Antifibrotic Therapy Delays Progression from Paroxysmal to Persistent Atrial Fibrillation

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1 Antifibrotic Therapy Delays Progression from Paroxysmal to Persistent Atrial Fibrillation José Jalife, M.D. Center for Arrhythmia Research University of Michigan No Disclosures

2 The mechanisms that maintain AF in the human heart are poorly understood. In particular, we simply do not know the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation

3 Some patients suffer paroxysmal AF indefinitely, mainly under anti-arrhythmic therapy, but a large proportion progress to persistent AF.

4 Evolution of AF in the sheep model of persistent AF Pacemaker on Pacemaker off = AF Self-sustained 1st episode Median time to 1 st AF episode 5.5 dias Median time in paroxistic AF 7 weeks (43.5 days) Persistent AF Median time to transition 7-9 weeks (55 days) >12 months We Compared three grups: Sham-operated Tansition (>7 dias in self-sustaining AF without conversion to sinus rhythm ), and Long-term Persistent AF (> 1 year in selfsustaining AF without conversion to sinus rhythm)

5 Sustained AF leads to progressive atrial dilatation without altering LV function Echocardiogram: Sham operated Persistent AF Sham operated Persistent AF No LV dilatation or LV dysfunction Normal posterior wall and IV septum NO tachycardia-induced cardiomyopathy 63 Kg sheep 65 Kg sheep LV ejection fraction Mitral valve regurgitation LA area RA area

6 Changes in serum levels of pro-collagen type III (PIIINP), a marker of cardiac fibrosis, in the sheep PAF model.

7 Structural remodeling during sustained AF Atrial Fibrosis A B

8 Galectin-3 (Gal-3): a Mediator of Tissue Fibrosis Gal-3: Protein with important regulatory roles in inflammation, immunity and cancer Produced by activated macrophages in response to injury Gal-3 in Heart Failure Mediator of extracellular matrix remodeling leading to progressive heart failure Elevated plasma levels in patients with certain forms of heart failure

9 Gal-3 inhibitor trial upstream therapy protocol to prevent persistent AF in the in-vivo ovine model of atrial tachypacing GM-CT-01 (12 mg/kg IV) twice per week Saline twice per week

10 Gal-3 inhibition lessens AF-induced atrial dilatation

11 Gal-3 inhibition reduces Fibrosis in the PLA 8 Fibrosis (%) P< Saline (n = 6) GMCT-01 (n=6) 100 µm SALINE PLA GMCT-01 PLA 100 µm

12 Gal-3 Inhibition increases the percentage of spontaneous terminations and reduces the ability to reinduce AF by rapid burst pacing A B

13 Conclusions 1. In the sheep model of atrial tachypacing persistent AF occurs in the absence of altered LV function and any other co-morbidities, which rules out other causes of remodeling 2. Sustained AF leads to atrial dilatation, increased atrial collagen and fibrosis 3. Electrophysiological remodeling is manifested as a progressive increase in AF frequency during the transition from paroxysmal to persistent AF 4. Gal-3 inhibition reduces both AF-induced structural and electrical remodeling in the sheep model of persistent AF. 5. Gal-3 inhibition is a potential new upstream therapy for the prevention of persistent AF.

14 Clinical Relevance? Galectin-3 levels in blood samples from the Left atrium and the coronary sinus Fifty-five patients underwent RFA for paroxysmal (29) and persistent AF (26). males: 45 [82%]; mean age: 63±8 years;, left atrial [LA] diameter: 45±7 mm, ejection fraction: 0.59±0.06 Paroxysmal AF (ng/ml) Persistent AF (ng/ml) P value Left atrium 11.7± ±3.3 P<0.044 Coronary sinus 12.2± ±3.5 P<0.026

15 There is hope for AF prevention!

16 Acknowledgements Yoshio Takemoto Kuljeet Kaur Cicero Willis-Pineda David Filgueiras-Rama Guadalupe Guerrero Sandeep Pandit Members, Center for Arrhythmia Research Hakan Oral Fred Morady Members UM Arrhythmia Service Rafael Ramirez Raphael Martins Daniela Ponce-Balbuena Raphael Martins Steven Ennis Omer Berenfeld UM-PUHSC JI NHLBI Leducq Foundation