Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease.

Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.

Management of aortic disease in children with FBN1-related Marfan syndrome.

Marfan syndrome (MFS) is a hereditary connective tissue disorder with an estimated prevalence of 1:5000-1:10 000 individuals. It is a pleiotropic disease characterized by specific ocular, cardiovascular, and skeletal features. The most common cardiovascular complication is aortic root dilatation which untreated can lead to life-threatening aortic root dissection, mainly occurring in adult patients. Prompt diagnosis, appropriate follow-up, and timely treatment can prevent aortic events. Currently there are no specific recommendations for treatment of children with MFS, and management is greatly based on adult guidelines. Furthermore, due to the scarcity of studies including children, there is a lack of uniform treatment across different centres. This consensus document aims at bridging these gaps of knowledge. This work is a joint collaboration between the paediatric subgroup of the European Network of Vascular Diseases (VASCERN, Heritable Thoracic Aortic Disease Working Group) and the Association for European Paediatric and Congenital Cardiology (AEPC). A group of experts from 12 different centres and 8 different countries participated in this effort. This document reviews four main subjects, namely, (i) imaging of the aorta at diagnosis and follow-up, (ii) recommendations on medical treatment, (iii) recommendations on surgical treatment, and (iv) recommendations on sport participation.

Five-year outcomes of endovascular treatment for aortic dissection from the Global Registry for Endovascular Aortic Treatment.

OBJECTIVE: The Global Registry for Endovascular Aortic Treatment (GREAT) is an International prospective multicenter registry collecting real-world data on performance of Gore aortic endografts. The purpose was to analyze the long-term outcomes and patient survival rates, as well as device performance in patients undergoing thoracic endovascular aortic repair for acute and chronic and complicated or uncomplicated type B aortic dissection (TBAD). METHODS: From August 2010 to October 2016, 5014 patients were enrolled in the GREAT registry. The study population were patients treated with thoracic endovascular aortic repair for TBAD through 5-year follow-up (days 0-2006). The primary outcomes for this analysis were all-cause and aortic-related mortality, stroke, aortic rupture, endoleaks, migration, fracture, compression, and any reintervention through 5 years. RESULTS: We identified 265 patients. The mean age was 60.9 ± 11.9 years (range, 19-84 years; 211 males [79.6%]). Devices used were the Gore TAG and Conformable Gore TAG Thoracic Endoprosthesis. There were 228 patients (86.0%) who underwent primary endovascular treatment (144 off-label [54.3%]); 22 (8.3%) underwent reintervention after prior endovascular procedure and 15 (5.7%) underwent reintervention after prior open procedure. Kaplan-Meier estimated freedom from all-cause mortality at 5 years was 71.1%. Freedom from aortic-related mortality through 5 years was 95.8%. There was no significant difference in freedom from all-cause mortality during the follow-up period in complicated or uncomplicated disease. At 30 days and through 5 years, respectively, for all the following outcomes, the aortic rupture rate was 1.1% (n = 3) and 1.9% (n = 5). The stroke rate was 1.1% (n = 3) and 4.2% (n = 11). The spinal cord ischemic event rate was 1.5% (n = 4) and 2.6% (n = 7). Reinterventions were required in 6.4% (n = 17) and 21.1% (n = 56) of patients. The need for conversion to open repair was 0.4% (n = 1) and 2.6% (n = 7). Additional graft placement was required in 3 patients (1.1%) and 16 patients (6.0%). The endoleak rate at 30 days was 3.4% (n = 9); type IA (n = 1 [0.4%]), type IB (n = 4 [1.5%]), type II (n = 1 [0.4%]), type III (n = 1 [0.4%]), and unspecified (n = 4 [1.6%]). Through 5 years, the endoleak rate was 12.1% (n = 32); type IA (n = 7 [2.6%]), type IB (n = 10 [3.8%]), type II (n = 9 [3.4%]), type III (n = 2 [0.8%]), and unspecified (n = 12 [4.5%]). There were no cases of stent migration, compression or fracture through 5 years. CONCLUSIONS: Results at the 5-year follow-up demonstrate that the use of the Gore TAG and Conformable Gore TAG Thoracic Endoprosthesis can be supported in treatment of TBAD (acute, chronic, complicated, and uncomplicated). These data demonstrate strong device durability, beneficial patient outcomes, and support for the treatment of thoracic aortic dissection with an endovascular approach. Complete 10-year follow-up in GREAT as planned will be advantageous.

