{'fraction_non_alphanumeric': 0.04558541266794626, 'fraction_numerical': 0.02495201535508637, 'mean_word_length': 4.545212765957447, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Abstract 18342: Development of Fibrotic Substrate for Atrial Fibrillation in Advanced Heart Failure is Driven Not by Inflammation but by Smad2/3 Dependent Replacement Fibrosis


 Introduction:
 Fibrosis is an important contributor to atrial fibrillation (AF) substrate in heart failure, with TGF-β signaling generating atrial fibrosis. Inflammation is also known to contribute to AF. However, it is not known: a) if inflammation underlies the development of atrial fibrosis, b) if TGF-β signaling is involved in the generation of atrial inflammation and c) what is the relative role of canonical SMAD2/3 versus non-canonical TGF-β-activated kinase 1 (TAK) signaling in the creation of atrial inflammation/fibrosis.
 
 
 Methods:
 21 dogs underwent transfection in the posterior left atria of either a plasmid expressing a dominant negative TGF-β type II receptor (pUBC-TGFβ-DN-RII) (N=9) or control vector (pUBC-LacZ) (N=12), followed by 3-4 weeks of right ventricular tachypacing (VTP) (240 bpm). After 3-4 weeks of VTP, the following were assessed: AF by open-chest mapping. Atrial tissue was assessed for signaling (pSMAD2/3 and pTAK) by western blot, fibrosis by trichrome staining and iflammation by CD68 staining.
 
 
 Results:
 The interstitial fibrosis in LacZ atria was replacement in character (Fig 1A). TGFβ-RII-DN dogs had a significant decrease in replacement fibrosis leading to a decrease in duration of inducible AF (LacZ 63.64 ± 12.12 s vs. TGFβ 26.52 ± 3.79 s, p < 0.05). While both groups demonstrated evidence of inflammation (CD68 staining), there was no difference in inflammation between the groups (Fig 1B). TGFβ-RII-DN dogs had a significant decrease in pSMAD2/3 but not pTAK, compared to pUBC-LacZ dogs.
 
 
 Conclusion:
 The development of fibrotic substrate for AF in advanced HF is driven not by inflammation but primarily by SMAD2/3 mediated myocardial replacement fibrosis. These findings may have important implications for mechanism-guided therapies for AF, with canonical TGF-β signaling appearing to be an attractive therapeutic target in AF.
 
 
 
