Effects of Low-Dose Colchicine on Serum High-Sensitivity C-Reactive Protein Level in Coronary Artery Disease Patients with Type 2 Diabetes Mellitus and Enhanced Inflammatory Response Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase 2, Dose-Finding Study2022 · Although cardiovascular mortality in Japan is lower than in other industrialized countries, clinical outcomes in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM) remain poor despite multiple evidence-based drug therapies and interventions. We assumed that part of residual risk in these patients may be attributable to enhanced inflammation, which can be inhibited presumably by colchicine. However, dose-responsiveness of anti-inflammatory effect of colchicine has not been elucidated. Therefore, we designed a multicenter, randomized, double-blinded, parallel-group study to explore the dose-dependent effects of low-dose colchicine on serum high-sensitivity C-reactive protein (hs-CRP) concentration and safety in CAD patients with T2DM and enhanced inflammatory response as a phase 2 study. Enhanced inflammatory response was defined as peripheral white-blood cell count ≥7,000/μL. Patients (<i>N</i> = 63) will be randomly assigned to two doses of colchicine 0.25 mg/day, 0.5 mg/day, or placebo in a 1:1:1 ratio once daily for 12 weeks. Changes in serum hs-CRP levels will be evaluated as the primary endpoint, and changes in flow-mediated vasodilation and plasma myeloperoxidase levels will be evaluated as secondary endpoints. The results of this study will contribute to the development of a protocol for a planned future phase 3 trial to estimate the reduction in CAD. The present study describes the rationale, design, and methods of the trial.
Renin-angiotensin system inhibitors can prevent intravenous lipid infusion-induced myocardial microvascular dysfunction and leukocyte activation2018 · 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.
