Patient-specific ascending aortic intervention criteria.

OBJECTIVES: Ascending aortic aneurysms pose a different risk to each patient. We aim to provide personalized risk stratification for such patients based on sex, age, body surface area, and aneurysm location (root vs ascending). METHODS: Root and ascending diameters, and adverse aortic events (dissection, rupture, death) of ascending thoracic aortic aneurysm patients were analyzed. Aortic diameter was placed in context vis-a-vis the normal distribution in the general population with similar sex, age, and BSA, by conversion to z scores. These were correlated of major adverse aortic events, producing risk curves with 'hinge points' of steep risk, constructed separately for the aortic root and mid ascending aorta. RESULTS: 1162 patients were included. Risk curves unveiled generalized thresholds of z = 4 for the aortic root, and z = 5 for the mid ascending aorta. These correspond to individualized thresholds of less than the standard criterion of 5.5 cm in the vast majority of patients. Indicative results include a 75 year-old typical male with 2.1 m2 body surface area, who was found to be at increased risk of adverse events if root diameter exceeds 5.15 cm, or mid ascending exceeds 5.27 cm. An automated calculator is presented which identifies patients at high risk of adverse events based on sex, age, height, weight, and root and ascending size. CONCLUSIONS: This analysis exploits a large sample of aneurysmal patients, demographic features of the general population, pre-dissection diameter, discrimination of root and supracoronary segments, and statistical tools to extract thresholds of increased risk tailor-made for each patient.

Patient-specific analysis of bicuspid aortic valve hemodynamics using a fully coupled fluid-structure interaction model.

Bicuspid aortic valve (BAV), the most common congenital heart disease, is prone to develop significant valvular dysfunction and aortic wall abnormalities such as ascending aortic aneurysm. Growing evidence has suggested that abnormal BAV hemodynamics could contribute to disease progression. In order to investigate BAV hemodynamics, we performed 3D patient-specific fluid-structure interaction (FSI) simulations with fully coupled blood flow dynamics and valve motion throughout the cardiac cycle. Results showed that the hemodynamics during systole can be characterized by a systolic jet and two counter-rotating recirculation vortices. At peak systole, the jet was usually eccentric, with asymmetric recirculation vortices and helical flow motion in the ascending aorta. The flow structure at peak systole was quantified using the vorticity, flow rate reversal ratio and local normalized helicity (LNH) at four locations from the aortic root to the ascending aorta. The systolic jet was evaluated with the peak velocity, normalized flow displacement, and jet angle. It was found that peak velocity and normalized flow displacement (rather than jet angle) gave a strong correlation with the vorticity and LNH in the ascending aorta, which suggests that these two metrics could be used for clinical noninvasive evaluation of abnormal blood flow patterns in BAV patients.

Midterm follow-up of composite graft replacement of the aortic root (30-year experience)-remarkably safe, effective, and durable.

Objectives: Contemporary operative choices for aortic root disease include aortic root replacement (ARR) and a variety of valve-sparing and aortic root-repair procedures. We evaluate ultra-long-term outcomes of ARR, focusing on survival, freedom from late reoperation, and adverse events. Methods: Prospectively kept records were used to accomplish long-term follow-up of patients who underwent ARR (4-pronged Yale survival assessment paradigm). Results: Between 1990 and 2020, 564 patients underwent ARR (mean 56 years, 84% male). A modified Cabrol procedure (Dacron coronary graft) was employed in 9.0% (51/564) and concomitant coronary artery bypass grafting in 9.4% (53/564). There were 12.8% (72/564) urgent/emergent and 7.4% (42/564) redo procedures. Operative mortality occurred in 12 patients (2.1%) overall, or 1.4% (8/554) of nondissection and 1.3% (6/468) of elective first-time operations. Six of the 12 deaths presented with acute type A dissection, urgent operation, or reoperative states. Operative mortality dropped to 0.6% during the past 10 years. In total, 11 patients developed endocarditis. Stroke occurred in 11 of 564 patients (2.0%), 4 of whom had presented with type A dissection. Late events included bleeding in 2.8% (16/564), thromboembolism in 1.4% (8/564), and reoperation of the root in 5 of 564 (0.9%) at 15 years and more distal aortic segments in 16/564 (2.8%). Survival was no different from age/sex-matched controls. Conclusions: This ultra-long-term experience finds ARR to be extraordinarily safe, effective, and durable, with minimal long-term bleeding, thromboembolism, or graft failure. This experience provides a standard of durability for ARR against which ultra-long-term outcomes with alternate procedures (valve-sparing, Ross, other) may be compared.