Sex-based outcomes after thoracic endovascular aortic repair: A systematic review and meta-analysis.

OBJECTIVE: As it remains unclear whether there are sex-based differences in clinical outcomes after thoracic endovascular aortic repair (TEVAR), this meta-analysis aimed to evaluate differences in early outcomes and overall survival between female and male patients who underwent TEVAR. METHODS: The PubMed, Embase, Web of Science, and Cochrane Central databases were searched for eligible studies published through June 10, 2023, that reported sex-based differences in clinical outcomes after TEVAR. The primary outcome was operative mortality; second outcomes included stroke, spinal cord ischemia, acute kidney injury, hospital length of stay, and overall survival. Patient characteristics, operative data, and early outcomes were aggregated using the random-effects model, presenting pooled risk ratio (RR) or standardized mean difference along with their corresponding 95% confidence intervals (CIs). Overall survival was assessed by reconstructing individual patient data to generate sex-specific pooled Kaplan-Meier curves. This study was registered in PROSPERO (CRD42023426069). RESULTS: Of the 1785 studies retrieved, 14 studies met all eligibility criteria, encompassing a total of 17,374 patients, comprising 5026 female and 12,348 male patients. Female patients were older, had a smaller maximum aortic diameter, had lower rates of smoking and coronary artery disease, and had higher rates of anemia. Intraoperatively, female patients were more likely to use iliac conduits and require blood transfusions. There were no sex-based differences in operative mortality (RR: 1.12, 95% CI: 0.90-1.40; P = .309), stroke (RR: 1.14, 95% CI: 0.95-1.38; P = .165), spinal cord ischemia (RR: 1.33, 95% CI: 0.83-2.14; P = .234), acute kidney injury (RR: 0.78, 95% CI: 0.52-1.17; P = .228), and hospital length of stay (standardized mean difference: 0.09, 95% CI: -0.03 to 0.20; P = .141). Pooled Kaplan-Meier estimates showed a worse overall survival in female patients compared with male patients (87.2% vs 89.8% at 2 years, log-rank P = .001). CONCLUSIONS: Among patients treated by TEVAR, female sex was not associated with increased risk of operative mortality or major morbidity. However, female patients exhibited a lower overall survival after TEVAR compared with male patients.

Use of physician-modified inverted limb in conjunction with Zenith fenestrated stent graft to rescue failed previous endovascular and open repair.

OBJECTIVE: To evaluate outcomes and performance of inverted limbs (ILs) when used in conjunction with Zenith fenestrated stent grafts (Zfens) to treat patients with short distance between the lowest renal artery (RA) and aortic or graft bifurcation (A/GB). METHODS: This study was a multicenter, retrospective review of prospectively maintained database of patients with complex aortic aneurysms, failed endovascular aneurysm repair (EVAR), or open surgical repair (OSR) with short distance between LRA and A/GB treated using a combination of Zfen and an IL between 2013 and 2023. Endpoints included technical success, aneurysm sac regression, long-term device integrity, and target vessel patency. We defined technical success as implantation of the device with no endoleak, conversion to an aorto-uni-iliac or OSR. RESULTS: During this time, 52 patients underwent endovascular rescue of failed repair. Twenty (38.5%) of them required relining of the failed repairs using IL due to lowest RA to A/GB length restrictions. Two patients had undergone rescue with a fenestrated cuff alone but developed type III endoleaks. One patient with no previous implant had a short distance between the lowest RA and aortic bifurcation to accommodate the bifurcated distal device, and two patients had failed OSR or anastomotic pseudoaneurysms. The majority (94%) were men with a mean age of 76.8 ± 6.1 years. The mean aortic neck diameter and aneurysm size were 32 ± 4 cm and 7.2 ± 1.3 cm, respectively. The median time laps between initial repair and failure was 36 months (interquartile range [IQR], 24-54 months). Sixteen patients (80%) were classified as American Society of Anesthesiologists class III, whereas four were class IV. Seventy-eight vessels were targeted and successfully incorporated. Technical success was 100%, and median estimated blood loss was 100 mL (IQR, 100-200 mL). Mean fluoroscopy time and dose were 61 ± 18 minutes and 2754 ± 1062 mGy, respectively. Average hospital length of stay was 2.75 ± 2.15 days. Postoperative complication occurred in one patient who required lower extremity fasciotomy for compartment syndrome. At a median follow-up of 50 months (IQR, 18-58 months), there were no device migration, components separation, aneurysmal related mortality, and type I or type III endoleak. Aneurysm sac regression (95%) or stabilization (5%) was observed in all patients, including in four patients (25%) with type II endoleak. CONCLUSIONS: The use of IL in conjunction with Zfen to treat patients with short distance between the lowest RA and A/GB is safe, effective, and has excellent long-term results. The technique expands the indication of Zfen, especially in patients with failed previous EVAR.

