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 versus ascending). METHODS: Root and ascending diameters, and adverse aortic events (dissection, rupture, death) of ascending thoracic aortic aneurysm patients were analysed. Aortic diameter was placed in context vis-a-vis the normal distribution in the general population with similar sex, age and body surface area, 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: A total of 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.

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.

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.

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.

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.

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.

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.

Full calcium jacket: Conservative management of a traumatic aortic injury.

We describe the case of an elderly male patient who presented with a proximal descending aortic aneurysm after a motorcycle accident in 1977. We concluded that the aorta had been transected at that time. In a rather unconventional manner, the aneurysm developed a circumferential layer of calcification that provided mechanical stability and likely prevented further degeneration. We chose not to pursue surgical intervention at the late stage of his presentation. The patient has been followed up for a period of 30 years, with no change in the size and shape of the now completely calcified aneurysm.

Extended law of laplace for measurement of the cloverleaf anatomy of the aortic root.

The cross-sectional shape of the aortic root is cloverleaf, not circular, raising controversy regarding how best to measure its radiographic "diameter" for aortic event prediction. We mathematically extended the law of Laplace to estimate aortic wall stress within this cloverleaf region, simultaneously identifying a new metric of aortic root dimension that can be applied to clinical measurement of the aortic root and sinuses of Valsalva on clinical computerized tomographic scans. Enforcing equilibrium between blood pressure and wall stress, finite element computations were performed to evaluate the mathematical derivation. The resulting Laplace diameter was compared with existing methods of aortic root measurement across four patient groups: non-syndromic aneurysm, bicuspid aortic valve, Marfan syndrome, and non-dilated root patients (total 106 patients, 62 M, 44 F). (1) Wall stress: Mean wall stress at the depth of the sinuses followed this equation: Wall stress = BP × Circumscribing circle diameter/(2 × Aortic wall thickness). Therefore, the diameter of the circle enclosing the root cloverleaf, that is, twice the distance between the center, where the sinus-to-commissure lines coincide, and the depth of the sinuses, may replace diameter in the Laplace relation for a cloverleaf cross-section (or any shaped cross-section with two or more planes of symmetry). This mathematically derived result was verified by computational finite element analyses. (2) Diameters: CT scan measurements showed a significant difference between this new metric, the Laplace diameter, and the sinus-to-commissure, mid-sinus-to-mid-sinus, and coronal measurements in all four groups (p-value < 0.05). The average Laplace diameter measurements differed significantly from the other measurements in all patient groups. Among the various possible measurements within the aortic root, the diameter of the circumscribing circle, enclosing the cloverleaf, represents the diameter most closely related to wall stress. This diameter is larger than the other measurements, indicating an underestimation of wall stress by prior measurements, and otherwise provides an unbiased, convenient, consistent, physics-based measurement for clinical use. "Diameter" applies to circles. Our mathematical derivation of an extension of the law of Laplace, from circular to cloverleaf cross-sectional geometries of the aortic root, has implications for measurement of aortic root "diameter." The suggested method is as follows: (1) the "center" of the aortic root is identified by drawing three sinus-to-commissure lines. The intersection of these three lines identifies the "center" of the cloverleaf. (2) The largest radius from this center point to any of the sinuses is identified as the "radius" of the aortic root. (3) This radius is doubled to give the "diameter" of the aortic root. We find that this diameter best corresponds to maximal wall stress in the aortic root. Please note that this diameter defines the smallest circle that completely encloses the cloverleaf shape, touching the depths of all three sinuses.

Bicuspid aortopathy does not require earlier surgical intervention.

