Aortic Research Articles

Comparison of open and hybrid endovascular repair for aortic arch: a multi-centre study of 1052 adult patients.

We aimed to evaluate early and late outcomes by comparing open total arch repair and endovascular arch repair using proximal landing zone analysis in a multicentre cohort. From 2008 to 2019, patients treated surgically for aortic arch disease at 6 centres were included, excluding cases with type A aortic dissection, additional aortic root replacement and extensive aortic aneurysm. In all patients and populations with proximal landing zones 0/1 (N = 144) and 2 (N = 187), early and late outcomes were compared using propensity score matching. A total of 1052 patients, including 331 (31%) and 721 (69%) patients undergoing endovascular arch repair and open total arch repair, respectively, were enrolled. After propensity score match (endovascular arch repair, 295; open total arch repair, 566), no significant difference was observed in in-hospital mortality rate (endovascular arch repair, 6.8%; open total arch repair, 6.2%; P = 0.716). Open total arch repair was associated with a lower risk of all-cause death [log-rank test; P = 0.010, hazard ratio (HR) 1.41 (95% confidence interval 1.17-1.71)]. The incidence of aorta-related death was higher in endovascular arch repair [Gray's test; P = 0.030, HR; 1.44 (95% confidence interval 1.20-1.73)]. When compared to endovascular arch repair with proximal landing zone 0/1, open total arch repair was associated with lower risks of all-cause death [log-rank test; P < 0.001, HR 2.04 (95% confidence interval 1.43-2.90)] and aorta-related death [Gray's test; P = 0.002, HR 1.67 (95% confidence interval; 1.25-2.24)]. There was no difference in the risk of all-cause death [log-rank test; P = 0.961, HR 0.99 (95% confidence interval 0.67-1.46)] and aorta-related death [Gray's test; P = 0.55, HR 1.31 (95% confidence interval 1.03-1.67)] between endovascular arch repair with proximal landing zone 2 and open total arch repair. Open total arch repair was considered the 1st choice based on early and late results; however, endovascular arch repair may be a useful option if the proximal landing zone is limited to zone 2.

Red blood cell distribution width to albumin ratio as novel prognostic biomarker in cardiovascular disease

Abstract Background The red blood cell distribution width-to-albumin ratio (RAR) is a novel, cost-effective, and accessible biomarker for inflammation. Although numerous studies have investigated the relationship between RAR values and mortality in cardiovascular diseases (CVD), the generalizability and robustness of these individual studies' results remain uncertain, underscoring the necessity for a meta-analysis. Purpose To explore the pooled association between RAR and all-cause mortality in several CVDs. Methods A systematic search for eligible studies was conducted across scientific databases, including Scopus, Web of Science, PubMed, and ProQuest, up to February 1, 2024. Mortality hazard ratios (HRs) for the highest versus lowest RAR categories were pooled using the Generic Inverse Variance method. A dose-response meta-analysis was performed using generalized least-squares regression to estimate trends of HRs across dose categories. Publication bias was assessed by inspecting funnel plots and performing Egger's test. Subgroup analyses were based on the underlying CVDs. Statistical analyses were executed in RStudio software, with the significance threshold set at p &amp;lt; 0.05. Results This systematic review and meta-analysis reviewed 16 high-quality studies published between 2021 and 2024 with 30,933 participants. The underlying diseases in the included studies were Acute Myocardial Infarction (AMI), Heart Failure (HF), Atrial Fibrillation (AF), aortic valvular disease, stroke and pulmonary embolism. The lowest quartile range for RAR was 0.80–1.20 ml/g, while the highest quartile ranged from 6.09 to 15.45 ml/g. Pooled results with a random-effect model showed that patients with higher RAR had significantly increased risk of all-cause mortality (HR 1.88, 95%CI 1.59–2.23, p&amp;lt;0.0001, I² = 91%). Non-linearity was observed in the dose-response relationship; thus, it was primarily illustrated using the restricted cubic spline model, with the linear model provided for comparison. A 1 ml/g increase in RAR corresponded to a 27% rise in the predicted HR for all-cause mortality (HR 1.27, 95%CI 1.16–1.39; p &amp;lt; 0.0001). Subgroup analyses based on the primary CVD diagnoses in the included studies confirmed a significant association between RAR values and all-cause mortality across all subgroups (AMI: HR 2.43, 95%CI 1.52–3.87, I² = 45%; HF: HR 1.78, 95%CI 1.13–2.81, I² = 94%; Stroke: HR 1.58, 95%CI 0.94–2.67, I² = 90%; Other CVD: HR 1.97, 95%CI 1.34–2.89, I² = 57%; p for interaction 0.24). Conclusion This is the first meta-analysis demonstrating the positive dose-response association between RAR values and all-cause mortality in CVD. Thus, RAR may be considered as a simple and practical prognostic biomarker in CVD.Forest plot based on CVD diagnosisDose-response RAR value to HR

