Reviewing hereditary connective tissue disorders: Proposals of harmonic medicolegal assessments.

Hereditary connective tissue disorders (HCTDs) are a heterogeneous group of inherited diseases. These disorders show genetic mutations with loss of function of primary components of connective tissue, such as collagen and elastic fibers. There are more than 200 conditions that involve hereditary connective tissue disorders, while the most known are Marfan syndrome, Osteogenesis Imperfecta, and Ehlers-Danlos syndromes. These disorders need continuous updates, multidisciplinary skills, and specific methodologic evaluations sharing many medicolegal issues. Marfan syndrome and Ehlers-Danlos syndromes show a high risk of early sudden death. As a consequence of this, postmortem genetic testing can identify novel genotype-phenotype correlations which help the clinicians to assess personalized cardiovascular screening programs among the ill subjects. Genetic testing is also essential to identify children suffering from Osteogenesis Imperfecta, especially when a physical abuse is clinically suspected. However, this is a well-known clinical problem even though there are still challenges to interpret genetic data and variants of unknown significance due to the current extensive use of new genetic/genomic techniques. Additionally, the more significant applications and complexities of genomic testing raise novel responsibilities on the clinicians, geneticists, and forensic practitioners as well, increasing potential liability and medical malpractice claims. This systematic review provides a detailed overview on how multidisciplinary skills belonging to clinicians, medicolegal consultants, radiologists, and geneticists can cooperate to manage HCTDs from autopsy or clinical findings to genetic testing. Thus, technical aspects need to be addressed to the medicolegal community since there is no consensus works or guidelines which specifically discuss these issues.

Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.

Inducing aortic aneurysm/dissection in zebrafish: evaluating the efficacy of ß-Aminopropionic Nitrile as a model.

Aortic aneurysm/dissection (AAD) poses a life-threatening cardiovascular emergency with complex mechanisms and a notably high mortality rate. Zebrafish (Danio rerio) serve as valuable models for AAD due to the conservation of their three-layered arterial structure and genome with that of humans. However, the existing studies have predominantly focused on larval zebrafish, leaving a gap in our understanding of adult zebrafish. In this study, we utilized ß-Aminopropionic Nitrile (BAPN) impregnation to induce AAD in both larval and adult zebrafish. Following induction, larval zebrafish exhibited a 28% widening of the dorsal aortic diameter (p < 0.0004, n = 10) and aortic arch malformations, with a high malformation rate of 75% (6/8). Conversely, adult zebrafish showed a 41.67% (5/12) mortality rate 22 days post-induction. At this time point, the dorsal aortic area had expanded by 2.46 times (p < 0.009), and the vessel wall demonstrated significant thickening (8.22 ± 2.23 µM vs. 26.38 ± 10.74 µM, p < 0.05). Pathological analysis revealed disruptions in the smooth muscle layer, contributing to a 58.33% aneurysm rate. Moreover, the expression levels of acta2, tagln, cnn1a, and cnn1b were decreased, indicating a weakened contractile phenotype. Transcriptome sequencing showed a significant overlap between the molecular features of zebrafish tissues post-BAPN treatment and those of AAD patients. Our findings present a straightforward and practical method for generating AAD models in both larval and adult zebrafish using BAPN.

Activation of the alternative complement pathway modulates inflammation in thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.

Delayed coronary perforation four days after percutaneous coronary intervention with subsequent cardiac tamponade: A case report.

Coronary artery perforation (CAP) is a rare but lethal complication of percutaneous coronary interventions (PCIs), and its incidence has been increasing with advances in PCI techniques. Delayed CAP presents a highly challenging complication, as it occurs 30 min-9 days after intervention, making subsequent diagnosis and treatment difficult. We present the case of a 63-year-old male patient who underwent PCI for an obtuse marginalis II because of posterior wall myocardial infarction. Following 4 days of uneventful postoperative stay, the patient developed angina pectoris and hypotension 4 h after reinitiation of anticoagulant therapy with edoxaban. Angiography revealed distal vessel perforation from a side branch of the obtuse marginalis II. The vessel was occluded using autologous fat embolization via a microcatheter, resulting in complete sealing of the perforation. After discharge, 4 weeks after the infarction, the patient started rehabilitation therapy. Distal vessel perforations are typically caused by wire damage. In our case, we also suspected distal wire perforation, which was initially not recognized possibly due to distal occlusion through the thrombotic material. The temporal correlation between the re-initiation of anticoagulant therapy and the occurrence of cardiac tamponade suggests that the thrombotic material was resolved due to the former. The management of delayed CAP does not differ from that of CAP; thus, this rare complication should be considered even days after PCI as it could prove lethal if not recognized early.