National registry insights on genetic aortopathies and thoracic endovascular aortic interventions.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) in patients with genetic aortopathies (GA) is controversial, given concerns of durability. We describe characteristics and outcomes after TEVAR in patients with GA. METHODS: All patients undergoing TEVAR between 2010 and 2023 in the Vascular Quality Iniatitive were identified and categorized as having a GA or not. Demographics, baseline, and procedural characteristics were compared among groups. Multivariable logistic regression was used to evaluate the independent association of GA with postoperative outcomes. Kaplan-Meier methods and multivariable Cox regression analyses were used to evaluate 5-year survival and 2-year reinterventions. RESULTS: Of 19,340 patients, 304 (1.6%) had GA (87% Marfan syndrome, 9% Loeys-Dietz syndrome, and 4% vascular Ehlers-Danlos syndrome). Compared with patients without GA, patients with GA were younger (50 years [interquartile range, 37-72 years] vs 70 years [interquartile range, 61-77 years]), more often presented with acute dissection (28% vs 18%), postdissection aneurysm (48% vs 17%), had a symptomatic presentation (50% vs 39%), and were less likely to have degenerative aneurysms (18% vs 47%) or penetrating aortic ulcer (and intramural hematoma) (3% vs 13%) (all P < .001). Patients with GA were more likely to have prior repair of the ascending aorta/arch (open, 56% vs 11% [P < .001]; endovascular, 5.6% vs 2.1% [P = .017]) or the descending thoracic aorta (open, 12% vs 2% [P = .007]; endovascular, 8.2% vs 3.6% [P = .011]). No significant differences were found in prior abdominal suprarenal repairs; however, patients with GA had more prior open infrarenal repairs (5.3% vs 3.2%), but fewer prior endovascular infrarenal repairs (3.3% vs 5.5%) (all P < .05). After adjusting for demographics, comorbidities, and disease characteristics, patients with GA had similar odds of perioperative mortality (4.6% vs 7.0%; adjusted odds ratio [aOR], 1.1; 95% confidence interval [CI], 0.57-1.9; P = .75), any in-hospital complication (26% vs 23%; aOR, 1.24; 95% CI, 0.92-1.6; P = .14), or in-hospital reintervention (13% vs 8.3%; aOR, 1.25; 95% CI, 0.84-1.80; P = .25) compared with patients without GA. However, patients with GA had a higher likelihood of postoperative vasopressors (33% vs 27%; aOR, 1.44; 95% CI, 1.1-1.9; P = .006) and transfusion (25% vs 23%; aOR, 1.39; 95% CI, 1.03-1.9; P = .006). The 2-year reintervention rates were higher in patients with GA (25% vs 13%; adjusted hazard ratio, 1.99; 95% CI, 1.4-2.9; P < .001), but 5-year survival was similar (81% vs 74%; adjusted hazard ratio, 1.02; 95% CI, 0.70-1.50; P = .1). CONCLUSIONS: TEVAR for patients with GA seemed to be safe initially, with similar odds for in-hospital complications, in-hospital reinterventions, and perioperative mortality, as well as similar hazards for 5-year mortality compared with patients without GA. However, patients with GA had higher 2-year reintervention rates. Future studies should assess long-term durability after TEVAR compared with the recommended open repair to appropriately weigh the risks and benefits of endovascular treatment in patients with GA.

Editor's Choice - Covered Stents Versus Bare Metal Stents in the Treatment of Aorto-iliac Disease: A Systematic Review and Individual Participant Data Meta-analysis.