Mitral valve phenotypes in SMAD3-related thoracic aortic disease: insights from the Montalcino Aortic Consortium

Abstract Background SMAD3 pathogenic variants (PV) predispose to heritable thoracic aortic aneurysms and dissections (HTAD). Mitral annular disjunction (MAD) associated with mitral valve prolapse (MVP) and mitral regurgitation (MR) was identified as a potential new marker of disease severity in Marfan syndrome. The prevalence and prognostic impact of these mitral phenotypes in other forms of HTAD are less known. Purpose We hypothesize that mitral abnormalities are increased in SMAD3-related HTAD and are associated with increased risk for valve and aortic complications. Methods The Montalcino Aortic Consortium (MAC) registry has enrolled participants with PV in 15 HTAD genes. Subjects &amp;gt;16 years old with complete imaging and clinical data were included in this study. MVP was defined according to current guidelines. MR was classified as mild, moderate, or severe. MAD was defined by a &amp;gt;3-millimeter gap between the posterior mitral valve leaflet hinge point and the inferolateral myocardium as confirmed by direct measurement of echocardiogram images. Frequencies of MVP, MR, and MAD were compared between MAC participants with SMAD3 PV and other HTAD PV. Associations between clinical and echo characteristics and the composite outcome of arrhythmia, aortic surgery, aortic dissection, or congestive heart failure was evaluated with multivariable logistic regression. Results In 671 MAC participants (129 with SMAD3 PV, 36 [IQR 19-51] years, 49% female), the prevalence of MVP was 15% and the prevalence of MR was 22%. Both MVP (31/129, 24%, vs. 67/542, 12%, OR 2.2 [1.4-3.6], P&amp;lt;0.001) and MR (40/129, 31%, vs. 108/542, 20%, OR 1.8 [1.2-2.8], P&amp;lt;0.006) were more common in participants with SMAD3 PV compared to other PV and were further enriched in cases with SMAD3 missense PV compared to loss of function PV (MR or MVP: 26/48, 54% vs. 7/30, 23%, OR 3.9 [1.4-10.8], P&amp;lt;0.007). Images were available from 238 MAC participants (67 with SMAD3 PV) to assess for MAD. MAD (29/67, 43%, vs. 28/171, 16%, OR 3.9 [2.1-7.3], P&amp;lt;0.0001), or the composite of MR, MVP, or MAD (42/67, 63%, vs. 69/171, 35%, OR 3.2 [1.8-5.7], P&amp;lt;0.0001) was more common with SMAD3 PV compared to other PV (Figure 1). Twelve participants with SMAD3 PV (18%) had prominent mitral phenotypes (&amp;gt;mild MR, &amp;gt;10 mm MAD, or MAD with MVP) but no significant aortic dilation (Z&amp;lt;3). When controlling for age and sex, MR or MVP, but not MAD, was independently associated with the composite outcome (OR 16 [2.4-110], Figure 2). Conclusion Mitral valve pathology, including MVP, MR, and MAD, is increased in individuals with SMAD3 PV compared to other HTAD PV. Prominent mitral phenotypes related to SMAD3 missense PV may identify a high-risk subgroup with adverse cardiovascular outcomes. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such patients, especially if they also have a family history of thoracic aortic disease.

Short-term mechanical circulatory support in adults with congenital heart disease: indications and outcomes