Aortic Dissection and a Previously Unreported ACTA2 Missense Variant Mutation in a Young Patient: A Case Report.

Hereditary connective tissue disease is known to cause aortic lesions at an early age. Familial aortic aneurysm/dissection is caused due to an ACTA2 mutation that affects smooth muscle structure. We present a case of a 15-year-old boy with a mild developmental disorder in whom no abnormalities were identified on previous physical examinations. The patient presented with severe left heart failure, extensive dissection from the ascending aorta to the common iliac artery, and myocardial and cerebral infarctions. He underwent an urgent Bentall surgery. Six months later, the patient underwent surgical reconstruction of the abdominal aorta from the aortic arch and returned to normal daily activities. Pathological examination demonstrated the absence of elastic fibers but presence of abundant reticular fibers and mucopolysaccharides from the tunica intima to the media. Genetic testing revealed a heterozygous missense variant of the ACTA2 gene. To the best of our knowledge, this is the first sporadic case of structurally abnormal smooth muscle organization resulting in clinical symptoms with no previously reported pathogenicity.

Methamphetamine induces thoracic aortic aneurysm/dissection through C/EBPß.

AIMS: Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism. METHODS AND RESULTS: A new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor ß-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase MMP2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein ß (C/EBPß) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBPß binding to MMP2 and MMP9 promoters. Blocking C/EBPß significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBPß-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBPß, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease. CONCLUSIONS: Our study demonstrated that METH exposure has a casual effect on TAAD. C/EBPß mediates METH-introduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBPß may be a potential factor for TAAD clinical diagnosis or treatment.

Neurovascular abnormalities in patients with Loeys-Dietz syndrome type III.

The aim of this article is to describe neurovascular findings in patients with Loeys Dietz syndrome type III and their possible clinical impact. Loeys Dietz syndrome type III, caused by pathogenic SMAD3 variants, is an autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis. Neurovascular abnormalities have been described in other heritable aortic syndromes, however, reliable data in Loeys Dietz syndrome type III is missing. In our tertiary center, all adult patients with confirmed Loeys Dietz syndrome type III are followed in a standardized aorta outpatient clinic including Computed Tomography Angiography (CTA) of the head and neck region at baseline and (tri) yearly during follow-up. We performed an analysis of the neurovascular imaging findings and clinical follow-up. The primary outcome was a combined endpoint of mortality, dissection, cerebral vascular event and intervention. In addition, tortuosity and vascular growth were assessed. In total 26 patients (mean age 38.4 years, 38.5% males) underwent 102 (mean 3.9 (1-8) per patient) neurovascular Computed Tomography Angiography scans between 2010 and 2021. In 84.6% some form of neurovascular abnormality was found. The abnormalities at baseline were aneurysm (26.9%) dissection flap (7.7%), arterial tortuosity (61.5%), arterial coiling (23.1%) and arterial kinking (3.8%). During follow up (mean 8.85 (1-11) years) one patient suffered from sudden death and one patient needed a neuro-radiological intervention. No cerebral bleeding or stroke occurred. In conclusion, neurovascular imaging in Loeys Dietz syndrome type III patients revealed abnormalities such as aneurysm, tortuosity, coiling and kinking in the vast majority of patients, but clinical events were rare. Neurovascular screening and follow up is advised in all Loeys Dietz syndrome type III patients.

The Aortic Pathologies: How Far We Understand It and Its Implications on Thoracic Aortic Surgery

Thoracic aortic diseases contribute to a major part of cardiac surgeries. The severity of pathologies varies significantly from emergency and life-threatening to conservatively managed conditions. Life-threatening conditions include type A aortic dissection and rupture. Aortic aneurysm is an example of a conservatively managed condition. Pathologies that affect the arterial wall can have a profound impact on the presentation of such cases. Several risk factors have been identified that increase the risk of emergency presentations such as connective tissue disease, hypertension, and vasculitis. The understanding of aortic pathologies is essential to improve management and clinical outcomes.

