BACKGROUND: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator pioglitazone antagonizes angiotensin II actions and possesses anti-inflammatory and antioxidant properties in vitro. There is evidence that pioglitazone improves ventricular remodeling in some experimental models. OBJECTIVE: The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atrial structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure. METHODS: Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses. RESULTS: Atrial fibrillation (AF) lasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits (mean duration of AF: 8.0 +/- 1.4 seconds). Pioglitazone reduced the duration of AF (3.5 +/- 0.2 seconds, P <.05) and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 +/- 2 ms vs 41 +/- 2 ms, P <.05) and atrial fibrosis (16.8% +/- 0.8% vs 10.9% +/- 0.7%, P <.05; control 1.6% +/- 0.2%), effects comparable to those of candesartan (duration of AF: 3.0 +/- 0.2 seconds; activation time 44 +/- 2 ms; fibrosis: 9.4% +/- 0.6%). Both pioglitazone and candesartan reduced transforming growth factor-beta1, tumor necrosis factor-alpha, and activated extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of pioglitazone or candesartan alone. CONCLUSION: Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR-gamma may be a potential therapeutic target for human AF.
BACKGROUND: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator pioglitazone antagonizes angiotensin II actions and possesses anti-inflammatory and antioxidant properties in vitro. There is evidence that pioglitazone improves ventricular remodeling in some experimental models. OBJECTIVE: The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atrial structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure. METHODS:Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses. RESULTS:Atrial fibrillation (AF) lasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits (mean duration of AF: 8.0 +/- 1.4 seconds). Pioglitazone reduced the duration of AF (3.5 +/- 0.2 seconds, P <.05) and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 +/- 2 ms vs 41 +/- 2 ms, P <.05) and atrial fibrosis (16.8% +/- 0.8% vs 10.9% +/- 0.7%, P <.05; control 1.6% +/- 0.2%), effects comparable to those of candesartan (duration of AF: 3.0 +/- 0.2 seconds; activation time 44 +/- 2 ms; fibrosis: 9.4% +/- 0.6%). Both pioglitazone and candesartan reduced transforming growth factor-beta1, tumor necrosis factor-alpha, and activated extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of pioglitazone or candesartan alone. CONCLUSION:Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR-gamma may be a potential therapeutic target for humanAF.
Authors: Andreas Goette; Jonathan M Kalman; Luis Aguinaga; Joseph Akar; Jose Angel Cabrera; Shih Ann Chen; Sumeet S Chugh; Domenico Corradi; Andre D'Avila; Dobromir Dobrev; Guilherme Fenelon; Mario Gonzalez; Stephane N Hatem; Robert Helm; Gerhard Hindricks; Siew Yen Ho; Brian Hoit; Jose Jalife; Young-Hoon Kim; Gregory Y H Lip; Chang-Sheng Ma; Gregory M Marcus; Katherine Murray; Akihiko Nogami; Prashanthan Sanders; William Uribe; David R Van Wagoner; Stanley Nattel Journal: Heart Rhythm Date: 2016-06-10 Impact factor: 6.343