Abstract Background An increasing number of adults with congenital heart disease (ACHD) present with heart failure (HF), which may require short- or long-term mechanical circulatory support (MCS), often around cardiac surgery or other interventions. Even though MCS has entered ACHD practice over the last few years, little is known on its indications and outcomes in this population. Purpose To assess the use and outcomes of short-term MCS in ACHD patients in a specialist centre, and assess the predictive power of the Survival After Veno-Arterial Extracorporeal Membrane Oxygenation (SAVE) score in this population. Methods Data on all ACHD patients who received MCS since 2008 in a single tertiary centre were collected. Immediate, short and longer-term outcomes were also collected, including death, complications, and weaning success. Logistic regression and ROC analysis were performed to identify predictors of in-hospital mortality. Result There were 65 episodes of MCS in 63 patients during the study period: age 36.9+-13.6 years, 61.5% male. Most patients had CHD of moderate or severe complexity (49.2% moderate and 10.8% severe according to ESC guidelines). The most common anatomical diagnoses were left outflow tract obstruction in 35.4%, Marfan syndrome in 20.0% and tetralogy of Fallot or pulmonary atresia in 10.8%. The most common indications for ECMO were perioperative support (not endocarditis) in 55.6%, HF in 14.3%, pneumonia in 12.7% and endocarditis-related surgery in 7.9%. A critical preoperative status was present in 26.8%; median PEACH score (a validated ACHD peri-operative risk score) was 1.0[1.0-3.0] and ACHS score was 0.6[0.6-1.0]. Median SAVE score was -4.0[-9.0–2.0], with 21(43.8%) in SAVE class 4 or 5. VA-ECMO was used in 69.2%, VV-ECMO in 21.5%, BiVAD-ECMO in 4.6% and RVAD support in 4.6% of patients. The median duration of ECMO support was 198.6[133.0-354.2] hours. Complications included ischemic stroke (15.4%), intracerebral bleeding (9.2%), and other thromboembolism (23.8%). Successful weaning was achieved in 56.2%, whereas 4.6% were switched to more definitive MCS. In-hospital mortality was 47.7%, and this was higher in patients receiving VA support (OR 4.92, 95%CI:1.32-23.93, p=0.03). For patients on VA-ECMO or BiVAD support, the presence of Marfan syndrome (OR 4.92, 95%CI:1.32-23.93, p=0.03) and a lower (worse) SAVE score (OR 1.3 per point reduction, 95%CI:1.11-1.59, p=0.004) were associated with in-hospital mortality. An adjusted SAVE score that accounted for the presence of heritable thoracic aortic diseases (HTAD, -3 points) performed well at predicting in-hospital mortality (AUC increasing from 0.73 to 0.8, Figure). Conclusions Short-term MCS is a useful temporary rescue intervention in patients with ACHD, as a bridge to recovery or durable support, with 1 in 2 patients surviving to hospital discharge. The SAVE score adjusted for HTAD can reliably predict outcomes in patients with VA-ECMO and requires external validation.Figure

Sex differences in aortic prognosis in Marfan patients, a retrospective longitudinal study from the REPAG registry

Abstract Introduction Previous studies(1-4) have suggested a more favourable aortic outcome among women with Marfan syndrome (MFS), although the precise underlying mechanism remains not completely understood. In this retrospective longitudinal study, we aim to evaluate sex differences in aortic events in a large cohort of Marfan patients seen in 11 tertiary centres in Spain. Methods Patients with diagnosis of Marfan syndrome (MFS) were included. Data on aortic events (AE) including elective aortic surgeries, acute aortic syndrome or death were incorporated. Survival free of the combined endpoint of death or first aortic event (elective aortic surgery or acute aortic syndrome) was compared between male and female by the Kaplan-Meier curves, log-rank test and subsequent Cox regression analysis. Results A total of 442 patients with MFS where included, 48.2% female and 56.2% index cases. Although systemic score and proband proportion was not different between both sexes, the diagnosis was earlier in males (p=0.01) (Table). Furthermore, among adult patients, males exhibited greater height, weight, and body surface area (BSA). Absolute aortic root diameter at baseline was greater in males, but not BSA-indexed diameters or z-scores. Combined endpoint of death or aortic event was observed in 192 patients (120 male, 72 female, p=&amp;lt;0.00001). Female sex had better survival free of the combined endpoint in a multivariable Cox analysis (HR 0.41 95% CI=0.30–0.55) with a mean survival free of the combined endpoint of 41.3yrs in male and 61.4 years in females (p&amp;lt;0.0001) (Figure).Although a higher proportion of elective aortic interventions as first event was observed in males (66.7% vs 52.8%), the proportion of type A dissections was similar between both sexes (26.7 vs 26.4%) with increased frequency of type B dissections in females as first aortic event (4.2 vs 15.3%) (p=0.026) Conclusions Male patients with MFS present higher aortic root diameters but similar BSA-indexed and zscores than females. Survival free of first aortic event or death is reduced in male with MFS, with greater frequency of elective aortic intervention. Although this last is driven by absolute aortic diameter, no increase on type A dissection was observed in women. These findings might suggest a potentially less aggressive manifestation of proximal aortic disease in women with MFS.Table:Comparison male and female Marfan