OBJECTIVES: Guidelines for surgical correction of patients with ascending thoracic aortic aneurysm (ATAA) with a bicuspid aortic valve (BAV) have oscillated over the years. In this study, we outline the natural history of the ascending aorta in patients with BAV and trileaflet aortic valve (TAV) ATAA followed over time, to ascertain if their behavior differs and to determine if a different threshold for intervention is required. METHODS: Aortic diameters and long-term complications (ie, adverse aortic events) of 2428 patients (554 BAV and 1874 TAV) with ATAA before operative repair were reviewed. Growth rates, yearly complication rates, event-free survival, and risk of complications as a function of aortic size were calculated. Long-term follow-up and precise cause of death granularity was achieved via a comprehensive 6-pronged approach. RESULTS: Aortic growth rate in patients with BAV vs TAV ATAA was 0.20 and 0.17 cm/year, respectively (P = .009), with the rate increasing with increasing aortic size. Yearly adverse aortic events rates increased with ATAA size and were lower for patients with BAV. The relative risk of adverse aortic events exhibited an exponential increase with aortic diameter. Patients with BAV had a lower all-cause and ascending aorta-specific adverse aortic events hazard. Age-adjusted 10-year event-free survival was significantly better for patients with BAV, and BAV emerged as a protective factor against type A dissection, rupture, and ascending aortic death. CONCLUSIONS: The threshold for surgical repair of ascending aneurysm with BAV should not differ from that of TAV. Prophylactic surgery should be considered at 5.0 cm for patients with TAV (and BAV) at expert centers.

Aortic Size at the Time of Type A and Type B Dissections.

BACKGROUND: Aortic diameter at time of dissection remains an indispensable risk-determining characteristic for prophylactic repair of thoracic aortic aneurysms. Histograms of aortic size at the time of dissection have the potential to shed more light on this relationship. METHODS: Size of the thoracic aorta at the time of dissection was determined from imaging of 407 naturally occurring, acute, flap-type ascending or descending aortic dissections treated at 1 institution (1990-2022). Histograms were constructed to depict aortic size at the time of dissection. Data were analyzed by logistic regression. RESULTS: There were 170 (69.11%) of 246 type A dissections (median, 5.07 cm; interquartile range, 4.60-5.67 cm) and 130 (80.75%) of 161 type B dissections (median, 4.2 cm; interquartile range, 3.60-4.87 cm) that occurred at diameters <5.5 cm. By unadjusted regression, factors associated with significantly increased odds of type A dissection at diameters <5.5 cm were female sex (odds ratio [OR], 2.06; P = .023), hypertension (OR, 1.82; P = .036), and smoking (OR, 1.92; P = .029). Patients with bicuspid aortic valve had significantly decreased odds of type A dissection at diameters <5.5 cm (OR, 0.3; P = .047). The recent "left shift" to 5.0 cm in the criterion for ascending aortic intervention could prevent an additional 29.3% of type A dissections. CONCLUSIONS: Aortic diameter at the time of type A dissection is consistent with the new guidelines that recommend surgical intervention at 5.0 cm. Type B dissection occurs at small sizes and cannot be prevented with a size criterion.

Fate of the unoperated ascending thoracic aortic aneurysm: three-decade experience from the Aortic Institute at Yale University.

AIMS: This study aims to outline the 'true' natural history of ascending thoracic aortic aneurysm (ATAA) based on a cohort of patients not undergoing surgical intervention. METHODS AND RESULTS: The outcomes, risk factors, and growth rates of 964 unoperated ATAA patients were investigated, over a median follow-up of 7.9 (maximum of 34) years. The primary endpoint was adverse aortic events (AAE), including dissection, rupture, and aortic death. At aortic sizes of 3.5-3.9, 4.0-4.4, 4.5-4.9, 5.0-5.4, 5.5-5.9, and ≥6.0 cm, the average yearly risk of AAE was 0.2%, 0.2%, 0.3%, 1.4%, 2.0%, and 3.5%, respectively (P < 0.001), and the 10-year survival free from AAE was 97.8%, 98.2%, 97.3%, 84.6%, 80.4%, and 70.9%, respectively (P < 0.001). The risk of AAE was relatively flat until 5 cm of aortic size, at which it began to increase rapidly (P for non-linearity <0.001). The mean annual growth rate was estimated to be 0.10 ± 0.01 cm/year. Ascending thoracic aortic aneurysms grew in a very slow manner, and aortic growth over 0.2 cm/year was rarely seen. Multivariable Cox regression identified aortic size [hazard ratio (HR): 1.78, 95% confidence interval (CI): 1.50-2.11, P < 0.001] and age (HR: 1.02, 95% CI: 1.00-1.05, P = 0.015) as significant independent risk factors for AAE. Interestingly, hyperlipidemia (HR: 0.46, 95% CI: 0.23-0.91, P = 0.025) was found to be a significant protective factor for AAE in univariable Cox regression. CONCLUSION: An aortic size of 5 cm, rather than 5.5 cm, may be a more appropriate intervention criterion for prophylactic ATAA repair. Aortic growth may not be an applicable indicator for intervention.

