Abstract 15374: Somatic Mutations of Dnmt3a Contribute to Pulmonary Vascular Remodeling and Right Ventricular Dysfunction in PAH

• Published in: Circulation (New York, N.Y.) N.Y.), 2022-11, Vol.146 (Suppl_1), p.A15374-A15374
• Main Authors: Al-Qazazi, Ruaa, Martin, Ashley Y, potus, francois, Rauh, Michael, Archer, Stephen L
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.15374

BackgroundPulmonary Arterial Hypertension (PAH) is an obliterative pulmonary vasculopathy in which structural changes are driven by inflammation, fibrosis, mitochondrial dysfunction, and pathological angiogenesis. While ~10% of cases of PAH have germline BMPR2 mutations (or one of 16 other recognized or putative PAH genes), the genetic basis for the majority of PAH patients remains unexplained. Somatic mutations in hematopoietic stem cells (HSC) are related to the disorders of clonal hematopoiesis of indeterminate potential (CHIP). Tet methylcytosine dioxygenase 2 (TET2) and DNA methyltransferase 3a (DNMT3A) are among the primary genes involved in CHIP. We found in a PAH-Biobank that 0.39% of PAH patients had somatic or germline TET2 mutations. Also, TET2-knockout mice can develop PAH spontaneously. Thus TET2 is a new PAH gene. We now hypothesize that CHIP driven by mutations of DNMT3A can also cause pulmonary vascular remodeling and right ventricular failure (RVF), contributing to PAH. MethodsStudies were performed on 9 month old DNMT3A knockout (-/-) mice and their relative controls (f/f) (N=5/group). The right ventricular (RV) function was assessed via cardiac ultrasound. Pulmonary artery medial wall thickness (PAMWT) and radial alveolar count (RAC) were assessed in lung tissue sections using light microscopy. ResultsIn DNMT3A -/- mice, there was a reduction in pulmonary artery acceleration time (PAAT) compared to controls (p=0.0268). There was also a significant reduction in percent RV free wall thickening (RVFWT %) compared to controls (57.44±9.97 DNMT3A-/-, 118.5±14.98 f/f; p=0.017). Both Tricuspid annular plane systolic excursion (TAPSE) and cardiac output (CO) were also significantly reduced in DNMT3A -/- mice (p