Mapping 18F-FDG PET uptake in the aortic wall and thrombus

Abstract Background Positron Emission Tomography (PET) uptake allows for the assessment of molecular activity, being 18F-FDG uptake indicative of glucose metabolism. PET uptake is commonly quantified manually by drawing regions of interest, which is subjective, poorly-reproducible and may miss relevant information. Purpose To develop and test an image analysis method to quantify and map 18F-FDG uptake on the whole aortic wall and thrombus. Methods PET-MRI was acquired in patients with thoracic or abdominal aortic aneurysms. The aorta was semi-automatically segmented in the MR angiography using 3DSlicer, generating a surface mesh that was expanded by 3 mm inward and outward. PET uptake was interpolated over this volume with a uniform spatial resolution of 1 mm. By means of 9 reference points, the aortic wall was discretized into 52 (thoracic) or 80 (thoraco-abdominal) standardized regions (i.e. wall patches). For each aortic patch and for the whole thrombus volume, the target to background Ratio (TBR) was calculated by dividing the uptake by a reference uptake in the left atrium. Two observers segmented the aorta and thrombus, located the anatomical reference points and quantified TBR. Inter-observer agreement for segmentation and aortic wall discretization was evaluated in terms of the 95% Hausdorff Distance (HD) and Dice Score Coefficient (DSC), while both median and 95% TBR in each region were tested via intra-class correlation coefficient (absolute value, single measure). Results Data from 20 patients with thoracic or abdominal aneurysms were analysed, 10 of them presented thrombus. The reproducibility of the segmentation of the aorta (median HD 3.16 IQR [2.42 - 3.94] mm, DSC 0.90 [0.89 - 0.92]) and of the thrombus (HD 4.87 [3.51 - 8.45] mm, DSC 0.85 [0.80 - 0.87]) were excellent. The inter-observer agreement in the localization of reference points was good (HD 5.10 [3.29 - 8.73] mm), resulting in excellent overlapping of the standardized aortic wall patches (HD 3.80 [2.44 - 5.08] mm). Inter-observer agreement of median and 95% TBR in each aortic patch were excellent (ICC of 0.90 and 0.93, respectively, Figure 1), with minimal bias (Figure 2). Similarly, excellent interobserver reproducibility was observed for median and 95% TBR in the thrombus (ICC of 0.97 and 0.96, respectively, Figure 2). Conclusions A robust and reproducible image analysis method to map PET uptake along the aortic wall was developed, extending the possibilities to study aortic diseases molecular activity and its association with local aortic characteristics.

Predictors of Type 1a Endoleak After Hybrid Thoracic Endovascular Aortic Repair for Aortic Arch Diseases.

This study analyzed the risk factors for type 1a endoleak after hybrid thoracic endovascular repair (TEVAR) for aortic arch diseases based on preoperative patient characteristics and multidetector computed tomography measurements. In all, 213 patients who underwent proximal landing zone 1 and 2 hybrid TEVAR for aortic arch pathologies (zone 1, n=82 [38.5%]; zone 2, n=131 [61.5%]; median age 72 years) between May 2008 and February 2020 were enrolled in this study; the median follow-up period was 6.0 years. The rates of type 1a endoleak at 1, 3, 5, and 10 years were 1.4%, 1.4%, 4.1%, and 4.1%, respectively. Multivariate Cox proportional hazard regression analysis revealed that the angle of the aortic arch was a significant risk factor for type 1a endoleak (hazard ratio 1.08; 95% confidence interval 0.85-0.99; P=0.045). The estimated area under the curve in receiver operating characteristic curve analysis was 0.76, and the cut-off value of the aortic arch angle was 95°. It is essential to prevent type 1a endoleak, the most severe complication of hybrid TEVAR. The risk factor for type 1a endoleak in this study was a sharper angle of the aortic arch (≤95°). For patients at high risk of type 1a endoleak, it is necessary to consider alternative procedures depending on a patient's surgical risk.

Early and Late Aortic-Related Mortality and Rupture After Fenestrated-Branched Endovascular Aortic Repair of Thoracoabdominal Aortic Aneurysms: A Prospective Multicenter Cohort Study.

