RESUMO
Arterial remodeling participates pivotally in many diseases including arterial aneurysms. In this issue of Immunity, Da Ros et al. (2017) report that, in experimental aortic aneurysm formation, neutralization of interleukin-1ß reduced arterial wall stiffness and hampered aneurysm development.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma Aórtico , Animais , Citocinas , Modelos Animais de Doenças , Interleucina-1beta , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador betaRESUMO
Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor ß (TGF-ß) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-ß. The results revealed that Smad4 inhibition activated interleukin-1ß (IL-1ß) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1ß antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-ß signaling, such as those driven by SMAD4 mutations.
Assuntos
Aneurisma Aórtico/prevenção & controle , Interleucina-1beta/antagonistas & inibidores , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Células Cultivadas , Quimiocina CCL2/antagonistas & inibidores , Interleucina-1beta/biossíntese , Camundongos , Miócitos de Músculo Liso/imunologia , NF-kappa B/fisiologia , Receptores CCR2/antagonistas & inibidores , Proteína Smad4/fisiologia , Tamoxifeno/farmacologiaRESUMO
BACKGROUND: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection. METHODS: Biotin-switch assay combined with liquid chromatography-tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and Apoe-/- mice infused with angiotensin II. Angiotensin II-induced aortic aneurysm model and ß-aminopropionitrile-induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis. RESULTS: Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and Apoe-/- mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis. CONCLUSIONS: SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.
Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Macrófagos , Septinas , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T , Proteínas rac1 de Ligação ao GTP , Animais , Humanos , Masculino , Camundongos , Angiotensina II/metabolismo , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Aneurisma Aórtico/genética , Dissecção Aórtica/metabolismo , Dissecção Aórtica/patologia , Dissecção Aórtica/genética , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Neuropeptídeos , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Septinas/metabolismo , Septinas/genética , Transdução de Sinais , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genéticaRESUMO
BACKGROUND: Vascular smooth muscle cells (VSMCs) are highly plastic. Vessel injury induces a phenotypic transformation from differentiated to dedifferentiated VSMCs, which involves reduced expression of contractile proteins and increased production of extracellular matrix and inflammatory cytokines. This transition plays an important role in several cardiovascular diseases such as atherosclerosis, hypertension, and aortic aneurysm. TGF-ß (transforming growth factor-ß) is critical for VSMC differentiation and to counterbalance the effect of dedifferentiating factors. However, the mechanisms controlling TGF-ß activity and VSMC phenotypic regulation under in vivo conditions are poorly understood. The extracellular matrix protein TN-X (tenascin-X) has recently been shown to bind TGF-ß and to prevent it from activating its receptor. METHODS: We studied the role of TN-X in VSMCs in various murine disease models using tamoxifen-inducible SMC-specific knockout and adeno-associated virus-mediated knockdown. RESULTS: In hypertensive and high-fat diet-fed mice, after carotid artery ligation as well as in human aneurysmal aortae, expression of Tnxb, the gene encoding TN-X, was increased in VSMCs. Mice with smooth muscle cell-specific loss of TN-X (SMC-Tnxb-KO) showed increased TGF-ß signaling in VSMCs, as well as upregulated expression of VSMC differentiation marker genes during vascular remodeling compared with controls. SMC-specific TN-X deficiency decreased neointima formation after carotid artery ligation and reduced vessel wall thickening during Ang II (angiotensin II)-induced hypertension. SMC-Tnxb-KO mice lacking ApoE showed reduced atherosclerosis and Ang II-induced aneurysm formation under high-fat diet. Adeno-associated virus-mediated SMC-specific expression of short hairpin RNA against Tnxb showed similar beneficial effects. Treatment with an anti-TGF-ß antibody or additional SMC-specific loss of the TGF-ß receptor reverted the effects of SMC-specific TN-X deficiency. CONCLUSIONS: In summary, TN-X critically regulates VSMC plasticity during vascular injury by inhibiting TGF-ß signaling. Our data indicate that inhibition of vascular smooth muscle TN-X may represent a strategy to prevent and treat pathological vascular remodeling.
