia induced by a 2-h infusion of lipid/heparin was assessed using dipyridamole stress-myocardial contrast echocardiography (MCE). Leukocyte activity and hemorheology were also assessed ex vivo using a microchannel flow analyzer, serum levels of oxidative stress markers, and IκB-α expression in mononuclear cells. Serum FFA elevation by the infusion of lipid/heparin significantly decreased myocardial capillary blood velocity and myocardial blood flow during hyperemia. Both candesartan and perindopril significantly prevented the FFA-induced decrease in capillary blood velocity and myocardial blood flow during hyperemia. Systemic FFA loading also caused an increase in the number of adherent leukocytes and prolonged the whole blood passage time. These effects were blocked completely by candesartan and partially by perindopril. Both agents prevented the FFA-induced enhancement of oxidative stress and IκB-α degradation in mononuclear cells. Conclusions:Both candesartan and perindopril can prevent FFA-induced myocardial microcirculatory dysfunction during hyperemia via modulation of leukocyte activation and microvascular endothelial function.

Clinically feasible method for assessing leukocyte rheology in whole blood

“…Abnormal activation states of leukocytes and leukocyte-platelet interactions play key roles in organ injury induced by atherosclerotic disease [1,2], diabetes mellitus, and other inflammatory conditions [3][4][5]. Leukocyte rheology is critical for modulating microvascular haemodynamics through transformation from resting to active states under conditions of inflammation or low shear stress [6][7][8][9], such as high-fat diets [4], triggered by free fatty acids [5][6][7] and ischemia/reperfusion. Decreased leukocyte deformability and increased leukocyte adherence to the post-capillary venular endothelium leads to microvascular dysfunction, in part, through increased blood viscosity [5][6][7].…”

“…Leukocyte rheology is critical for modulating microvascular haemodynamics through transformation from resting to active states under conditions of inflammation or low shear stress [6][7][8][9], such as high-fat diets [4], triggered by free fatty acids [5][6][7] and ischemia/reperfusion. Decreased leukocyte deformability and increased leukocyte adherence to the post-capillary venular endothelium leads to microvascular dysfunction, in part, through increased blood viscosity [5][6][7]. Because of its larger volume and higher cellular viscosity, each leukocyte is equivalent to approximately 700 erythrocytes in its tendency to block 5 μm capillary channels [8].…”

“…Because of its larger volume and higher cellular viscosity, each leukocyte is equivalent to approximately 700 erythrocytes in its tendency to block 5 μm capillary channels [8]. The rheology of leukocytes has significant implications on their functional behaviour, including flow-through capillaries and interactions with endothelial cells [5][6][7][8][9][10].…”

“…However, clinically feasible methods for determining leukocyte activation and the hemorheological character of blood, a non-Newtonian fluid, are limited. A microchannel flow analyser (MCFAN) with a conventional siliconized chip (BK 7-7-4.5D) is a generally accepted ex vivo capillary model for the evaluation of whole blood rheology [5][6][7][14][15][16]. However, the BK 7-7-4.5 model differs from in vivo microvessels in its abrupt narrowing and shorter capillary length.…”

“…Although the number of adhesive leukocytes per unit area has been reported as an index of leukocyte activation [5][6][7], its use is not clinically feasible because the measurement is time-consuming. EDTA-2Na scavenges metal ions (Ca 2+ and Mg 2+ ) essential to the activation of platelets and some leukocytes [8,19].…”