Identification of Cardiac Fibrosis in Young Adults With a Homozygous Frameshift Variant in SERPINE1

Abstract

Importance: Cardiac fibrosis is exceedingly rare in young adults. Identification of genetic variants that cause early-onset cardiomyopathy may inform novel biological pathways. Experimental models and a single case report have linked genetic deficiency of plasminogen activator inhibitor-1 (PAI-1), a downstream target of cardiac transforming growth factor β, with cardiac fibrosis.

Objective: To perform detailed cardiovascular phenotyping and genotyping in young adults from an Amish family with a frameshift variant (c.699_700dupTA) in SERPINE1, the gene that codes for PAI-1.

Design, setting, and participants: This observational study included participants from 3 related nuclear families from an Amish community in the primary analysis and participants from the extended family in the secondary analysis. Participants were recruited from May 2015 to December 2016, and analysis took place from June 2015 to June 2020.

Main outcomes and measures: (1) Multimodality cardiovascular imaging (transthoracic echocardiography and cardiac magnetic resonance imaging), (2) whole-exome sequencing, and (3) induced pluripotent stem cell-derived cardiomyocytes.

Results: Among 17 participants included in the primary analysis, the mean (interquartile range) age was 23.7 (20.9-29.9) years and 9 individuals (52.9%) were confirmed to be homozygous for the SERPINE1 c.699_700dupTA variant. Late gadolinium enhancement was present in 6 of 9 homozygous participants (67%) with absolute PAI-1 deficiency vs 0 of 8 in the control group (P = .001). Late gadolinium enhancement patterns tended to be dense and linear, usually subepicardial but also midmyocardial and transmural with noncoronary distributions. Targeted whole-exome sequencing analysis identified that homozygosity for c.699_700dupTA SERPINE1 was the only shared pathogenic variant or variant of uncertain significance after examination of cardiomyopathy genes among those with late gadolinium enhancement. Induced pluripotent stem cell-derived cardiomyocytes from participants homozygous for the SERPINE1 c.699_700dupTA variant exhibited susceptibility to cardiomyocyte injury in response to angiotensin II (increased transforming growth factor β1 secretion and release of lactate dehydrogenase) compared with control induced pluripotent stem cell-derived cardiomyocytes. In a secondary analysis based on echocardiography in 155 individuals across 3 generations in the extended family, no difference in global longitudinal strain was observed in carriers for the SERPINE1 c.699_700dupTA variant compared with wild-type participants, supporting an autosomal recessive inheritance pattern.

Conclusions and relevance: In this study, a highly penetrant, autosomal recessive, cardiac fibrosis phenotype among young adults with homozygous frameshift variant for SERPINE1 was identified, suggesting an optimal range of PAI-1 levels are needed for cardiac homeostasis.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Khan reports grants from National Institutes of Health/National Center for Advancing Translational Sciences and American Heart Association during the conduct of the study. Dr Shah reports grants from Actelion, AstraZeneca, Pfizer, Novartis, and Corvia Medical and personal fees from Amgen, Aria CV, AstraZeneca, Axon, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cardiora, Cyclerion Therapeutics, Cytokinetics, Eisai, GlaxoSmithKline, Imara, Ionis Pharmaceuticals, Ironwood, Keyto, Merck, MyoKardia, Regeneron Pharmaceuticals, Sanofi, Shifamed, United Therapeutics, Actellion, Pfizer, and Novartis outside the submitted work. Dr Strande reports grants from National Institutes of Health outside the submitted work. Dr McNally reports grants from National Institutes of Health and American Heart Association to Northwestern University during the conduct of the study; grants from National Institutes of Health, US Department of Defense, and Solid Biosciences to Northwestern University outside the submitted work; personal fees from AstraZeneca, Amgen, Avidity, Cytokinetics, Exonics/Vertex, Pfizer, Invitae, and Janssen outside the submitted work; and is founder of Ikaika Therapeutics, unrelated to this content. Dr Lee reports grants from Abbott Laboratories outside the submitted work. Dr Carr reports grants from Siemens, Bayer, and Guerbet and personal fees from Bracco (advisory board), Siemens (advisory board), and Bayer (speaker) outside the submitted work. Dr Shapiro reports other support from Bioverativ (advisory board and research), Catalyst Biosciences (advisory board), Genentech/Roche (advisory board, speakers bureau, and research), Agios Pharmaceuticals (research), BioMarin Pharmaceutical (research), Daiichi Sankyo (research), Glover Blood Therapeutics (research), Kedrion (research), Liminal Sciences (Prometic BioTherapeutics) (consultant and research), OPKO Health (research), Octapharma Plasma (research), Pfizer (advisory board and research), Novo Nordisk (advisory board, consultant, speakers bureau, and research), Sangamo Therapeutics (research), Takeda (advisory board and research), and Sigilon (advisory board) to their institution outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Late Gadolinium Enhancement From 2 Representative Participants Who Are Homozygous for the Null SERPINE1 Allele (c.699_700dupTA) From the Old-Order Amish Kindred

A pattern of dense late gadolinium enhancement is shown (multiple bright foci denoted by arrowheads) in 2 representative individuals who are homozygous for the loss-of-function variant in SERPINE1. In contrast, areas with normal myocardium are black.

Figure 2.. Whole-Exome Sequencing Heat Map Among Old-Order Amish Participants Stratified by Presence or Absence of Late Gadolinium Enhancement or Early-Onset Cardiac Fibrosis

Whole-exome sequencing heat map demonstrates that homozygosity in the loss-of-function variant in SERPINE1 is the only shared variant among all individuals with late gadolinium enhancement. None of the other variants of uncertain significance identified in cardiomyopathy genes cosegregate with the late gadolinium enhancement phenotype. Chr indicates chromosome.