OBJECTIVE: To assess the comparative safety and efficacy of covered stents (CS) and bare metal stents (BMS) in the endovascular treatment of aorto-iliac disease in patients with peripheral arterial disease. DATA SOURCES: A systematic review was conducted adhering to the PRISMA 2020 and PRISMA for Individual Participant Data 2015 guidelines. REVIEW METHODS: A search of PubMed, Scopus, and Web of Science for articles published by December 2023 was performed. The primary endpoint was primary patency. Certainty of evidence was assessed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: Eleven studies, comprising 1 896 patients and 2 092 lesions, were included. Of these, nine studies reported on patients' clinical status, with 35.5% classified as Rutherford 4 - 6. Overall primary patency for CS and BMS at 48 months was 91.2% (95% confidence interval [CI] 84.1 - 99.0%) (GRADE, moderate) and 83.5% (95% CI 70.9 - 98.3%) (GRADE, low). The one stage individual participant data meta-analyses indicated a significant risk reduction for primary patency loss favouring CS (hazard ratio [HR] 0.58, 95% CI 0.35 - 0.95) (GRADE, very low). The 48 month primary patency for CS and BMS when treating TransAtlantic Inter-Society Consensus (TASC) C and D lesions was 92.4% (95% CI 84.7 - 100%) (GRADE, moderate) and 80.8% (95% CI 64.5 - 100%) (GRADE, low), with CS displaying a decreased risk of patency loss (HR 0.39, 95% CI 0.27 - 0.57) (GRADE, moderate). While statistically non-significant differences were identified between CS and BMS regarding technical success, 30 day mortality rate, intra-operative and immediate post-operative procedure related complications, and major amputation, CS displayed a decreased re-intervention risk (risk ratio 0.59, 95% CI 0.40 - 0.87) (GRADE, low). CONCLUSION: This review has illustrated the improved patency of CS compared with BMS in the treatment of TASC C and D lesions. Caution is advised in interpreting overall primary patency outcomes given the substantial inclusion of TASC C and D lesions in the analysis. Ultimately, both stent types have demonstrated comparable safety profiles.

Impact of valve-sparing aortic root replacement on aortic fluid dynamics and biomechanics in patients with syndromic heritable thoracic aortic disease.

OBJECTIVES: Patients with syndromic heritable thoracic aortic diseases (sHTAD) who underwent prophylactic aortic root replacement are at high risk of distal aortic events, but the underlying mechanisms are poorly understood. This prospective, longitudinal study aims to assess the impact of valve-sparing aortic root replacement (VSARR) on aortic fluid dynamics and biomechanics in these patients, and to examine whether they present altered haemodynamics or biomechanics prior to surgery compared to sHTAD patients with no indication for surgery (sHTAD-NSx) and healthy volunteers (HV). METHODS: Sixteen patients with Marfan or Loeys-Dietz syndrome underwent two 4D flow CMR studies before (sHTAD-preSx) and after VSARR (sHTAD-postSx). Two age, sex and BSA matched cohorts of 40 HV and 16 sHTAD-NSx patients with available 4D flow CMR, were selected for comparison. In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR), wall shear stress (WSS), pulse wave velocity (PWV) and aortic strain were analysed in the ascending (AscAo) and descending aorta (DescAo). RESULTS: All patients with sHTAD presented altered haemodynamics and increased aortic stiffness (p<0.05) compared to HV, both in the AscAo (median PWV 7.4 in sHTAD-NSx; 6.8 in sHTAD-preSx; 4.9m/s in HV) and DescAo (median PWV 9.1 in sHTAD-NSx; 8.1 in sHTAD-preSx; 6.3m/s in HV). Patients awaiting VSARR had markedly reduced in-plane (median IRF -2.2 vs 10.4 cm2/s in HV, p=0.001), but increased through-plane flow rotation (median SFRR 7.8 vs 3.8% in HV, p=0.002), and decreased WSS (0.36 vs 0.47N/m2 in HV, p=0.004) in the proximal DescAo. After VSARR, proximal DescAo in-plane rotational flow (p=0.010) and circumferential WSS increased (p=0.011), no longer differing from HV, but through-plane rotational flow, axial WSS and stiffness remained altered. Patients in which aortic tortuosity was reduced after surgery showed greater post-surgical increase in IRF compared to those in which tortuosity increased (median IRF increase 18.1 vs 3.3cm²/s, p=0.047). Most AscAo flow alterations were restored to physiological values after VSARR. CONCLUSIONS: In patients with sHTAD, VSARR partially restores downstream fluid dynamics to physiological levels. However, some flow disturbances and increased stiffness persist in the proximal DescAo. Further longitudinal studies are needed to evaluate whether persistent alterations contribute to post-surgical risk.