Assuntos
Músculo Liso Vascular , Miócitos de Músculo Liso , Transdução de Sinais , Tenascina , Remodelação Vascular , Animais , Humanos , Masculino , Camundongos , Angiotensina II , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/prevenção & controle , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/genética , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neointima , Fenótipo , Tenascina/metabolismo , Tenascina/genética , Tenascina/deficiência , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. METHODS: Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H2S system and the findings were confirmed in transgenic mice. RESULTS: Higher plasma H2S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD. CONCLUSIONS: Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.
Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Animais , Camundongos , Cistationina gama-Liase/genética , Células Endoteliais/metabolismo , Endotélio/metabolismo , Histona Desacetilase 1 , Sulfeto de Hidrogênio/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Proteína S , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
BACKGROUND: Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified. METHODS: We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis. RESULTS: Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix-producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting-/- mice, the aortic stress-induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues. CONCLUSIONS: Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.
Assuntos
Aneurisma da Aorta Torácica , Aneurisma Aórtico , Dissecção Aórtica , Humanos , Camundongos , Animais , Epigenômica , Fenótipo , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Dissecção Aórtica/genética , Miócitos de Músculo Liso/metabolismo , DNA/metabolismo , Cromatina/metabolismo , Epigênese Genética , Células CultivadasRESUMO
BACKGROUND: Triglyceride-glucose (TyG) index is an emerging surrogate indicator of insulin resistance, which has been demonstrated as a risk factor for various cardiovascular diseases including coronary syndrome, in-stent restenosis, and heart failure. However, association of TyG index with incident aortic dissection (AD) and aortic aneurysm (AA) remains to be investigated. METHODS: This study included 420,292 participants without baseline AD/AA from the large-scale prospective UK Biobank cohort. The primary outcome was incident AD/AA, comprising AD and AA. Multivariable-adjusted Cox proportional hazards regression models and restricted cubic spline (RCS) analyses were applied to assess the relationship between TyG index and the onset of AD/AA. In addition, the association between TyG index and incident AD/AA was examined within subgroups defined by age, gender, smoking status, drinking status, diabetes, hypertension, and BMI. RESULTS: Over a median follow-up period of 14.8 (14.1, 15.5) years, 3,481 AD/AA cases occurred. The incidence of AD/AA rose along with elevated TyG index. RCS curves showed a linear trend of TyG index with risk of incident AD/AA. TyG index was positively associated with risk of incident AD/AA after adjusting for age, gender, smoking status, drinking status, BMI, hypertension, LDL-c, and HbA1c, with adjusted HRs of 1.0 (reference), 1.20 (95% CI 1.08-1.35), 1.21 (95% CI 1.08-1.35), and 1.30 (95% CI 1.16-1.45) for TyG index quartiles 2, 3, and 4, respectively. Especially, participants in the highest TyG index quartile had highest risk of developing AA, with an adjusted HR of 1.35 (95% CI 1.20-1.52). CONCLUSIONS: TyG index is independently associated with a higher risk of incident AD/AA, indicating the importance of using TyG index for risk assessment of AD/AA, especially for AA.
Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Biomarcadores , Glicemia , Triglicerídeos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Dissecção Aórtica/epidemiologia , Dissecção Aórtica/sangue , Dissecção Aórtica/diagnóstico , Estudos Prospectivos , Fatores de Risco , Incidência , Reino Unido/epidemiologia , Medição de Risco , Triglicerídeos/sangue , Aneurisma Aórtico/epidemiologia , Aneurisma Aórtico/sangue , Aneurisma Aórtico/diagnóstico , Idoso , Glicemia/metabolismo , Biomarcadores/sangue , Fatores de Tempo , Adulto , Bancos de Espécimes Biológicos , Prognóstico , Resistência à Insulina , Valor Preditivo dos Testes , Biobanco do Reino UnidoRESUMO
BACKGROUND: In observational and experimental studies, diabetes has been reported as a protective factor for aortic dissection. 3-Hydroxybutyrate, a key constituent of ketone bodies, has been found to favor improvements in cardiovascular disease. However, whether the protective effect of diabetes on aortic dissection is mediated by 3-hydroxybutyrate is unclear. We aimed to investigate the causal effects of diabetes on the risk of aortic dissection and the mediating role of 3-hydroxybutyrate in them through two-step Mendelian randomization. MATERIALS AND METHODS: We performed a two-step Mendelian randomization to investigate the causal connections between diabetes, 3-hydroxybutyrate, and aortic dissection and calculate the mediating effect of 3-hydroxybutyrate. Publicly accessible data for Type 1 diabetes, Type 2 diabetes, dissection of aorta and 3-hydroxybutyrate were obtained from genome-wide association studies. The association between Type 1 diabetes and dissection of aorta, the association between Type 2 diabetes and dissection of aorta, and mediation effect of 3-hydroxybutyrate were carried out separately. RESULTS: The IVW method showed that Type 1 diabetes was negatively associated with the risk of aortic dissection (OR 0.912, 95% CI 0.836-0.995), The weighted median, simple mode and weighted mode method showed consistent results. The mediated proportion of 3-hydroxybutyrate on the relationship between Type 1 diabetes and dissection of aorta was 24.80% (95% CI 5.12-44.47%). The IVW method showed that Type 2 diabetes was negatively associated with the risk of aortic dissection (OR 0.763, 95% CI 0.607-0.960), The weighted median, simple mode and weighted mode method showed consistent results. 3-Hydroxybutyrate does not have causal mediation effect on the relationship between Type 2 diabetes and dissection of aorta. CONCLUSION: Mendelian randomization study revealed diabetes as a protective factor for dissection of aorta. The protective effect of type 1 diabetes on aortic dissection was partially mediated by 3-hydroxybutyrate, but type 2 diabetes was not 3-hydroxybutyrate mediated.
Assuntos
Ácido 3-Hidroxibutírico , Aneurisma Aórtico , Dissecção Aórtica , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Dissecção Aórtica/genética , Dissecção Aórtica/epidemiologia , Dissecção Aórtica/etiologia , Ácido 3-Hidroxibutírico/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Fatores de Risco , Aneurisma Aórtico/genética , Aneurisma Aórtico/epidemiologia , Aneurisma Aórtico/etiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Medição de Risco , Fatores de Proteção , Fenótipo , Biomarcadores/sangue , Análise de MediaçãoRESUMO
OBJECTIVE: The MANTA device is a plug-based vascular closure device (VCD) designed for large bore femoral arterial access site closure. It showed promising results in transcatheter aortic valve replacement cases. In this study, we report our results and evaluate the MANTA VCD in percutaneous endovascular aortic aneurysm repair (pEVAR). METHODS: All data of consecutive patients who underwent an elective pEVAR between October 2018 and December 2022 were retrospectively reviewed. In all patients at least one common femoral artery was intended to close with the MANTA VCD. Depending on the sheath size, the 14Fr or 18Fr MANTA VCD was used. On the preoperative computed tomography scan, the diameter of the common femoral artery (CFA) was measured and the amount of calcification based on the Peripheral Arterial Calcium Scoring System (PACSS) was scored. Primary outcome was procedural technical success. Procedural technical success was defined as placement of the MANTA closure device resulting in vascular closure with patent CFA, without requiring immediate open or endovascular surgery. The secondary outcomes were access site complications requiring reintervention and all-cause mortality at 30-day follow-up. RESULTS: In total, 152 consecutive patients underwent pEVAR with 291 common femoral artery closure procedures with the Manta VCD. Mean age was 74.1 ± 6.4 years, with a mean body mass index of 27.7 ± 4.4 kg/m2. The mean diameter of the CFA was 10.5 ± 1.9 mm. In 52.6% of the cases, there were no calcification on the preoperative computed tomography scan. The 18Fr and 14Fr Manta VCD were used 169 and 122 times, respectively. The technical success rate was 96.6%. Major vascular complications were reported in 4.5% of the cases, without any death-related events. CONCLUSIONS: This single-center retrospective cohort study analyzed the procedural technical success, major vascular complications and all-cause mortality at 30-day follow-up of the MANTA vascular closure device in 152 pEVAR patients with 291 common femoral artery closure procedures. The technical success rate was 96,6%. Major vascular complications were reported in 4.5% of the cases, without any death related events. We concluded that the MANTA device is a safe and feasible option with a high rate of technical success in patients undergoing pEVAR.