KIF6 Trp719Arg Genetic Variant Increases Risk for Thoracic Aortic Dissection.

BACKGROUND: KIF6 (kinesin family member 6), a protein coded by the KIF6 gene, serves an important intracellular function to transport organelles along microtubules. In a pilot study, we found that a common KIF6 Trp719Arg variant increased the propensity of thoracic aortic aneurysms (TAA) to suffer dissection (AD). The present study aims for a definite investigation of the predictive ability of KIF6 719Arg vis à vis AD. Confirmatory findings would enhance natural history prediction in TAA. METHODS: 1108 subjects (899 aneurysm and 209 dissection patients) had KIF6 719Arg variant status determined. RESULTS: The 719Arg variant in the KIF6 gene correlated strongly with occurrence of AD. Specifically, KIF6 719Arg positivity (homozygous or heterozygous) was substantially more common in dissectors (69.8%) than non-dissectors (58.5%) (p = 0.003). Odds ratios (OR) for suffering aortic dissection ranged from 1.77 to 1.94 for Arg carriers in various dissection categories. These high OR associations were noted for both ascending and descending aneurysms and for homozygous and heterozygous Arg variant patients. The rate of aortic dissection over time was significantly higher for carriers of the Arg allele (p = 0.004). Additionally, Arg allele carriers were more likely to reach the combined endpoint of dissection or death (p = 0.03). CONCLUSIONS: We demonstrate the marked adverse impact of the 719Arg variant of the KIF6 gene on the likelihood that a TAA patient will suffer aortic dissection. Clinical assessment of the variant status of this molecularly important gene may provide a valuable "non-size" criterion to enhance surgical decision making above and beyond the currently used metric of aortic size (diameter).

A machine learning approach for predicting complications in descending and thoracoabdominal aortic aneurysms.

OBJECTIVE: To use machine learning to predict rupture, dissection, and all-cause mortality for patients with descending and thoracoabdominal aortic aneurysms in an effort to improve on diameter-based surgical intervention criteria. METHODS: Retrospective data from 1083 patients with descending aortic diameters 3.0 cm or greater were collected, with a mean follow-up time of 3.52 years and an average descending diameter of 4.13 cm. Six machine learning classifiers were trained using 44 variables to predict the occurrence of dissection, rupture, or all-cause mortality within 1, 2, or 5 years of initial patient encounter for a total of 54 (6 × 3 × 3) separate classifiers. Classifier performance was measured using area under the receiver operator curve. RESULTS: Machine learning models achieved area under the receiver operator curves of 0.842 to 0.872 when predicting type B dissection, 0.847 to 0.856 when predicting type B dissection or rupture, and 0.820 to 0.845 when predicting type B dissection, rupture, or all-cause mortality. All models consistently outperformed descending aortic diameter across all end points (area under the receiver operator curve = 0.713-0.733). Feature importance inspection showed that other features beyond aortic diameter, such as a history of myocardial infarction, hypertension, and patient sex, play an important role in improving risk prediction. CONCLUSIONS: This study provides surgeons with a more accurate, machine learning-based, risk-stratification metric to predict complications for patients with descending aortic aneurysms.