Aortic root aneurysm with right atrial clot: a rare combination

Though the incidence of aneurysms involving the aortic root and/or ascending aorta is common, the combination of aortic root aneurysm and the right atrial clot is extremely rare. No such case is reported in literature till date. This case report presents a 52-year gentleman who came to our emergency department with complaints of breathlessness, abdominal distention, pedal swelling, and decreased urine output with extremely poor general condition. After hemodynamic stabilization and preoperative optimization and workup, he was managed with Bentall procedure with right atrial clot removal. The immediate postoperative course was normal except for deranged liver function tests. The patient was discharged on postoperative day ten.

Abstract 17228: Not Just Another Knick In The Wall: An Unusual Case Of Multiple Arterial Aneurysms

Case Presentation: 47-year-old Liberian woman with a history of latent TB and no prior cardiac history presented with dyspnea, palpitations, and weight loss. She had fevers, tachycardia, and cervical lymphadenopathy. Cardiac exam showed widened pulse pressure, systolic and diastolic murmur, and features of heart failure. TTE showed dilated left ventricle with preserved ejection fraction, aortic root aneurysm compressing left atrium, severe aortic and mitral regurgitation, and moderate pericardial effusion with no tamponade. CT angiogram of neck, chest and abdomen showed right subclavian artery mycotic aneurysm, large left supraclavicular lymphadenopathy, multiple aortic arch, and descending thoracic aorta mycotic aneurysms. She underwent emergent surgical intervention. Intraoperative TEE revealed rupture of aortic root aneurysm into left ventricular outflow tract causing a fistula, perforated anterior mitral leaflet, and distortion of the left atrial wall. She underwent mitral and aortic tissue valve replacement, aortic root replacement, and a pericardial patch repair of the left atrial wall. Subsequently, she underwent right subclavian artery aneurysm resection, right carotid axillary bypass, and vertebral artery reimplantation. Aortic valve pathology was suggestive of endocarditis with negative cultures. Lymph node biopsy revealed non-necrotizing granulomatous inflammation with no evidence of acid-fast bacilli, fungi, and malignancy. Autoimmune workup was negative. A PET CT showed post-surgical inflammatory changes with no evidence of malignancy. Discussion: We describe an unusual case of multiple large arterial aneurysms causing severe valvular insufficiency requiring emergent surgical intervention. The patient underwent extensive workup which was unrevealing. She was treated for subacute bacterial endocarditis and suspected Bechet’s disease. Thus, the quest for a definitive diagnosis continues to elude us.

hiPSC Modeling of Lineage-Specific Smooth Muscle Cell Defects Caused by TGFBR1 A230T Variant, and its Therapeutic Implications for Loeys-Dietz Syndrome

Background: Loeys-Dietz Syndrome (LDS) is an inherited disorder predisposing individuals to thoracic aortic aneurysm and dissection (TAAD). Currently, there are no medical treatments except surgical resection. Although the genetic basis of LDS is well-understood, molecular mechanisms underlying the disease remain elusive impeding the development of a therapeutic strategy. In addition, aortic smooth muscle cells (SMC) have heterogenous embryonic origins depending on their spatial location, and lineage-specific effects of pathogenic variants on SMC function, likely causing regionally constrained LDS manifestations, have been unexplored. Methods: We identified an LDS family with a dominant pathogenic variant in TGFBR1 gene ( TGFBR1 A230T ) causing aortic root aneurysm and dissection. To accurately model the molecular defects caused by this mutation, we used human-induced pluripotent stem cells (hiPSC) from subject with normal aorta to generate hiPSC carrying TGFBR1 A230T , and corrected the mutation in patient-derived hiPSC using CRISPR-Cas9 gene editing. Following their lineage-specific SMC differentiation through cardiovascular progenitor cell (CPC) and neural crest stem cell (NCSC) lineages, we employed conventional molecular techniques and single-cell RNA-sequencing (scRNA-seq) to characterize the molecular defects. The resulting data led to subsequent molecular and functional rescue experiments employing Activin A and rapamycin. Results: Our results indicate the TGFBR1 A230T mutation impairs contractile transcript and protein levels, and function in CPC-SMC, but not in NCSC-SMC. ScRNA-seq results implicate defective differentiation even in TGFBR1 A230T/+ CPC-SMC including disruption of SMC contraction, and extracellular matrix formation. Comparison of patient-derived and mutation-corrected cells supported the contractile phenotype observed in the mutant CPC-SMC. TGFBR1 A230T selectively disrupted SMAD3 and AKT activation in CPC-SMC, and led to increased cell proliferation. Consistently, scRNA-seq revealed molecular similarities between a loss-of-function SMAD3 mutation ( SMAD3 c.652delA/+ ) and TGFBR1 A230T/+ . Lastly, combination treatment with Activin A and rapamycin during or after SMC differentiation significantly improved the mutant CPC-SMC contractile gene expression, and function; and rescued the mechanical properties of mutant CPC-SMC tissue constructs. Conclusions: This study reveals that a pathogenic TGFBR1 variant causes lineage-specific SMC defects informing the etiology of LDS-associated aortic root aneurysm. As a potential pharmacological strategy, our results highlight a combination treatment with Activin A and rapamycin that can rescue the SMC defects caused by the variant.

Epigenetic modulation in the pathogenesis and treatment of inherited aortic aneurysm conditions

Shprintzen-Goldberg syndrome (SGS) is a rare systemic connective tissue disorder characterized by craniofacial, skeletal, neurodevelopmental, cutaneous, and cardiovascular manifestations, including aortic root aneurysm. It has significant phenotypic overlap with both Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). We previously reported that SGS is caused by heterozygous mutations in the Sloan-Kettering Institute proto-oncogene (SKI), which encodes a potent suppressor of transforming growth factor beta (TGFβ) target gene expression. Herein, we show that mouse lines harboring orthologous amino acid substitutions in Ski recapitulate multiple human SGS phenotypic manifestations, including skin collagen deposition, skeletal kyphosis, behavioral hypoactivity, and aortic root aneurysm. Furthermore, aortic root aneurysm in SGS mice is associated with both increased acetylation of histone H3 at lysine-27 (H3K27) and TGFβ target gene expression, all of which can be ameliorated by pharmacological CBP/P300 inhibition in vivo; similar findings were seen in cultured dermal fibroblast from SGS patients. Aortic root growth is also abrogated in a mouse model of MFS by selective CBP/P300 inhibition in association with blunted expression of TGFβ target genes. These data document excessive H3K27 acetylation and hence TGFβ target gene expression in the pathogenesis of inherited presentations of aortic root aneurysm and the therapeutic potential of pharmacological epigenetic modulation.