Assuntos
Aneurisma Aórtico , Procedimentos Endovasculares , Dispositivos de Oclusão Vascular , Humanos , Idoso , Idoso de 80 Anos ou mais , Procedimentos Endovasculares/efeitos adversos , Técnicas Hemostáticas , Estudos Retrospectivos , Resultado do Tratamento , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/cirurgia , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/cirurgiaRESUMO
OBJECTIVE: Globally, there has been a marked increase in aortic aneurysm-related deaths between 1990 and 2019. We sought to understand the underlying etiologies for this mortality trend by examining secular changes in both demographics and the prevalence of risk factors, and how these changes may vary across sociodemographic index (SDI) regions. METHODS: We queried the Global Burden of Disease Study (GBD) for aortic aneurysm deaths from 1990 to 2019 overall and by age group. We identified the percentage of aortic aneurysm deaths attributable to each risk factor identified by GBD modeling (smoking, hypertension, lead exposure, and high sodium diet) and their respective changes over time. We then analyzed aneurysm mortality by SDI region. RESULTS: The number of aortic aneurysm-related deaths have increased from 94,968 in 1990 to 172,427 in 2019, signifying an 81.6% increase, which greatly exceeds the 18.2% increase in all-cause mortality observed over the same time interval. Examination of age-specific mortality demonstrated that the number of aortic aneurysm deaths markedly correlated with advancing age. However, when considering rate of death rather than mortality count, overall age-standardized death rates decreased 18% from 2.72 per 100,000 in 1990 to 2.21 per 100,000 in 2019. Analysis of the specific risk factors associated with aneurysm death revealed that the percentage of deaths attributable to smoking decreased from 45.6% in 1990 to 34.6% in 2019, and deaths attributable to hypertension decreased from 38.7% to 34.7%. Globally, hypertension surpassed smoking as the leading risk factor. The reported rate of death was consistently greater as SDI increased, and this effect was most pronounced among low-middle and middle SDI regions (173.2% and 170.4%, respectively). CONCLUSIONS: Despite an overall increase in the number of aneurysm deaths, there was a decrease in the age-standardized death rate, demonstrating that the observed increased number of aortic aneurysm deaths between 1990 and 2019 was primarily driven by an overall increase in the age of the global population. Fortunately, it appears that the increase in overall aneurysm-related deaths has been modulated by improved risk factor modification, in particular smoking. Given the rise in aneurysm-related deaths, global expansion of vascular specialty capabilities is warranted and will serve to amplify improvements in population-based aneurysm health achieved with risk factor control.
Assuntos
Aneurisma Aórtico , Humanos , Fatores de Risco , Idoso , Pessoa de Meia-Idade , Aneurisma Aórtico/mortalidade , Masculino , Feminino , Idoso de 80 Anos ou mais , Prevalência , Medição de Risco , Adulto , Fatores de Tempo , Saúde Global , Carga Global da Doença/tendências , Causas de Morte , Distribuição por Idade , Fatores Etários , Adulto Jovem , Fumar/efeitos adversos , Fumar/mortalidade , Fumar/epidemiologiaRESUMO
OBJECTIVE: With an aging patient population, an increasing number of octogenarians are undergoing elective endovascular abdominal aortic aneurysm repair (EVAR) in the United States. Multiple studies have shown that, for the general population, use of local anesthetic (LA) for EVAR is associated with improved short-term and long-term outcomes as compared with performing these operations under general anesthesia (GA). Therefore, this study aimed to study the association of LA for elective EVARs with perioperative outcomes, among octogenarians. METHODS: The Vascular Quality Initiative database (2003-2021) was used to conduct this study. Octogenarians (Aged ≥80 years) were selected and sorted into two study groups: LA (Group I) and GA (Group II). Our primary outcomes were length of stay and mortality. Secondary outcomes included operative time, estimated blood loss, return to operating room, cardiopulmonary complications, and discharge location. RESULTS: Of the 16,398 selected patients, 1197 patients (7.3%) were included