The role of anatomic shape features in the prognosis of uncomplicated type B aortic dissection initially treated with optimal medical therapy.

OBJECTIVE: Currently, the long-term outcomes of uncomplicated type B aortic dissection (TBAD) patients managed with optimal medical therapy (OMT) remain poor. Aortic expansion is a major factor that determines patient long-term survival. The objective of this study was to investigate the association between anatomic shape features and (i) OMT outcome; (ii) aortic growth rate for TBAD patients initially treated with OMT. METHODS: 108 CT images of TBAD in the acute and chronic phases were collected from 46 patients who were initially treated with OMT. Statistical shape models (SSM) of TBAD were constructed to extract shape features from the earliest initial CT scans of each patient by using principal component analysis (PCA) and partial least square (PLS) regression. Additionally, conventional shape features (e.g., aortic diameter) were quantified from the earliest CT scans as a baseline for comparison. We identified conventional and SSM features that were significant in separating OMT "success" and failure patients. Moreover, the aortic growth rate was predicted by SSM and conventional features using linear and nonlinear regression with cross-validations. RESULTS: Size-related SSM and conventional features (mean aortic diameter: p=0.0484, centerline length: p=0.0112, PCA score c1: p=0.0192, and PLS scores t1: p=0.0004, t2: p=0.0274) were significantly different between OMT success and failure groups, but these features were incapable of predicting the aortic growth rate. SSM shape features showed superior results in growth rate prediction compared to conventional features. Using multiple linear regression, the conventional, PCA, and PLS shape features resulted in root mean square errors (RMSE) of 1.23, 0.85, and 0.84 mm/year, respectively, in leave-one-out cross-validations. Nonlinear support vector regression (SVR) led to improved RMSE of 0.99, 0.54, and 0.43 mm/year, for the conventional, PCA, and PLS features, respectively. CONCLUSION: Size-related shape features of the earliest scan were correlated with OMT failure but led to large errors in the prediction of the aortic growth rate. SSM features in combination with nonlinear regression could be a promising avenue to predict the aortic growth rate.

Significant unfavorable geometrical changes in ascending aorta despite stable diameter at follow-up.

OBJECTIVE: The clinical importance of following up on the ascending aortic diameter lies in the fundamental presumption that wall pathology eventually manifests as a change in shape. However, the diameter describes the vessel locally, and the 55 mm criterion fails to prevent most dissections. We hypothesized that geometric changes across the ascending aorta are not necessarily imprinted on its diameter; i.e. the maximum diameter correlates weakly and insignificantly with elongation, surface stretching, engorgement, and tortuosity. METHODS: Two databases were interrogated for patients who had undergone at least 2 ECG-gated CT scans. The absence of motion artifacts permitted the generation of exact copies of the ascending aorta which then underwent three-dimensional analysis producing objective and accurate measurements of the centreline length, surface, volume, and tortuosity. The correlations of these global variables with the diameter were explored. RESULTS: Twenty-two patients, 13 male and 9 female, were included. The mean age at the first and last scan was 63.7 and 67.1 y, respectively. The mean diameter increase was approximately 1 mm/y. There were no dissections, while 7 patients underwent preemptive surgery. The yearly change rate of the global variables, normalized to height if applicable, showed statistically insignificant, weak, or negligible correlation with diameter increments at follow-up. Most characteristically, a patient's aorta maintained its diameter, while undergoing 1 mm/y elongation, 151 mm2/(y·m) stretching, 2366 mm3/(y·m) engorgement, and 0.02/y tortuosity. CONCLUSION: Maximum diameter provides a local description of the ascending aorta and cannot fully portray the pathological process across this vessel. Following up the diameter is not suggestive of length, surface, volume, and tortuosity changes.

Evidence Accumulates: Patients with Ascending Aneurysms Are Strongly Protected from Atherosclerotic Disease.