The two therapeutic strategies of surgical intervention and medical management in a patient with enhanced-fibrinolytic type of disseminated intravascular coagulation after aortic replacement for Stanford type A aortic dissection with chronic heart and renal failure.

BACKGROUND: Management of the enhanced-fibrinolytic type of disseminated intravascular coagulation (DIC) caused by aortic disorders is the two strategies of surgical intervention and medical treatment based on the patient's age and comorbidities. CASE PRESENTATION: An 81-year-old woman with a history of two previous aortic surgeries and chronic heart and renal failure was admitted for uncontrollable subcutaneous hemorrhage. The hemorrhage was caused by the enhanced-fibrinolytic type of disseminated intravascular coagulation (DIC) caused by periprosthetic graft hematoma after aortic replacement for Stanford type A aortic dissection. Open thoracic hemostasis temporarily controlled the subcutaneous hemorrhage, but she was readmitted for the recurrence seven months after discharge. On the second admission, the combination of anticoagulant and antifibrinolytic agents was successful. CONCLUSION: Management of the enhanced-fibrinolytic type of DIC caused by aortic disorders is important of a successful combination of surgical and medical therapy tailored the patient's condition.

Early and mid-term results after endovascular repair of thoracoabdominal aortic aneurysms using the off-the-shelf multibranched t-Branch device: a national multi-center study.

Objective: The multibranched off-the-shelf Zenith® t-Branch (Cook Medical, Bloomington, IN) device is commonly chosen for endovascular repair of thoracoabdominal aortic aneurysms. The aim of this study was to report early and mid-term outcomes in all patients treated with the t-Branch in Norway; Design and Methods: A retrospective multicenter study with Norwegian centers performing complex endovascular aortic repair was undertaken. T-Branch patients from 2014 to 2020 were included. All postoperative computed tomography angiography images were reviewed, and demographic, anatomical, perioperative and follow-up data were analyzed; Results: Seventy patients were treated in a single-step (n = 55) or staged (n = 15) procedure. Symptomatic presentation was seen in 20 patients, six of which had a contained rupture. Technical success was 87% (n = 59), with failures caused by unsuccessful bridging of target vessels (n = 4), target vessel bleeding (n = 3), persisting type 1c endoleak (n = 1) and t-Branch malrotation (n = 1). 30-day mortality was 9% (n = 6) and was associated with high BMI (p = .038). The spinal cord ischemia rate was 21% (n = 15) and was associated with type II aneurysms (OR 5.4, 95% CI 1.1-26.7, p = .04), smoking (OR 6.0, 95% CI 1.3-27.6, p = .02) and intraoperative blood loss (OR 1.1, 95% CI 1.0-1.3, p = .01). Survival at one, two and three years was 84 ± 4%, 70 ± 6% and 67 ± 6%, respectively. Freedom from aortic-related reinterventions at one, two and three years was 80 ± 5%, 65 ± 7% and 50 ± 8%, respectively; Conclusion: The study showed low early mortality (9%) and satisfactory mid-term survival. Technical success was achieved in acceptable 87% of procedures. The rate of spinal cord ischemia was high, occurring in 21% of patients.

This paper provides a national experience of all TAAA patients treated with the multibranched t-Branch stent graft in Norway in a multi-center study. As we aimed at including all Norwegian patients operated with the device, the paper adds real-world data on t-Branch outcomes from four regional smaller-volume vascular centers.The paper provides technical and clinical mid-term results with several patients being followed up for >3 years.Technical success was achieved in 87% of procedures.The 30-day mortality rate was 9% and survival at one, two and three years was 85 ± 4%, 70 ± 6% and 67 ± 6%, respectively.Spinal cord ischemia was associated with Crawford type II aneurysms, smoking and intraoperative blood loss.

Multiple aortic root pseudoaneurysms with dissecting aneurysm of the interventricular septum diagnosed by multimodal imaging.

Aortic root pseudoaneurysm is a devastating complication post aortic valve replacement with a high mortality rate. And dissecting aneurysm into the interventricular septum is a rare variant of aortic root pseudoaneurysm, which is scarcely reported. Multimodal imaging is of great value in its diagnosis and differential diagnosis.