in Group I, and 15,201 patients (92.7%) were in Group II. Procedural time was significantly shorter for the LA group (114.6 vs 134.6; P < .001), as was estimated blood loss (152 vs 222 cc; P < .001). Length of stay was significantly shorter (1.8 vs 2.6 days; P < .001), and patients were more likely to be discharged home (LA 88.8% vs GA 86.9%; P = .036) in the LA group. Group I also experienced fewer pulmonary complications; only 0.17% experienced pneumonia and 0.42% required ventilator support compared with 0.64% and 1.02% in Group II, respectively. This finding corresponded to fewer days in the intensive care unit for Group I (0.41 vs 0.69 days; P < .001). No significant difference was seen in 30-day mortality cardiac, renal, or access site-related complications. Return to operating room was also equivocal between the two groups. Multivariate regression analysis confirmed GA was associated with a significantly longer length of stay and significantly higher rates of non-home discharge (adjusted odds ratio [AOR], 1.59; P < .001 and AOR, 1.40; P = .025, respectively). When stratified by the New York Heart Association classification system, classes I, II, III, and IV (1.55; P < .001; 1.26; P = .029; 2.03; P < .001; 4.07; P < .001, respectively) were associated with significantly longer hospital stays. CONCLUSIONS: The use of LA for EVARs in octogenarians is associated with shorter lengths of stay, fewer respiratory complications, and home discharge. These patients also experienced shorter procedure times and less blood loss. There was no statistically significant difference in 30-day mortality, return to operating room, or access-related complications. LA for octogenarians undergoing EVAR should be considered more frequently to shorten hospital stays and decrease complication rates.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma Aórtico , Implante de Prótese Vascular , Procedimentos Endovasculares , Idoso de 80 Anos ou mais , Humanos , Estados Unidos , Anestesia Local/efeitos adversos , Octogenários , Fatores de Risco , Fatores de Tempo , Complicações Pós-Operatórias/epidemiologia , Anestésicos Locais , Aneurisma Aórtico/cirurgia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/complicações , Resultado do Tratamento , Estudos RetrospectivosRESUMO
OBJECTIVE: The aim of this study was to investigate the mid-term results of stented-assisted balloon-induced intimal disruption and relamination (STABILISE) in patients with aortic dissection with the implementation of volumetric analysis. METHODS: This was a single-center retrospective analysis of prospectively collected data. From May 2017 to September 2022, 42 patients underwent STABILISE for acute complicated or subacute high-risk aortic dissection. STABILISE was completed with distal extended endovascular aortic repair in 24 patients. A computed tomography scan was performed at baseline, before hospital discharge, and at 1, 3, and 5 years. Perfused total aortic, true lumen, and false lumen volumes were assessed for thoracic, visceral, and aorto-iliac segment. The ratio between false lumen and total volume was named perfusion dissection index (PDI). Complete remodeling was defined as PDI = 0, and positive remodeling as PDI ≤0.1. RESULTS: Technical success was 97.6%. No 30-day deaths, spinal cord injuries, or retrograde dissections were observed. Mean follow-up was 44 ± 19.4 months. Thoracic diameter was lower at last available computed tomography scan (36.7 vs 33.0 mm; P = .01). Aortic growth >5 mm was observed in 9.5% of the patients. Thoracic and visceral aortic complete remodeling were 92.8% and 83.3%, respectively, with no difference between acute and subacute group. Distal extended endovascular aortic repair significantly increased complete remodeling in the aorto-iliac segment, compared with STABILISE alone (69.6% vs 21.4%; P < .001). Freedom from vascular reinterventions at 3 years was 83.1% (95% confidence interval, 71.5%-96.6%). Total PDI ≤0.1 at first postoperative control was a predictor of vascular reinterventions (P < .0001). CONCLUSIONS: STABILISE is a safe and feasible technique associated with high mid-term rates of complete remodeling in the thoracic and visceral aorta. Volumetric analysis allows the quantification of aortic remodeling and represents a predictor of aortic reinterventions.