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder that affects the skeletal, ocular, and cardiovascular system. The disease's severity and clinical manifestations vary greatly due to pathogenic variants which, combined with a lack of research on the correlation between MFS's genotype and phenotype, make MFS a challenging disease to diagnose. This study aims to further the understanding of MFS by shedding light on the clinical manifestation of a novel variant in fibrillin-1 (FBN1)-the protein responsible for the genetic defects that lead to MFS. METHODS: A patient was diagnosed with MFS by combining a clinical examination (based on the 2010 revision to Ghent nosology criteria) with a targeted next-generation sequence analysis. The functional analysis of the causal mutation and the clinical details of the affected patient were then analyzed. RESULTS: The FBN1 heterozygous variant c.5081_5082insT, which is known to delete large fragments from amino acids 1702 to 2871, was found in the proband patient and her son. The two also displayed the skeletal and cardiovascular manifestations of MFS. In addition, the 14-year-old son was identified as having a dilated aortic bulb at the same rupture site of the proband's dissection, and the proband's mother also died at age 32 due to aortic dissection. CONCLUSIONS: The FBN1 variant c.5081_5082insT (p.Leu1694fs*9) is a pathogenic mutation that can cause MFS patients to experience early-onset familial thoracic aortic aneurysms (TAA). We hope that this discovery can provide further insight into the treatment of MFS patients with truncating variants in exons 42-65.

Direct proximal right subclavian artery cannulation during surgery of the thoracic aorta.

OBJECTIVE: To evaluate outcomes of single sternum access for right subclavian artery cannulation without infraclavicular incision in surgery of the thoracic aorta. METHODS: Between January 2015 and December 2019, 44 consecutive patients underwent surgery of the thoracic aorta with cannulation of the right subclavian artery, after sternotomy and before pericardiotomy, through a direct percutaneous cannula with a single access without additional infraclavicular skin incision. The indication for surgery was type A acute aortic dissection in 29 patients (65.9%), proximal aortic aneurysm in 11 (25%), and aneurysm of the aortic arch in 4 (9%). Operative procedures were replacement of the ascending aorta in 23 patients, Bentall procedure in 10, hemiarch replacement in 6, and total arch replacement in 5. The mean cardiopulmonary bypass (CPB) and cross-clamp times were 185 ± 62 minutes and 138 ± 41 minutes, respectively. RESULTS: The in-hospital mortality rate was 6.8%. Permanent neurologic dysfunction occurred in 3 patients (6.8%) and temporary neurologic dysfunction occurred in 4 patients (9.0%). There were no vascular complications related to this technique. No lesions to the vagus and recurrent laryngeal nerves have been reported. CONCLUSIONS: In our experience, a single sternum access for right subclavian artery cannulation avoids the risk and complications of an infraclavicular incision required for axillary artery cannulation. This technique is safe and represent a valid option for CBP and antegrade cerebral perfusion during surgery of the thoracic aorta.

The Aortic Pathologies: How Far We Understand It and Its Implications on Thoracic Aortic Surgery

Abstract Thoracic aortic diseases contribute to a major part of cardiac surgeries. The severity of pathologies varies significantly from emergency and life-threatening to conservatively managed conditions. Life-threatening conditions include type A aortic dissection and rupture. Aortic aneurysm is an example of a conservatively managed condition. Pathologies that affect the arterial wall can have a profound impact on the presentation of such cases. Several risk factors have been identified that increase the risk of emergency presentations such as connective tissue disease, hypertension, and vasculitis. The understanding of aortic pathologies is essential to improve management and clinical outcomes.

Early Detection of Aortic Degeneration in a Mouse Model of Sporadic Aortic Aneurysm and Dissection Using Nanoparticle Contrast-Enhanced Computed Tomography.

[Figure: see text].

Colossal left main to right atrium fistula ligation complicated by left circumflex STEMI.

Congenital left main (LM) coronary artery to right atrium fistulas with progression to aneurysm development are rare. Most patients remain asymptomatic, but for those with progressive symptoms, intervention is required. However, there are potential life-threatening complications associated with surgical intervention. We present a case of an extremely rare markedly aneurysmal LM to right atrial fistula treated with surgical ligation complicated by inferolateral ST-elevation myocardial infarction several days post-operatively treated successfully using mechanical aspiration thrombectomy, a stent-retriever, balloon angioplasty, and subsequent intravascular ultrasound-guided percutaneous coronary intervention with drug-eluting stent.