Fenestrated-branched endovascular aortic repair (FB-EVAR) has been used as a minimally invasive alternative to open surgical repair to treat patients with thoracoabdominal aortic aneurysms (TAAAs). The aim of this study was to evaluate aortic-related mortality (ARM) and aortic aneurysm rupture after FB-EVAR of TAAAs. Patients enrolled in 8 prospective, nonrandomized, physician-sponsored investigational device exemption studies between 2005 and 2020 who underwent elective FB-EVAR of asymptomatic intact TAAAs were analyzed. Primary end points were ARM, defined as any early mortality (30 days or in hospital) or late mortality from aortic rupture, dissection, organ or limb malperfusion attributable to aortic disease, complications of reinterventions, or aortic rupture. Secondary end points were early major adverse events, TAAA life-altering events (defined as death, permanent spinal cord injury, permanent dialysis, or stroke), all-cause mortality, and secondary interventions. A total of 1109 patients were analyzed; 589 (53.1%) had extent I-III and 520 (46.9%) had extent IV TAAAs. Median age was 73.4 years (interquartile range, 68.1-78.3 years); 368 (33.2%) were women. Early mortality was 2.7% (n=30); congestive heart failure was associated with early mortality (odds ratio, 3.30 [95% CI, 1.22-8.02]; P=0.01). Incidence of early aortic rupture was 0.4% (n=4). Incidence of early major adverse events and TAAA life-altering events was 20.4% (n=226) and 7.7% (n=85), respectively. There were 30 late ARMs; 5-year cumulative incidence was 3.8% (95% CI, 2.6%-5.4%); older age and extent I-III TAAAs were independently associated with late ARM (each P<0.05). Fourteen late aortic ruptures occurred; 5-year cumulative incidence was 2.7% (95% CI, 1.2%-4.3%); extent I-III TAAAs were associated with late aortic rupture (hazard ratio, 5.85 [95% CI, 1.31-26.2]; P=0.02). Five-year all-cause mortality was 45.7% (95% CI, 41.7%-49.4%). Five-year cumulative incidence of secondary intervention was 40.3% (95% CI, 35.8%-44.5%). ARM and aortic rupture are uncommon after elective FB-EVAR of asymptomatic intact TAAAs. Half of the ARMs occurred early, and most of the late deaths were not aortic related. Late all-cause mortality rate and the need for secondary interventions were 46% and 40%, respectively, 5 years after FB-EVAR. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02089607, NCT02050113, NCT02266719, NCT02323581, NCT00583817, NCT01654133, NCT00483249, NCT02043691, and NCT01874197.

Progressive Understanding of Aortic Disease.

Progressive Understanding of Aortic Disease.

Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease.

Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS. Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

Preoperative Depression is Associated With a Higher Risk of Bleeding in Type a Aortic Dissection Repair: A Population Study of National Inpatient Sample From 2015-2020.

Depression is highly prevalent in patients with aortic diseases. While depression has been shown to predispose patients to adverse outcomes after surgery, its impact on postoperative outcomes in Stanford Type A Aortic Dissection (TAAD) has not been established. This study aimed to conduct a population-based examination of the effect of preoperative depression on in-hospital outcomes after TAAD using the National/Nationwide Inpatient Sample (NIS) database, the largest all-layer database in the US. Patients undergoing TAAD repair were identified in NIS from the last quarter of 2015-2020. Multivariable logistic regressions were used to compare in-hospital outcomes between patients with and without preoperative depression, adjusted for demographics, comorbidities, hospital characteristics, primary payer status, and transfer status. There were 321 (7.50%) patients with depression and 3961 (92.50%) non-depressive patients who underwent TAAD repair. Patients with and without depression had comparable in-hospital mortality (11.84% vs 15.37%, P = 0.35). However, Patients with depression had a higher risk of hemorrhage/hematoma (83.49% vs 76.6%, aOR 1.593, 95 CI 1.161-2.184, P < 0.01) and a higher rate of transfer out (40.81% vs 32.62%, aOR 1.396, 95 CI 1.077-1.81, P = 0.01). All other in-hospital complications, hospital length of stay (LOS), and total hospital charge were comparable between patients with and without depression. Preoperative depression is associated with a higher risk of bleeding after TAAD repair. This may be due to anti-depression treatment, such as Selective Serotonin Reuptake Inhibitors (SSRIs), that can disrupt platelet function and lead to abnormal bleeding. While depression is not associated with other major outcomes, preoperative depression screening, as well as hemostatic monitoring and appropriate blood management in patients with depression may be crucial in preventing bleeding complications in TAAD repair.

Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium.

Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium registry. MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using χ2 or Fisher exact tests. MR and MVP were enriched in Montalcino Aortic Consortium participants (672) with pathogenic variants (PV) in transforming growth factor-β pathway genes. The combination of MR and MVP was associated with mitral surgery and arrhythmias. In the subgroup with available images, MAD was enriched in SMAD3 PV compared with other transforming growth factor-β PV (prevalence ratio 1.8 [1.1-2.8], P <0.02). Severe disjunction (>10 mm) was only observed in the transforming growth factor-β subgroup and was further enriched in participants with SMAD3 PV (prevalence ratio 3.1 [1.1-8.6]). MVP (prevalence ratio 5.2 [3.0-9.0]) and MR (PR 2.7 [1.8-3.9]) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events. Pathological mitral valve phenotypes are more prevalent in individuals with PV in transforming growth factor-β pathway genes, particularly SMAD3. MR and MVP but not MAD are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for heritable thoracic aortic disease should be considered for such individuals, especially if they also have a family history of heritable thoracic aortic disease.