Assuntos
Dissecção Aórtica , Stents , Humanos , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Masculino , Feminino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Fatores de Tempo , Implante de Prótese Vascular/instrumentação , Implante de Prótese Vascular/efeitos adversos , Remodelação Vascular , Angiografia por Tomografia Computadorizada , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/cirurgia , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/efeitos adversos , Angioplastia com Balão/instrumentação , Angioplastia com Balão/efeitos adversos , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Valor Preditivo dos Testes , Reoperação , Aortografia , Fatores de RiscoRESUMO
Aortic wall injuries may occur after interventional treatment of aortic coarctation (CoA), especially after balloon angioplasty. We reported on a patient who presented with an intra-stent aneurysm formation after direct stenting of a native near atretic aortic CoA by using a BeGraft Aortic stent. This evidence supports the need to maintain a strict follow-up protocol. A computed tomography scan is mandatory, after covered stent implantation as well, especially in high-risk cases and even in the absence of any immediate apparent complication.
Assuntos
Aneurisma Aórtico , Coartação Aórtica , Humanos , Resultado do Tratamento , Aorta/lesões , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/cirurgia , Stents/efeitos adversos , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/cirurgiaRESUMO
Transcatheter aortic valve implantation (TAVI) has traditionally been indicated for the treatment of aortic stenosis. However, in this case report, we describe a successful TAVI procedure in a 46-year-old male patient who had previously undergone David aortic valve-sparing aortic root replacement for type 1 aortic dissection. The patient presented with aortic valve insufficiency 4 years after the initial surgery and was subsequently treated with a 34 mm Medtronic CoreValve Evolut R prosthesis via TAVI. This case highlights the feasibility of TAVI as a viable treatment option for postoperative aortic valve insufficiency in patients with prior ascending aortic or aortic arch surgery.
Assuntos
Dissecção Aórtica , Insuficiência da Valva Aórtica , Valva Aórtica , Implante de Prótese Vascular , Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Humanos , Masculino , Dissecção Aórtica/cirurgia , Dissecção Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/fisiopatologia , Pessoa de Meia-Idade , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/instrumentação , Resultado do Tratamento , Implante de Prótese Vascular/instrumentação , Implante de Prótese Vascular/efeitos adversos , Valva Aórtica/cirurgia , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Desenho de Prótese , Prótese Vascular , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma Aórtico/cirurgia , Aneurisma Aórtico/diagnóstico por imagem , AortografiaRESUMO
Abdominal aortic aneurysms (AAA) result from maladaptive remodeling of the vascular wall and reduces structural integrity. Angiotensin II (AngII) infusion has become a standard laboratory model for studying AAA initiation and progression. We determined the different vasoactive responses of various mouse arteries to Ang II. Ex vivo isometric tension analysis was conducted on 18-week-old male C57BL/6 mice (n = 4) brachiocephalic arteries (BC), iliac arteries (IL), and abdominal (AA) and thoracic aorta (TA). Arterial rings were mounted between organ hooks, gently stretched and an AngII dose response was performed. Rings were placed in 4% paraformaldehyde for immunohistochemistry analysis to quantify peptide expression of angiotensin type 1 (AT1R) and 2 receptors (AT2R) in the endothelium, media, and adventitia. Results from this study demonstrated vasoconstriction responses in IL were significantly higher at all AngII doses when compared to BC, and TA and AA responses (maximum constriction-IL: 68.64 ± 5.47% vs. BC: 1.96 ± 1.00%; TA: 3.13 ± 0.16% and AA: 2.75 ± 1.77%, p < 0.0001). Expression of AT1R was highest in the endothelium of IL (p < 0.05) and in the media and (p < 0.05) adventitia (p < 0.05) of AA. In contrast, AT2R expression was highest in endothelium (p < 0.05), media (p < 0.01, p < 0.05) and adventitia of TA. These results suggest that mouse arteries display different vasoactive responses to AngII, and the exaggerated response in IL arteries may play a role during AAA development.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma Aórtico , Hormônios Peptídicos , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Artéria Ilíaca , Angiotensina II/farmacologia , Artérias , Aneurisma da Aorta Abdominal/induzido quimicamente , Angiotensina IRESUMO