Clinical Presentation and Management of the Cervical Aortic Arch in the Adult Population: A Review of Case Reports.

The cervical aortic arch (CAA) is an uncommon congenital anomaly in aortic development, characterized by an elongated aortic arch extending at or above the medial ends of the clavicles. Our objective was to examine the clinical and surgical characteristics of this infrequent condition in the adult population. PubMed, ScienceDirect, SciELO, DOAJ, and Cochrane Library databases were searched until December 2023 for case reports describing the presence of a cervical aortic arch in patients aged ≥18 years. Case reports and series were included if the following criteria were met: (1) description of the cervical aortic arch, (2) age ≥18 years, and (3) English language. The literature search identified 2,325 potentially eligible articles, 61 of whom met our inclusion criteria and included a combined number of 71 patients. Mean age was 38.6 ± 15.4 years, with a female prevalence of 67.1% (47/70). Two-thirds of the CAA were left-sided (48/71, 67.6%), and 62.0% (44/71) of patients presented a concomitant arch aneurysm. Asymptomatic patients were 45.7% (32/70), while of those that were symptomatic, 60.5% (23/38) had symptoms related to vascular-induced compression of trachea and esophagus. Surgery was performed in 42 patients (62.7%) among 67 cases that reported the patient's treatment, and 5 patients (11.9%) among those surgically treated underwent the procedure through an endovascular approach. CAA is an uncommon congenital abnormality that presents challenges in diagnosis and treatment due to its high anatomical variability, diverse clinical manifestations, and presence of concomitant diseases. Surgery seems to be a safe and effective option for the resolution of symptoms.

Aorto-left ventricular tunnel: the necessity of early surgical intervention.

Aorto-left ventricular tunnel, also known as aorto-left ventricular fistula, is a rare CHD characterised by an abnormal connection between the aorta and the left ventricle. This article presents a comprehensive case report on aorto-left ventricular tunnel, encompassing clinical presentation, diagnostic approaches, treatment options, and outcomes, with a specific focus on the necessity of early surgical intervention.

Aortic root morphometry revisited-Clinical implications for aortic valve interventions.

The complex anatomy of the aortic root is of great importance for many surgical and transcatheter cardiac procedures. Therefore, the aim of this study was to provide a comprehensive morphological description of the nondiseased aortic root. We morphometrically examined 200 autopsied human adult hearts (22.0% females, 47.9 ± 17.7 years). A meticulous macroscopic analysis of aortic root anatomy was performed. The largest cross-section area of the aortic root was observed in coaptation center plane (653.9 ± 196.5 mm2), followed by tubular plane (427.7 ± 168.0 mm2) and basal ring (362.7 ± 159.1 mm2) (p < 0.001). The right coronary sinus was the largest (area: 234.3 ± 85.0 mm2), followed by noncoronary sinus (218.7 ± 74.8 mm2) and left coronary sinus (201.2 ± 78.08 mm2). The noncoronary sinus was the deepest, followed by right and left coronary sinus (16.4 ± 3.2 vs. 15.9 ± 3.1 vs. 14.9 ± 2.9 mm, p < 0.001). In 68.5% of hearts, the coaptation center was located near the aortic geometric center. The left coronary ostium was located 15.6 ± 3.8 mm above sinus bottom (within the sinus in 91.5% and above sinutubular junction in 8.5%), while for right coronary ostium, it was 16.2 ± 3.5 mm above (83.5% within sinus and 16.5% above). In general, males exhibited larger aortic valve dimensions than females. A multiple forward stepwise regression model showed that anthropometric variables might predict the size of coaptation center plane (age, sex, and heart weight; R2 = 31.8%), tubular plane (age and sex; R2 = 25.6%), and basal ring (age and sex; R2 = 16.9%). In conclusion, this study presents a comprehensive analysis of aortic-root morphometry and provides a platform for further research into the intricate interplay between structure and function of the aortic root.

Identification of Variants of Uncertain Significance in the Genes Associated with Thoracic Aortic Disease in Russian Patients with Nonsyndromic Sporadic Subtypes of the Disorder.