Identification of Genetic Variants Associated with Hereditary Thoracic Aortic Diseases (HTADs) Using Next Generation Sequencing (NGS) Technology and Genotype-Phenotype Correlations.

Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta. The diseases have an insidious evolution and can be encountered as an isolated manifestation or can also be associated with systemic, extra-aortic manifestations (syndromic HTADs). Along with the development of molecular testing technologies, important progress has been made in deciphering the heterogeneous etiology of HTADs. The aim of this study is to identify the genetic variants associated with a group of patients who presented clinical signs suggestive of a syndromic form of HTAD. Genetic testing based on next-generation sequencing (NGS) technology was performed using a gene panel (Illumina TruSight Cardio Sequencing Panel) or whole exome sequencing (WES). In the majority of cases (8/10), de novo mutations in the FBN1 gene were detected and correlated with the Marfan syndrome phenotype. In another case, a known mutation in the TGFBR2 gene associated with Loeys-Dietz syndrome was detected. Two other pathogenic heterozygous variants (one de novo and the other a known mutation) in the SLC2A10 gene (compound heterozygous genotype) were identified in a patient diagnosed with arterial tortuosity syndrome (ATORS). We presented the genotype-phenotype correlations, especially related to the clinical evolution, highlighting the particularities of each patient in a family context. We also emphasized the importance of genetic testing and patient monitoring to avoid acute aortic events.

Transient High Salt Intake Promotes T-Cell-Mediated Hypertensive Vascular Injury.

Dietary high salt (HS) intake has a strong impact on cardiovascular diseases. Here, we investigated the link between HS-aggravated immune responses and the development of hypertensive vascular disease. ApolipoproteinE-deficient mice were transiently treated with HS (1% NaCl) via drinking water for 2 weeks, followed by a washout period, and subsequent Ang II (angiotensin II) infusion (1000 ng/kg per min for 10 days) to induce abdominal aortic aneurysms/dissections and inflammation. While transient HS intake alone triggered nonpathologic infiltration of activated T cells into the aorta, subsequent Ang II infusion increased mortality and the incidence of abdominal aortic aneurysms/dissections and atherosclerosis compared with hypertensive control mice. There were no differences in blood pressure between both groups. In transient HS-treated hypertensive mice, the aortic injury was associated with increased inflammation, accumulation of neutrophils, monocytes, CD69+CD4+ T cells, as well as CD4+ and CD8+ memory T cells. Mechanistically, transient HS intake increased expression levels of aortic RORγt as well as splenic CD4+TH17 and CD8+TC1 T cells in Ang II-treated mice. Isolated aortas of untreated mice were incubated with supernatants of TH17, TH1, or TC1 cells polarized in vitro under HS or normal conditions which revealed that secreted factors of HS-differentiated TH17 and TC1 cells, but not TH1 cells accelerated endothelial dysfunction. Our data suggest that transient HS intake induces a subclinical T-cell-mediated aortic immune response, which is enhanced by Ang II. We propose a 2-hit model, in which HS acts as a predisposing factor to enhance hypertension-induced TH17 and TC1 polarization and aortic disease.

Identifying HIF1A and HGF as two hub genes in aortic dissection and function analysis by integrating RNA sequencing and single-cell RNA sequencing data.

Aortic dissection (AD) is a severe aortic disease with high mortality, and its pathogenesis remains elusive. To explore the regulatory mechanisms of AD, we integrated public RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) datasets to screen the hub genes of AD and further analyzed their functions, which may provide references to the diagnosis and treatment of AD. Four AD-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis and differential expression analysis were applied to identify overlapping genes in dataset GSE153434. Protein-protein interaction (PPI) network was constructed based on overlapping genes. Five methods (closeness, degree, EPC, MCC, and MNN) were used to pick hub genes. The receiver operating characteristic curve was used to evaluate the diagnostic efficiency of the hub genes in extra datasets GSE98770 and GSE52093. scRNA-seq dataset GSE213740 was used to explore the expression and function of the hub genes at the single-cell level. Quantitative real-time polymerase chain reaction was used to verify the expression of hub genes in beta-aminopropionitrile (BAPN)-induced mouse thoracic aortic aneurysm and dissection (TAAD) model. A total of 71 overlapping genes were screened by intersecting the significant genes in the pink module and the differentially expressed genes. A PPI network with 45 nodes and 74 edges was generated, and five top hub genes (HIF1A, HGF, HMOX1, ITGA5, and ITGB3) were identified. All the hub genes had area under the curve values above 0.55. scRNA-seq data analysis showed that HIF1A was significantly upregulated in macrophages and HGF was significantly upregulated in vascular smooth muscle cells (SMCs) of the ascending aortas in AD patients. HIF1A may transcriptionally regulate multiple downstream target genes involving inflammation (TLR2, ALOX5AP, and MIF), glycolysis (ENO1, LDHA, and GAPDH), tissue remodeling (PLAU), and angiogenesis (SERPIN and VEGFA). HGF may participate in the signaling among SMCs, fibroblasts, and endothelial cells through binding to different receptors (MET, EGFR, IGF1R, and KDR). The mRNA expression of Hif1a, Hgf, and their target genes, including Alox5ap, Serpine1, Tlr2, Plau, Egfr, and Igf1r, was significantly upregulated in aortic tissues of BAPN-treated mice. By integrating RNA-seq and scRNA-seq data, we identified HIF1A and HGF as two hub genes with good diagnostic efficiency for AD. HIF1A in macrophages may promote AD formation by promoting inflammation, glycolysis, tissue remodeling, and angiogenesis, and HGF may mediate signaling among SMCs, fibroblasts, and endothelial cells in the development of AD.