BACKGROUND: The role of increased smooth muscle cell (SMC) integrin αv signaling in Marfan syndrome (MFS) aortic aneurysm remains unclear. Herein, we examine the mechanism and potential efficacy of integrin αv blockade as a therapeutic strategy to reduce aneurysm progression in MFS. METHODS: Induced pluripotent stem cells (iPSCs) were differentiated into aortic SMCs of the second heart field (SHF) and neural crest (NC) lineages, enabling in vitro modeling of MFS thoracic aortic aneurysms. The pathological role of integrin αv during aneurysm formation was confirmed by blockade of integrin αv with GLPG0187 in Fbn1C1039G/+ MFS mice. RESULTS: iPSC-derived MFS SHF SMCs overexpress integrin αv relative to MFS NC and healthy control SHF cells. Furthermore, integrin αv downstream targets (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment of MFS SHF SMCs with GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS NC SMCs and control SMCs, which normalized with GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin αv, p-AktThr308, and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6-14 weeks) had reduced aneurysm growth, elastin fragmentation, and reduction of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. CONCLUSIONS: The integrin αv-FAK-AktThr308 signaling pathway is activated in iPSC SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-AktThr308 signaling in Fbn1C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.
Assuntos
Aneurisma da Aorta Torácica , Aneurisma Aórtico , Aneurisma da Raiz da Aorta , Células-Tronco Pluripotentes Induzidas , Síndrome de Marfan , Camundongos , Animais , Integrina alfaV/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/prevenção & controle , Aneurisma Aórtico/genética , Aneurisma Aórtico/prevenção & controle , Fibrilina-1/genética , Fibrilina-1/metabolismo , Miócitos de Músculo Liso/metabolismoRESUMO
OBJECTIVE: Evidence is lacking to guide the management of infective native aortic aneurysm (INAA). The aim of this study was to establish expert consensus on surgical and antimicrobial treatment and follow up, and to define when an INAA is considered cured. METHODS: Delphi methodology was used. The principal investigators invited 47 international experts (specialists in infectious diseases, radiology, nuclear medicine, and vascular and cardiothoracic surgery) via email. Four Delphi rounds were performed, three weeks each, using an online questionnaire with initially 28 statements. The panellists rated the statements on a five point Likert scale. Comments on statements were analysed, statements were revised and added or deleted, and the results were presented in the iterative rounds. Consensus was defined as ≥ 75% of the panel rating a statement as strongly agree or agree on the Likert scale, and consensus on the final assessment was defined as Cronbach's alpha > 0.80. RESULTS: All 49 panellists completed all four rounds, resulting in 100% participation. One statement was added based on the results and comments of the panel, resulting in 29 final statements: three on need for consensus, 20 on treatment, five on follow up, and one on definition of cure. All 29 statements reached agreement of ≥ 86%. Cronbach's alpha increased for each consecutive round; round 1, 0.85; round 2, 0.90; round 3, 0.91; and round 4, 0.94. Thus, consensus was reached for all statements. CONCLUSION: INAAs are rare, and high level evidence to guide optimal management is lacking. This consensus document was established with the aim of helping clinicians manage these challenging patients, as a supplement to current guidelines. The presented consensus will need future amendments in accordance with newly acquired knowledge.