Usefulness of oral anticoagulation in patients with coronary aneurysms: Insights from the CAAR registry.

OBJECTIVES: To assess the Usefulness of oral anticoagulation therapy (OAT) in patients with coronary artery aneurysm (CAA). BACKGROUND: Data on the most adequate antithrombotic CAA management is lacking. METHODS: Patients included in CAAR (Coronary Artery Aneurysm Registry, Clinical Trials.gov: NCT02563626) were selected. Patients were divided in OAT and non-OAT groups, according to anticoagulation status at discharge and 2:1 propensity score matching with replacement was performed. The primary endpoint of the analysis was a composite and mutual exclusive endpoint of myocardial infarction, unstable angina (UA), and aneurysm thrombosis (coronary ischemic endpoint). Net adverse clinical events, major adverse cardiovascular events, their single components, cardiovascular death, re-hospitalizations for heart failure, stroke, aneurysm thrombosis, and bleeding were the secondary ones. RESULTS: One thousand three hundred thirty-one patients were discharged without OAT and 211 with OAT. In the propensity-matched sample (390 patients in the non-OAT group, 195 patients in the OAT group), after 3 years of median follow-up (interquartile range 1-6 years), the rate of the primary endpoint (coronary ischemic endpoint) was significantly less in the OAT group as compared to non-OAT group (8.7 vs. 17.2%, respectively; p = .01), driven by a significant reduction in UA (4.6 vs. 10%, p < .01) and aneurysm thrombosis (0 vs. 3.1%, p = .03), along with a non-significant reduction in MI (4.1 vs. 7.7%, p = .13). A non-significant increase in bleedings, mainly BARC type 1 (55%), was found in the OAT-group (10.3% in the non-OAT vs. 6.2% in the OAT group, p = .08). CONCLUSION: OAT decreases the composite endpoint of UA, myocardial infarction, and aneurysm thrombosis in patients with CAA, despite a non-significant higher risk of bleeding.

Iatrogenic catheter-induced ostial coronary artery dissections: Prevalence, management, and mortality from a cohort of 55,968 patients over 10 years.

OBJECTIVE: We sought to describe the prevalence, management strategies and evaluate the prognosis of patients with iatrogenic catheter-induced ostial coronary artery dissection (ICOCAD). BACKGROUND: ICOCAD is a rare but potentially devastating complication of cardiac catheterisation. The clinical manifestations of ICOCAD vary from asymptomatic angiographic findings to abrupt vessel closure leading to myocardial infarction and death. METHODS: 55,968 patients who underwent coronary angiography over a 10-year period were screened for ICOCAD as defined by the National Heart, Lung, and Blood Institute. The management and all-cause mortality were retrieved from local and national databases. RESULTS: The overall prevalence of ICOCAD was 0.09% (51/55,968 patients). Guide catheters accounted for 75% (n = 37) of cases. Half of the ICOCAD cases involved the right coronary artery while the remaining were related to left main stem (23/51; 45%) and left internal mammary artery (2/51; 4%). Two-thirds of ICOCAD were high grade (type D, E, and F). The majority of cases were type F dissections (n = 18; 66%), of which two third occurred in females in their 60s. The majority of ICOCAD patients (42/51; 82%) were treated with percutaneous coronary intervention while the remaining underwent coronary artery bypass grafting (3/51; 6%) or managed conservatively (6/51; 12%). Three deaths occurred during the index admission while 48/51 patients (94.1%) were safely discharged without further mortality over a median follow-up of 3.6 years. CONCLUSIONS: ICOCAD is a rare but life-threatening complication of coronary angiography. Timely recognition and prompt bailout PCI is a safe option for majority of patients with good clinical outcomes.

Management of Lower Limb Ischemia During Operative Repair of Acute Type A Aortic Dissection by Distal Crossover Grafts: a Case Series.

