Plaque Thrombosis is Reduced by Attenuating Plaque Inflammation with Pioglitazone and is Evaluated by Fluorodeoxyglucose Positron Emission Tomography

Abstract

SUMMARY Introduction:The relationship between the beneficial effects of pioglitazone in reducing clinical events and plaque inflammatory burden remains unknown. This study aimed to determine whether pioglitazone can reduce the number of plaque thrombosis incidences and whether decreasing plaque inflammation is the mechanism by which pioglitazone reduces plaque thromboses. Methods and Results: therosclerotic rabbits were divided into two groups: the atherosclerosis group (n = 13) and pioglitazone group (n = 10). The rabbits underwent pharmacological triggering to induce thrombosis. Serum inflammatory markers, FDG uptake, macrophage, and neovessel staining detected arterial inflammation. PET/CT scans were performed twice (baseline and posttreatment scans). Plaque area, macrophages, and neovessels were measured and the histologic sections were matched with the PET/CT scans. Serum MMP-9 and hsCRP were lower in the pioglitazone group compared to the atherosclerosis group. The SUVmean significantly decreased in the pioglitazone group (0.62 AE 0.21 vs. 0.55 AE 0.19, P = 0.008), but increased in the atherosclerosis group (0.61 AE 0.15 vs. 0.91 AE 0.20, P < 0.000). The incidence rate of plaque rupture, plaque area, macrophage density, and neovessel density was significantly lower in rabbits with pioglitazone than without (15% vs. 38%, P < 0.001; 18.00 AE 2.30 vs. 27.00 AE 1.60; P < 0.001; 8.80 AE 3.94 vs. 28.26 AE 2.49; P < 0.001; 16.50 AE 3.09 vs. 29.00 AE 2.11; P < 0.001, respectively). Moreover, plaque area and macrophage density were positively correlated with SUV values. Conclusions: Our study suggests that pioglitazone can reduce the number of plaque thrombosis incidences by decreasing plaque inflammation.

Pioglitazone Therapy in Patients With Stroke and Prediabetes

“…Pioglitazone also has antiatherosclerotic effects; it reduces insulin resistance by activating peroxisome proliferator–activated receptors–γ and also causes partial minor activation of peroxisome proliferator–activated receptors–α, which promotes uptake, use, and catabolism of fatty acids …”

“…3 Insulin resistance is associated with increased blood pressure, serum low-density lipoprotein cholesterol, triglycerides, coagulation, inflammatory markers, platelet reactivity, reduced high-density lipoprotein cholesterol, and vascular reactivity. [4][5][6] Pioglitazone also has antiatherosclerotic effects 7,8 ; it reduces insulin resistance by activating peroxisome proliferatoractivated receptors-γ and also causes partial minor activation of peroxisome proliferator-activated receptors-α, 9 which promotes uptake, use, and catabolism of fatty acids. 10 In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study, fatal/nonfatal stroke was reduced by 47%.…”

Pioglitazone combined with atorvastatin promotes plaque stabilization in a rabbit model

“…Zhang et al found that pioglitazone can attenuate plaque inflammation further reducing the risk of plaque thrombosis. 10 The Actos Now for Prevention of Diabetes study revealed that pioglitazone slows the progression of atherosclerosis independent of changes in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. 12 In our study, the addition of pioglitazone to atorvastatin treatment provided additive benefits to risk factors for atherosclerosis, such as metabolic and inflammatory parameters.…”

“…However, considering the important role of inflammation in atherosclerotic plaque progression, recent studies have explored the effect of anti-inflammatory treatments other than statins in lowering the incidence of cardiovascular events. [10][11][12] Thiazolidinedione drugs (TZDs) are agonists of peroxisome proliferator-activated receptor-γ and are widely used as antidiabetic agents. In addition to their antidiabetic ability, data from clinical studies and animal models suggest that TZDs can also regulate the inflammatory response by reducing plasma levels of inflammatory markers such as matrix metalloproteinase-9 (MMP-9) and C-reactive protein (CRP).…”

“…In addition to their antidiabetic ability, data from clinical studies and animal models suggest that TZDs can also regulate the inflammatory response by reducing plasma levels of inflammatory markers such as matrix metalloproteinase-9 (MMP-9) and C-reactive protein (CRP). 10,12,13 These changes may slow atherosclerotic plaque progression and reduce the incidence of cardiovascular events.…”