Assuntos
Aneurisma Aórtico , Humanos , Consenso , Técnica Delphi , SeguimentosRESUMO
OBJECTIVE: Selenium (Se) is a key part of the body's oxidation defence system. However, it is unclear whether Se affects the development of aortic aneurysm (AA). An animal experiment was conducted to clarify the role of Se in AA development. METHODS: C57BL/6N male mice were fed with a Se deficient (Se-D, < 0.05 mg/kg), Se adequate (Se-A, 0.2 mg/kg), or Se supplemented (Se-S, 1 mg/kg) diet for 8 weeks. Subsequently, an AA murine model (Se-D, n = 11; Se-A, n = 12; Se-S, n = 15) was established using angiotensin II (Ang II, 1 mg/kg/min) for four weeks plus ß-aminopropionitrile (BAPN, 1 mg/mL) for the first two weeks. Saline replaced Ang II, and BAPN was removed during the modelling process for sham mice (Se-A, n = 9). To determine whether Se deficiency promoted aortic dilation via matrix metalloproteinase-2 (MMP-2), the non-specific MMP inhibitor doxycycline (Dox, 100 mg/kg/day) was given to Se-D AA mice (n = 7) for two weeks. RESULTS: The maximum aortic diameter in Se-D AA model mice was significantly increased compared with Se-A AA model mice. MMP-2 expression and activity in the aortic media of Se-D AA model mice was significantly increased compared with Se-A AA model mice. A large number of vascular smooth muscle cells (VSMCs) were found aggregating in the media of the non-dilated aorta of Se-D AA model mice, which was completely inhibited by Dox. The percentage of VSMCs in aortic media of Se-D AA model mice was significantly higher than in Se-A AA model mice. The maximum aortic diameter and occurrence rate of AA in Se-D AA model mice with Dox were significantly reduced compared with Se-D AA model mice. CONCLUSION: Se deficiency promoted dilatation of the aorta in AA model mice by increasing expression and activity of VSMC derived MMP-2, causing abnormal aggregation and proliferation of VSMCs in aortic media.
Assuntos
Aneurisma Aórtico , Selênio , Masculino , Camundongos , Animais , Metaloproteinase 2 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Dilatação , Selênio/farmacologia , Selênio/metabolismo , Aminopropionitrilo/farmacologia , Camundongos Endogâmicos C57BL , Aorta/metabolismo , Modelos Animais de Doenças , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.MethodsâandâResults: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06-0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01-0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69-28.19). Chronic kidney disease (CKD) was associated with death. CONCLUSIONS: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.
Assuntos
Aneurisma Infectado , Aneurisma da Aorta Abdominal , Aneurisma da Aorta Torácica , Aneurisma Aórtico , Implante de Prótese Vascular , Procedimentos Endovasculares , Insuficiência Renal Crônica , Humanos , Estudos Retrospectivos , Mortalidade Hospitalar , Implante de Prótese Vascular/efeitos adversos , Resultado do Tratamento , Aneurisma Aórtico/complicações , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/complicações , Aneurisma Infectado/cirurgia , Aneurisma Infectado/complicações , Insuficiência Renal Crônica/complicações , Procedimentos Endovasculares/métodos , Fatores de Risco , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Pathogenesis and diagnostic biomarkers of aortic dissection (AD) can be categorized through the analysis of differential metabolites in serum. Analysis of differential metabolites in serum provides new methods for exploring the early diagnosis and treatment of aortic dissection. OBJECTIVES: This study examined affected metabolic pathways to assess the diagnostic value of metabolomics biomarkers in clients with AD. METHOD: The serum from 30 patients with AD and 30 healthy people was collected. The most diagnostic metabolite markers were determined using metabolomic analysis and related metabolic pathways were explored. RESULTS: In total, 71 differential metabolites were identified. The altered metabolic pathways included reduced phospholipid catabolism and four different metabolites considered of most diagnostic value including N2-gamma-glutamylglutamine, PC(phocholines) (20:4(5Z,8Z,11Z,14Z)/15:0), propionyl carnitine, and taurine. These four predictive metabolic biomarkers accurately classified AD patient and healthy control (HC) samples with an area under the curve (AUC) of 0.9875. Based on the value of the four different metabolites, a formula was created to calculate the risk of aortic dissection. Risk score = (N2-gamma-glutamylglutamine × -0.684) + (PC (20:4(5Z,8Z,11Z,14Z)/15:0) × 0.427) + (propionyl carnitine × 0.523) + (taurine × -1.242). An additional metabolic pathways model related to aortic dissection was explored. CONCLUSION: Metabolomics can assist in investigating the metabolic disorders associated with AD and facilitate a more in-depth search for potential metabolic biomarkers.