Abstract 18013: Tranilast Prevents Hypertensive Atrial Electrical and Structural Remodeling Independent of Systolic Blood Pressure Level: a Comparative Study with Blood Pressure Lowering Therapies
Introduction: Hypertension is a major independent risk factor for atrial fibrillation (AF). Whether the abnormal atrial remodeling due to hypertension can be prevented or reversed remains poorly defined. Recent work suggests that anti-fibrotic drug, Tranilast, has beneficial effects in AF. Here, we compared the effects of Tranilast against blood pressure lowering therapies on the substrate for AF in hypertensive sheep.
Methods: 39 sheep with induced ‘one-kidney, one-clip’ (1K1C) hypertension were studied: hypertensive controls (n=7) and hypertensive with Tranilast (600mg, orally, bd) treatment at 12 weeks; the remaining sheep were sequentially assigned to treatment with Amlodipine (10mg daily, n=6) or Atenolol (100mg daily, n=6) or clamp removal (n=6) for a further 16 weeks. 7 other sheep were included as normotensive controls. Open chest epicardial mapping was performed to assess atrial electrophysiological parameters: effective refractory period (ERP), conduction velocity/heterogeneity and AF inducibility. Detailed structural analysis was also performed.
Results: All 1K1C animals developed hypertension with mean systolic blood pressure (SBP) of 156±7 mmHg from baseline mean of 114±8 mmHg. Sixteen weeks of Amlodipine, Atenolol and clamp removal treatment reduced SBP to 133±3 mmHg (p<0.001), 131±11 mmHg (p=0.007) and 125±7 mmHg (p<0.001) respectively, while SBP was unchanged in the Tranilast group 162±5 mmHg (p=NS). Atrial ERP was significantly increased in animals treated with Amlodipine and Atenolol only. Compared to hypertensive group, Tranilast and blood pressure lowering therapies significantly reduced: atrial conduction slowing/heterogeneity (p<0.001); transmural atrial myocyte hypertrophy and endomysial fibrosis (all p<0.05); pro-fibrotic cytokines (CTGF & TGF-ß1, both p<0.001); interstitial collagen deposition and atrial inflammatory infiltrates (both p<0.001). All treated animals also showed significantly increased Connexin 43 expression (p<0.001) and reduced AF inducibility (p<0.05).
Conclusions: Despite higher blood pressure levels, anti-remodeling effects of Tranilast are comparable to the reverse remodeling effects of blood pressure lowering therapies both electrically and structurally.
Author Disclosures: S. Thanigaimani: None. D.H. Lau: None. A.G. Brooks: None. D.J. Kelly: None. P. Kuklik: None. R. Mahajan: None. D. Twomey: None. J. Manavis: None. T. Kuchel: None. S. Govindarajan: None. J. Selvanayagam: None. K.C. Roberts-Thomson: None. P. Sanders: None.
- © 2014 by American Heart Association, Inc.