Rosiglitazone Attenuates Atrial Structural Remodeling and Atrial Fibrillation Promotion in Alloxan‐Induced Diabetic Rabbits

Abstract

SUMMARYIntroduction: The pleiotropic effects of glitazones may favorably affect atrial remodeling. We sought to investigate the effects of peroxisome proliferator-activated receptor-c (PPARc) activator rosiglitazone on atrial structural remodeling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits. Methods: Twenty alloxan-induced diabetic rabbits were randomly divided into two groups (10 animals in each group), namely the diabetic rosiglitazone group (treated with rosiglitazone 2 mg/day/kg for 4 weeks) and the nontreated diabetic group, while 10 additional healthy rabbits served as controls. Moreover, isolated Langendorff-perfused rabbit hearts were used to evaluate atrial electrophysiological parameters and vulnerability to AF, examined by burst pacing. Histological examination was also performed, whereas plasma oxidative stress and inflammatory biomarkers were measured. Results: The duration of induced AF was significantly prolonged in the alloxan-induced diabetic rabbits compared with controls (1.6 AE 0.4 s vs. 0 s; P < 0.05). Rosiglitazone treatment significantly reduced the duration of induced AF in the treated rabbits (1.6 AE 0.4 s vs. 1.2 AE 0.05 s; P < 0.05). Moreover, rosiglitazone attenuated atrial structural remodeling reducing the interatrial activation time (35.4 AE 12.1 ms vs. 24.2 AE 10.8 ms, P < 0.05; control 23.3 AE 10.4 ms) and the atrial interstitial fibrosis as well (collagen volume fraction: 5.6 AE 3.9% vs. 2.4 AE 2.1%, P < 0.05; control 1.6 AE 0.8%). Rosiglitazone increased plasma superoxide dismutase (SOD) activity and, on the other hand, decreased malondialdehyde (MDA), hs-C-reactive protein, and tumor necrosis factor-a levels. Conclusion: Rosiglitazone attenuates arrhythmogenic atrial structural remodeling and AF promotion in alloxaninduced diabetic rabbits. Also, it seems to modulate oxidative stress and inflammation in this experimental model.

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

“…We have shown that rosiglitazone attenuates atrial structural remodeling reducing the interatrial activation time and the atrial interstitial fibrosis in alloxan-induced diabetic rabbits [31].. Also, rosiglitazone treatment increased plasma antioxidant enzyme superoxide dismutase (SOD) activity and decreased oxidant stress and inflammatory markers including malondialdehyde (MDA), C-reactive protein (CRP), and TNF-α levels. [32] We have previously described two patients with diabetes who experienced a remarkable improvement in their paroxysmal AF episodes following treatment with rosiglitazone [33]. However, two large RCTs, namely RECORD [34] and PROactive [35] which enrolled high-risk patients with type 2 diabetes failed to demonstrate a significant reduction of AF risk from TZDs compared with controls.…”

Diabetes mellitus and atrial fibrillation: Pathophysiological mechanisms and potential upstream therapies

“…Experimental studies have demonstrated that TZDs prevent atrial electrical and structural remodeling through their antiinflammatory and antioxidant properties [75][76][77][78][79]. The possible targets of PPAR-c agonists include transforming growth factor-b (TGF-b), tumor necrosis factor-a (TNF-a), atrial natriuretic peptide (ANP), superoxide dismutase (SOD), malondialdehyde (MDA), NADPH oxidase subunits, and voltage-dependent Ca 2+ currents [80].…”

Probucol prevents atrial ion channel remodeling in an alloxan-induced diabetes rabbit model

“…The exact underlying pathophysiological mechanisms of such remodeling processes are not fully understood [5]. In an alloxan-induced diabetic rabbit model, our group had previously demonstrated that hyperglycemic conditions lead to increased interstitial fibrosis and higher likelihood of AF development[7], as well as reduction of the Na + current ( I Na ) and increasement of the Ca 2+ current ( I CaL ) in the atria [8]. In the past, it had been demonstrated that an increase in oxidative stress leads to shortened action potential durations (APDs) in the atria due to the elevated transient outward K + current [10] and promotes Ca 2+ release from the intracellular store [11].…”