OBJECTIVE: To describe our experience of nine patients with extra-anatomical bypass for clinically ischemic distal limb during repair of acute Type A aortic dissection (ATAAD). METHODS: We retrospectively examined a series of nine patients who underwent surgery for ATAAD. We identified a subset of the patients who presented with concomitant radiographic and clinical signs of lower limb ischemia. All but one patient (axillobifemoral bypass) underwent femorofemoral crossover grafting by the cardiac surgeon during cooling. RESULTS: One hundred eighty-one cases of ATAAD underwent surgery during the study period with a mortality of 19.3%. Nine patients had persistent clinical evidence of lower limb ischemia (4.9%) and underwent extra-anatomical bypass during cooling. Two patients underwent additional fasciotomies. Mean delay from symptoms to surgery in these nine patients was 9.5 hours. Two patients had bilateral amputations despite revascularisation and, of note, had long delays in presentation for surgery (> 12 hours). There were no mortalities during these inpatient episodes. Outpatient radiographic follow-up at the first opportunity demonstrated 100% patency. CONCLUSION: Our experience suggests that, during complicated aortic dissection, limb ischemia may have a devastating outcome including amputation when diagnosis and referral are delayed. Early diagnosis and surgery are crucial in preventing this potentially devastating complication.

Management of lower limb ischemia during operative repair of acute type a aortic dissection by distal crossover grafts: a case series

Abstract Objective: To describe our experience of nine patients with extra-anatomical bypass for clinically ischemic distal limb during repair of acute Type A aortic dissection (ATAAD). Methods: We retrospectively examined a series of nine patients who underwent surgery for ATAAD. We identified a subset of the patients who presented with concomitant radiographic and clinical signs of lower limb ischemia. All but one patient (axillobifemoral bypass) underwent femorofemoral crossover grafting by the cardiac surgeon during cooling. Results: One hundred eighty-one cases of ATAAD underwent surgery during the study period with a mortality of 19.3%. Nine patients had persistent clinical evidence of lower limb ischemia (4.9%) and underwent extra-anatomical bypass during cooling. Two patients underwent additional fasciotomies. Mean delay from symptoms to surgery in these nine patients was 9.5 hours. Two patients had bilateral amputations despite revascularisation and, of note, had long delays in presentation for surgery (> 12 hours). There were no mortalities during these inpatient episodes. Outpatient radiographic follow-up at the first opportunity demonstrated 100% patency. Conclusion: Our experience suggests that, during complicated aortic dissection, limb ischemia may have a devastating outcome including amputation when diagnosis and referral are delayed. Early diagnosis and surgery are crucial in preventing this potentially devastating complication.

Smooth Muscle Sirtuin 1 Blocks Thoracic Aortic Aneurysm/Dissection Development in Mice.

PURPOSE: Advancing age is the major risk factor for thoracic aortic aneurysm/dissection (TAAD). However, the causative link between age-related molecules and TAAD remains elusive. Here, we investigated the role of Sirtuin 1 (SIRT1, also known as class III histone deacetylase), the best studied member of the longevity-related Sirtuin family, in TAAD development in vivo. METHODS: We used male smooth muscle-specific SIRT1 transgenic (ST-Tg) mice, smooth muscle-specific SIRT1 knockout (ST-KO) mice, and their wild-type (WT) littermates on a C57BL/6J background to establish a TAAD model induced by oral administration of 3-aminopropionitrile fumarate (BAPN). We analyzed the incidence and fatality rates of TAAD in the groups. We examined matrix metallopeptidase 2 (MMP2) and MMP9 expression in aortas or cultured A7r5 cells via western blotting and real-time polymerase chain reaction (PCR). We performed chromatin immunoprecipitation (ChIP) to clarify the epigenetic mechanism of SIRT1-regulated MMP2 expression in vascular smooth muscle cells (VSMCs). RESULTS: BAPN treatment markedly increased the incidence of TAAD in WT mice but caused less disease in ST-Tg mice. Moreover, ST-KO mice had the highest BAPN-induced TAAD fatality rate of all the groups. Mechanistically, SIRT1 overexpression resulted in lower MMP2 and MMP9 expression after BAPN treatment in both mouse aortas and cultured A7r5 cells. The downregulation of BAPN-induced MMP2 expression by SIRT1 was mediated by deacetylation of histone H3 lysine 9 (H3K9) on the Mmp2 promoter in the A7r5 cells. CONCLUSION: Our findings suggest that SIRT1 expression in SMCs protects against TAAD and could be a novel therapeutic target for TAAD management.