Ascending thoracic aortic aneurysms may be fatal upon rupture or dissection and remain a leading cause of death in the developed world. Understanding the pathophysiology of the development of ascending thoracic aortic aneurysms may help reduce the morbidity and mortality of this disease. In this review, we will discuss our current understanding of the protective relationship between ascending thoracic aortic aneurysms and the development of atherosclerosis, including decreased carotid intima-media thickness, low-density lipoprotein levels, coronary and aortic calcification, and incidence of myocardial infarction. We also propose several possible mechanisms driving this relationship, including matrix metalloproteinase proteins and transforming growth factor-ß.

"Big Data" Analyses Underlie Clinical Discoveries at the Aortic Institute.

This issue of the Yale Journal of Biology and Medicine (YJBM) focuses on Big Data and precision analytics in medical research. At the Aortic Institute at Yale New Haven Hospital, the vast majority of our investigations have emanated from our large, prospective clinical database of patients with thoracic aortic aneurysm (TAA), supplemented by ultra-large genetic sequencing files. Among the fundamental clinical and scientific discoveries enabled by application of advanced statistical and artificial intelligence techniques on these clinical and genetic databases are the following: From analysis of Traditional "Big Data" (Large data sets). 1. Ascending aortic aneurysms should be resected at 5 cm to prevent dissection and rupture. 2. Indexing aortic size to height improves aortic risk prognostication. 3. Aortic root dilatation is more malignant than mid-ascending aortic dilatation. 4. Ascending aortic aneurysm patients with bicuspid aortic valves do not carry the poorer prognosis previously postulated. 5. The descending and thoracoabdominal aorta are capable of rupture without dissection. 6. Female patients with TAA do more poorly than male patients. 7. Ascending aortic length is even better than aortic diameter at predicting dissection. 8. A "silver lining" of TAA disease is the profound, lifelong protection from atherosclerosis. From Modern "Big Data" Machine Learning/Artificial Intelligence analysis: 1. Machine learning models for TAA: outperforming traditional anatomic criteria. 2. Genetic testing for TAA and dissection and discovery of novel causative genes. 3. Phenotypic genetic characterization by Artificial Intelligence. 4. Panel of RNAs "detects" TAA. Such findings, based on (a) long-standing application of advanced conventional statistical analysis to large clinical data sets, and (b) recent application of advanced machine learning/artificial intelligence to large genetic data sets at the Yale Aortic Institute have advanced the diagnosis and medical and surgical treatment of TAA.

Long-term follow-up of Cabrol fistula for uncontrollable bleeding: A life-saving procedure.

Objective: Surgeons shy away from using the Cabrol fistula (perigraft space to right atrium [RA] shunt) due to unfamiliarity, concern for persistent left-to-right shunting, and fear of "painting-over" anastomotic defects that will result in later problems. We review nearly 2 decades of experience with application of the Cabrol fistula in a large thoracic aortic practice, with emphasis on precise surgical techniques, early and late outcomes, and detailed radiographic analysis. Methods: Operative records of all procedures in which the Cabrol fistula was used were retrieved and analyzed, with precise review of the details of construction of each Cabrol fistula and clinical and radiologic (echocardiographic and computed tomographic) patient follow-up. Results: The Cabrol fistula successfully controlled the bleeding in all cases. There were no late false aneurysms at any anastomotic sites. There was no continued flow through any fistula. Good perioperative and long-term survival was achieved in these complex cases that found themselves at a very dangerous crux before application of the Cabrol fistula. Conclusions: The Cabrol fistula is an important tool for the thoracic aortic surgeon to have in the toolbox. We found the Cabrol fistula to be extremely effective at controlling bleeding, with no late persistent fistula flow and no late false aneurysm formation. Without the fistula, outcome in these patients would likely have been lethal. We recommend the Cabrol fistula technique strongly for life-saving application in rare cases of bleeding uncontrollable by conventional methods.

Safety of cerebrospinal fluid drainage in descending and thoracoabdominal aortic replacement surgery.