Nonsyndromic sporadic thoracic aortic aneurysm (nssTAA) is characterized by diverse genetic variants that may vary in different populations. Our aim was to identify clinically relevant variants in genes implicated in hereditary aneurysms in Russian patients with nssTAA. Forty-one patients with nssTAA without dissection were analyzed. Using massive parallel sequencing, we searched for variants in exons of 53 known disease-causing genes. Patients were found to have no (likely) pathogenic variants in the genes of hereditary TAA. Six variants of uncertain significance (VUSs) were identified in four (9.8%) patients. Three VUSs [FBN1 c.7841C>T (p.Ala2614Val), COL3A1 c.2498A>T (p.Lys833Ile), and MYH11 c.4993C>T (p.Arg1665Cys)] are located in genes with "definitive" disease association (ClinGen). The remaining variants are in "potentially diagnostic" genes or genes with experimental evidence of disease association [NOTCH1 c.964G>A (p.Val322Met), COL4A5 c.953C>G (p.Pro318Arg), and PLOD3 c.833G>A (p.Gly278Asp)]. Russian patients with nssTAA without dissection examined in this study have ≥1 VUSs in six known genes of hereditary TAA (FBN1, COL3A1, MYH11, NOTCH1, COL4A5, or PLOD3). Experimental studies expanded genetic testing, and clinical examination of patients and first/second-degree relatives may shift VUSs to the pathogenic (benign) category or to a new class of rare "predisposing" low-penetrance variants causing the pathology if combined with other risk factors.

Neutrophil Extracellular Traps in Cardiovascular and Aortic Disease: A Narrative Review on Molecular Mechanisms and Therapeutic Targeting.

Neutrophil extracellular traps (NETs), composed of DNA, histones, and antimicrobial proteins, are released by neutrophils in response to pathogens but are also recognized for their involvement in a range of pathological processes, including autoimmune diseases, cancer, and cardiovascular diseases. This review explores the intricate roles of NETs in different cardiovascular conditions such as thrombosis, atherosclerosis, myocardial infarction, COVID-19, and particularly in the pathogenesis of abdominal aortic aneurysms. We elucidate the mechanisms underlying NET formation and function, provide a foundational understanding of their biological significance, and highlight the contribution of NETs to inflammation, thrombosis, and tissue remodeling in vascular disease. Therapeutic strategies for preventing NET release are compared with approaches targeting components of formed NETs in cardiovascular disease. Current limitations and potential avenues for clinical translation of anti-NET treatments are discussed.

An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5, from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases.

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.

Association Between Cardiac Size, Systolic Function, and Complications in Vascular Ehlers-Danlos Syndrome.

Purpose: Vascular Ehlers-Danlos syndrome (vEDS) is a rare and aggressive heritable aortic disease caused by pathogenic variants in COL3A1 gene, characterized by spontaneous arterial dissection and organ rupture. The purpose of this study is to evaluate ventricular size and function and to explore their associations with complications in vEDS. Methods: Adults with genetically confirmed vEDS who underwent clinical cardiac MRI were retrospectively compared with controls matched for age and sex. Cardiac MRI analysis included assessment of ventricular volumetry and arterial vasculature. vEDS-related complications were evaluated including dissection, aneurysm, and pneumothorax. Multivariable logistic regression was performed. Results: We studied 26 individuals with vEDS (38.6 ± 15.6 years, 50.0% female) and 26 healthy controls. Median clinical follow-up was 2.4 (1.1-3.6) years. Left and right ventricular ejection fractions were lower in vEDS compared with controls (LVEF 58 ± 6% vs 61 ± 4%, P = .03; RVEF 54 ± 5% vs 58 ± 4%, P = .03). After controlling for age, sex, and antihypertensive medication, LV end-diastolic volume indexed to body surface area (LVEDVi) predicted dissections (OR 1.1, 95% CI 1.01-1.2, P = .04) and aneurysms (OR 1.1, 95% CI 1.01-1.3, P = .03). Indexed LV end systolic volume (LVESVi) also predicted aneurysms (OR 1.2, 95% CI 1.03-1.5, P = .02). LVEF predicted the presence of any complication (OR 0.71, 95% CI 0.52-0.99, P = .04). Pneumothorax occurred exclusively in vEDS group among those with LVEF <58% (below the mean), 50.0% versus 0.0%, P = .02. Those with LVEF <58% had more frequent dissection and/or aneurysm (75.0% vs 12.5%, P = .04). Conclusion: Lower LVEF and larger cardiac size are associated with complications in vEDS.

2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. Structure: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

An FBN1 deep intronic variant is associated with pseudoexon formation and a variable Marfan phenotype in a five generation family.

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies.