Abstract 20137: A Novel Form of Familial Fibrotic Cardiomyopathy Associated With Homozygous Loss-of-Function SERPINE1 Mutation
Introduction: Inbred homozygous mice with complete genetic deficiency of plasminogen activator inhibitor-1 (PAI-1), but not heterozygous mice, develop age-dependent cardiac-specific fibrosis. A unique loss-of-function mutation in SERPINE1 (c.699_700dupTA), which encodes PAI-1, in the Old Order Amish provides a novel opportunity to assess the cardiopulmonary effects of complete PAI-1 deficiency in humans.
Methods: We studied 10 participants homozygous for the null SERPINE1 allele (26±6 years) through echocardiography (TTE), cardiac magnetic resonance imaging (cMRI), and spirometry. . Homozygotes were age-matched to 21 unaffected or heterozygous members of the Berne Amish (27±5 years) who underwent TTE and spirometry, and 10 healthy non-Amish controls (37±10 years) who underwent cMRI. Associations were tested through polygenic models adjusted for age, sex, and relatedness in SOLAR.
Results: As predicted based on genotype, homozygous participants had no circulating PAI-1. Mean LVEF in homozygous participants (59±6%) was similar to controls (61±7%, p=NS) as were lung volumes (p=NS). Tricuspid annular plane systolic excursion and global longitudinal strain (GLS) were significantly lower (p<0.01 for both) and sum wall motion score index was significantly higher (p=0.01) in homozygous participants compared to controls. Late gadolinium enhancement (LGE) was present in 7 (70%) of the homozygous participants (Figure) with mean fibrosis burden of 6.7±6.8% (range 1-19%) compared to no LGE in the controls (p=0.007).
Conclusion: Homozygous null SERPINE1 participants had significantly lower GLS and cardiac fibrosis with LGE. These results describe the discovery of a novel fibrotic cardiomyopathy in the only known human kindred with complete deficiency of PAI-1. These novel findings confirm and extend the selective cardiac pathophysiology seen in murine models and validate a role for PAI-1 in the regulation of myocardial fibrosis in humans.
Author Disclosures: S.S. Khan: None. S.J. Shah: None. E. Klyachko: None. P. Flevaris: None. D.C. Lee: None. M. Cuttica: None. J.C. Carr: None. B.C. Benefield: None. L. Nelson: None. M. Heiman: None. S. Gupta: None. A.D. Shapiro: None. D.E. Vaughan: None.
- © 2016 by American Heart Association, Inc.