Background: Spinal cord injury (SCI) remains a significant morbidity of surgical repair of descending thoracic aortic aneurysms (DTAA) and thoracoabdominal aortic aneurysms (TAAA). We present our 17-year experience with cerebrospinal fluid drainage (CSFD) as a protective strategy during open surgical repair of descending and thoracoabdominal aortic disease. Methods: We conducted a retrospective chart review of 132 patients who underwent open surgical repair of DTAA and TAAA and dissections with concurrent use of CSFD for spinal cord protection. Information regarding survival, postoperative course, and complications related to CSFD use were extracted from electronic health records (EHR) and analyzed. Results: Mean patient age was 65.4±13.0 years, and 82 (62.1%) were male. A CSFD was successfully inserted in all patients. The mean hospital length of stay after surgery was 12.2±11.2 days, and in-hospital mortality was 7.6%. Postoperative transient paresis was observed in 5 patients (3.8%), and permanent paraplegia was seen in 4 (3.0%). CSFD related complications were reported in 25 patients (19%). Complications included persistent cerebrospinal fluid (CSF) leakage, blood-tinged CSF (with subdural hematoma reported in 3 patients) and spinal cutaneous fistula in 9 (7%), 14 (11%), and 1 (1%), respectively. Long term survival was 50.9% at 15 years. Conclusions: CSFD is associated with minor complications, without major sequalae. It is a safe practice and likely contributes innocuously to decreased SCI in patients undergoing open repair of DTAA and TAAA.

Genetic Overlap of Spontaneous Dissection of Either the Thoracic Aorta or the Coronary Arteries.

Ascending thoracic aortic dissection (ATAD) is a well-known vascular cause of sudden death. Spontaneous coronary artery dissections (SCAD) are emerging as an important cause of early-onset myocardial infarction and sudden death. Genetic variants in multiple connective tissue genes have been recognized to underlie ATAD; other genetic variants have similarly been recognized to underlie SCAD. Little data are available regarding any genetic commonality between ATAD and SCAD. Our objective is to determine and characterize any genetic overlap between genes coding for ATAD and SCAD. We identified and reviewed 17 retrospective and prospective genetic studies of thoracic aortic dissection and SCAD published between 2016 and 2022 identified through PubMed and Orbis. Articles highlighting the significant plausible triggers for ATAD or SCAD individually were analyzed. No previous study reviewed both ATAD and SCAD genetics together. Separate lists of causative genes were constructed for ATAD and SCAD-and then commonalities were sought. A Venn diagram was constructed to display the genetic overlap and common physiologic pathways involved. We identified a definite, meaningful overlap of 15 independent genes based on a genome-wide association study or other genetic methods. The associated genetic pathways involved various biologic processes including elastin degradation, smooth muscle cell function, and the TGFß-pathway. The overlapping genes included the following: COL3A1, TGFB2, SMAD3, MYLK, TGFBR2, TGFBR1, LOX, FBN1, NOTCH1, ELN, COL5A1, COL5A2, COL1A2, MYH11, and TLN1. The corresponding molecular pathways were investigated and correlated for both diseases. We are not aware of other studies searching for genetic commonalities between ATAD and SCAD. We have successfully identified overlapping genes-and their corresponding molecular pathways-for ATAD and SCAD. We hope that these insights will lead to further clinical and scientific understanding of each disease through study of their fundamental commonalities.

Comparison of Genes Associated with Thoracic and Abdominal Aortic Aneurysms.

Aneurysms impacting the ascending thoracic aorta and the abdominal aorta affect patient populations with distinct clinical characteristics. Through a literature review, this paper compares the genetic associations of ascending thoracic aortic aneurysm (ATAA) with abdominal aortic aneurysms (AAA). Genes related to atherosclerosis, lipid metabolism, and tumor development are associated specifically with sporadic AAA, while genes controlling extracellular matrix (ECM) structure, ECM remodeling, and tumor growth factor ß function are associated with both AAA and ATAA. Contractile element genes uniquely predispose to ATAA. Aside from known syndromic connective tissue disease and poly-aneurysmal syndromes (Marfan disease, Loeys-Dietz syndrome, and Ehlers-Danlos syndrome), there is only limited genetic overlap between AAA and ATAA. The rapid advances in genotyping and bioinformatics will elucidate further the various pathways associated with the development of aneurysms affecting various parts of the aorta.

The natural history of aortic root aneurysms.

The aortic root has a different embryologic origin from all other segments of the human aorta, a feature that likely confers unique susceptibilities, anatomical patterns, and clinical behavior of aneurysm disease in this vital location. In this manuscript, we review the natural history of ascending aortic aneurysm, with a specific focus on the aortic root. The specific central message is that root dilatation is more malignant than ascending dilatation.

Nonsize Criteria for Surgical Intervention on the Ascending Thoracic Aorta.