Endovascular Treatment of Complex Aorto-Iliac Atherosclerotic Occlusive Disease With Chimney Covered Endovascular Reconstruction of Aortic Bifurcation.

Treatment of atherosclerotic occlusive disease of the infrarenal aorta poses several challenges. Traditionally, open surgery has been the preferred method of treatment in standard risk patients, although, it is burdened by high morbidity and mortality. There are many classifications to establish the patient risk for surgery. Among the most common is the American College of Cardiology (ACC)/American Heart Association (AHA) classification. ACC/AHA high-risk patients benefit from the increase in endovascular technology and skills. The treatment modality of atherosclerotic aortic disease has shifted towards a minimally invasive approach, including kissing stents, covered endovascular reconstruction of the aortic bifurcation (CERAB) and, aorto-uniiliac stent grafts. When there is an involvement of vital branches such as the inferior mesenteric (with concomitant occluded superior mesenteric artery) or the renal arteries, Chimney- CERAB technique has been successfully utilized to overcome this challenge. We present three patients with aortoiliac occlusive disease (AIOD) successfully treated with the chimney- CERAB technique to preserve a large inferior mesenteric artery in the setting of occlusion/near occlusion of the other mesenteric vessels.

Dynamic contrast-enhanced MRA of the aorta using a Golden-angle RAdial Sparse Parallel (GRASP) sequence: comparison with conventional time-resolved cartesian MRA (TWIST).

To compare the application of two contrast-enhanced time-resolved magnetic resonance angiography sequences on an aortic disease patient cohort: the conventional Cartesian-sampling-based, Time-resolved angiography With Interleaved Stochastic Trajectories (TWIST) sequence, and the radial-sampling-based Golden-angle RAdial Sparse Parallel (GRASP) sequence. TWIST is highly sensitive to patient movement, which can lead to blurring and reduced sharpness of vascular structures, particularly in dynamic regions like the aorta. Such motion artifacts can compromise diagnostic accuracy. Radial-sampling-based techniques are less sensitive to motion than cartesian sampling and are expected to improve the image quality in body parts subjected to motion. 30 patients (60.9 ± 16.1y.o.) with various aortic diseases underwent a 1.5T magnetic resonance angiography examination. Assessment of image quality in the ascending aorta (AA), descending aorta (DA), and abdominal aorta (AbA) on a 4-point Likert scale (1 = excellent, 4 = non-diagnostic) as well as max. aortic diameters (Dmax) were performed. T-test and multilevel mixed-effect proportional-odds models were used for the image analysis. GRASP offered superior depiction of vascular structures in terms of vascular contrast for qualitative analysis(TWIST, reader 1: 1.6 ± 0.5; reader 2: 1.9 ± 0.4; reader 3: 1.1 ± 0.4; GRASP, reader 1: 1.5 ± 0.5; reader 2: 1.4 ± 0.5; reader 3: 1.0 ± 0.2) and vessel sharpness for qualitative (TWIST, reader 1: 1.9 ± 0.6; reader 2: 1.6 ± 0.6; reader 3: 2.0 ± 0.3; GRASP, reader 1: 1.4 ± 0.6; reader 2: 1.2 ± 0.4; reader 3: 1.3 ± 0.6) and quantitative analysis (TWIST, AA = 0.12 ± 0.04, DA = 0.12 ± 0.03, AbA = 0.11 ± 0.03; GRASP, AA = 0.20 ± 0.05, DA = 0.22 ± 0.06, AbA=0.20 ± 0.05). Streaking artefacts of GRASP were more visible compared to TWIST (TWIST, reader 1: 2.2 ± 0.6; reader 2: 1.9 ± 0.3; reader 3: 2.0 ± 0.5; GRASP, reader 1: 2.6 ± 0.6; reader 2: 2.3 ± 0.5; reader 3: 2.8 ± 0.6).Aortic Dmax comparison among the sequence showed no clinical relevance. GRASP outperformed TWIST in SNR, vessel sharpness, and reduction in image blurring; streaking artefacts were stronger with GRASP, but did not affect diagnostic image quality.