For decades, aortic surgery has relied on size criteria for intervention on the ascending aorta. While diameter has served well, diameter alone falls short of an ideal criterion. Herein, we examine the potential application of other, nondiameter criteria in aortic decision-making. These findings are summarized in this review. We have conducted multiple investigations of specific alternate nonsize criteria by leveraging our extensive database, which includes complete, verified anatomic, clinical, and mortality data on 2,501 patients with thoracic aortic aneurysm (TAA) and dissections (198 Type A, 201 Type B, and 2102 TAAs). We examined 14 potential intervention criteria. Each substudy had its own specific methodology, reported individually in the literature. The overall findings of these studies are presented here, with a special emphasis on how the findings can be incorporated into enhanced aortic decision-making-above and beyond sheer diameter. The following nondiameter criteria have been found useful in decision-making regarding surgical intervention. (1) Pain: In the absence of other specific cause, substernal chest pain mandates surgery. Well-developed afferent neural pathways carry warning signals to the brain. (2) Aortic length/tortuosity: Length is emerging as a mildly better predictor of impending events than diameter. (3) Genes: Specific genetic aberrations provide a powerful predictor of aortic behavior; malignant genetic variants obligate earlier surgery. (4) Family history: Aortic events closely follow those in relatives with a threefold increase in likelihood of aortic dissection for other family members once an index family dissection has occurred. (5) Bicuspid aortic valve: Previously thought to increase aortic risk (as a "Marfan light" situation), current data show that bicuspid valve is not a predictor of higher risk. (6) Diabetes actually protects against aortic events, via mural thickening and fibrosis. (7) Biomarkers: A specialized "RNA signature test" identifies aneurysm-bearing patients in the general population and promises to predict impending dissection. (8) Aortic stress: Blood pressure (BP) elevation from anxiety/exertion precipitates dissection, especially with high-intensity weightlifting. (9) Root dilatation imposes higher dissection risk than supracoronary ascending aneurysm. (10) Inflammation on positron emission tomography (PET) imaging implies high rupture risk and merits surgical intervention. (11) A KIF6 p.Trp719Arg variant elevates aortic dissection risk nearly two-fold. (12) Female sex confers some increased risk, which can be largely accommodated by using body-size-based nomograms (especially height nomograms). (13) Fluoroquinolones predispose to catastrophic dissection events and should be avoided rigorously in aneurysm patients. (14) Advancing age makes the aorta more vulnerable, increasing likelihood of dissection. In conclusion, nondiameter criteria can beneficially be brought to bear on the decision to observe or operate on specific TAA.

PyTorch-FEA: Autograd-enabled finite element analysis methods with applications for biomechanical analysis of human aorta.

BACKGROUND AND OBJECTIVES: Finite-element analysis (FEA) is widely used as a standard tool for stress and deformation analysis of solid structures, including human tissues and organs. For instance, FEA can be applied at a patient-specific level to assist in medical diagnosis and treatment planning, such as risk assessment of thoracic aortic aneurysm rupture/dissection. These FEA-based biomechanical assessments often involve both forward and inverse mechanics problems. Current commercial FEA software packages (e.g., Abaqus) and inverse methods exhibit performance issues in either accuracy or speed. METHODS: In this study, we propose and develop a new library of FEA code and methods, named PyTorch-FEA, by taking advantage of autograd, an automatic differentiation mechanism in PyTorch. We develop a class of PyTorch-FEA functionalities to solve forward and inverse problems with improved loss functions, and we demonstrate the capability of PyTorch-FEA in a series of applications related to human aorta biomechanics. In one of the inverse methods, we combine PyTorch-FEA with deep neural networks (DNNs) to further improve performance. RESULTS: We applied PyTorch-FEA in four fundamental applications for biomechanical analysis of human aorta. In the forward analysis, PyTorch-FEA achieved a significant reduction in computational time without compromising accuracy compared with Abaqus, a commercial FEA package. Compared to other inverse methods, inverse analysis with PyTorch-FEA achieves better performance in either accuracy or speed, or both if combined with DNNs. CONCLUSIONS: We have presented PyTorch-FEA, a new library of FEA code and methods, representing a new approach to develop FEA methods to forward and inverse problems in solid mechanics. PyTorch-FEA eases the development of new inverse methods and enables a natural integration of FEA and DNNs, which will have numerous potential applications.