Baseline Diameter Does Not Predict Growth Rate in a Presurgical Ascending Thoracic Aortic Aneurysm Population.

Patients with ascending thoracic aortic aneurysm are recommended to undergo routine imaging surveillance. Although maximal diameter is the primary metric of disease severity, recent American College of Cardiology/American Heart Association guidelines emphasize the importance of aortic growth in determining surgical candidacy and risk. As diameter increases, it is assumed that aortic growth rate accelerates because of increased wall tension; however, this relationship is poorly studied. We aim to investigate the relationship between ascending thoracic aortic aneurysm diameter and growth rate using vascular deformation mapping, a validated technique for 3-dimensional growth mapping with submillimeter accuracy. We retrospectively identified adult patients with ascending aortic dilation (≥4.0 cm) and serial gated computed tomography angiograms separated by ≥2 years, excluding confirmed heritable thoracic aortic disease. Ascending growth rate was defined as 90th percentile radial wall deformation by vascular deformation mapping. Maximal diameter measurements were derived from the baseline computed tomography angiogram, and aortic length and body size-adjusted indexes were calculated. Among 258 included patients (63.2% men; age of 63 years [interquartile range, 55-69 years]), mean±SD baseline diameter was 46.3±3.6 mm and median growth rate was 0.21 mm/year (interquartile range, 0.13-0.38 mm/year). No correlation was noted between growth rate and baseline diameter (r=0.02, P=0.74) or other aortic size metrics. On multivariate analysis, age was independently predictive of growth rate (β=-0.007, P=0.021), alongside weight (β=0.003, P=0.016) and the presence of moderate or severe aortic valve insufficiency (β=0.146, P=0.049). Maximal aortic diameter is not predictive of aortic growth rate, in this contemporary cohort of patients with sizes under current surgical thresholds (<55 mm).

Cardiac CT vs Echocardiography for Intracardiac Thrombus Detection in Ischemic Stroke: A Systematic Review and Meta-Analysis of 43 Studies.

Ischemic stroke, a leading cause of mortality, necessitates understanding its mechanism for effective prevention. Echocardiography, especially transesophageal echocardiography (TEE), is the gold standard for detection of cardiac sources of stroke including left atrial thrombus, although its invasiveness, operator skill dependence, and limited availability in some centers prompt exploration of alternatives, such as cardiac CT (CCT). We conducted a systematic review and meta-analysis assessing the ability of CCT in the detection of intracardiac thrombus compared with echocardiography. We searched 4 databases up through September 8, 2023. Major search terms included a combination of the terms "echocardiograph," "CT," "TEE," "imaging," "stroke," "undetermined," and "cryptogenic." The current systematic literature review of the English language literature was reported in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. We assessed risk of bias using the QUADAS-2 tool and used random-effects meta-analysis to calculate different diagnostic metrics. The meta-analysis investigating CCT vs echocardiography for intracardiac thrombus detection yielded a total of 43 studies of 9,552 patients. Risk-of-bias assessment revealed a predominantly low risk of bias in the flow and timing, index test, and patient selection domains and a predominantly unclear risk of bias in the reference standard domain. The analysis revealed an overall sensitivity of 98.38% (95% CI 89.2-99.78) and specificity of 96.0% (95% CI 92.55-97.88). Subgroup analyses demonstrated that delayed-phase, electrocardiogram-gated CCT had the highest sensitivity (100%; 95% CI 0-100) while early-phase, nongated CCT exhibited a sensitivity of 94.31% (95% CI 28.58-99.85). The diagnostic odds ratio was 98.59 (95% CI 44.05-220.69). Heterogeneity was observed, particularly in specificity and diagnostic odds ratio estimates. CCT demonstrates high sensitivity, specificity, and diagnostic odds ratios in detecting intracardiac thrombus compared with traditional echocardiography. Limitations include the lack of randomized controlled studies, and other cardioembolic sources of stroke such as valvular disease, cardiac function, and aortic arch disease were not examined in our analysis. Large-scale studies are warranted to further evaluate CCT as a promising alternative for identifying intracardiac thrombus and other sources of cardioembolic stroke.

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”