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.

"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.

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.

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.

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.

Impact of Mutation on the Structural Stability and the Conformational Landscape of Inhibitor-Resistant TEM ß-Lactamase: A High-Performance Molecular Dynamics Simulation Study.

Gain-of-function mutations and structural adjustment toward ß-lactamase inhibitors in the TEM-type ß-lactamases among the uropathogenic E. coli (UPEC) culminate in treatment complications and demands detailed investigation. In this study, uncharacterized amino acid substitutions, M69L/I84V/W165G/V184A/V262I/N276S, in inhibitor-resistant TEM (IRT) ß-lactamase isolated from clinical UPEC were subjected to extensive molecular dynamics (EMD) simulations for 100 ns to estimate parameters such as root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), the radius of gyration (Rg), contour plot (Rg/RMSD), secondary structure element (SSE), etc. Residue interaction networks, principal component analysis (PCA), and correlation heatmaps were generated to predict the relation between functionally important atomic motions to uncover the structural stability of the mutants. To avoid the false positive conclusion of the simulation study, we performed three identically parameterize replicas of 100 ns each. Alterations in hydrophobic interactions resulted in conformation changes exhibited as comparable residue interaction networks. Besides, PCA and porcupine plot analysis based on the ensemble of structure from molecular dynamics trajectories revealed the collective atomic motions of the IRT variants that impart structural flexibility to their active site loop. This study conducted on IRT mutants that delineate intricate protein motions contributes to their stability and folding, which is an absolute necessity for designing candidate molecules owing to the clinical threat of emerging resistance against potent ß-lactam antibiotics.

Root Dilatation Is More Malignant Than Ascending Aortic Dilation.

Background Data from the International Registry of Acute Aortic Dissection indicate that the guideline criterion of 5.5 cm for ascending aortic intervention misses many dissections occurring at smaller dimensions. Furthermore, studies of natural behavior have generally treated the aortic root and the ascending aorta as 1 unit despite embryological, anatomical, and functional differences. This study aims to disentangle the natural histories of the aforementioned aortic segments, allowing natural behavior to define specific intervention criteria for root and ascending segments of the aorta. Methods and Results Diameters of the aortic root and mid-ascending segment were measured separately. Long-term complications (dissection, rupture, and death) were analyzed retrospectively for 1162 patients with ascending thoracic aortic aneurysm. Cox regression analysis suggested that aortic root dilatation (P=0.017) is more significant in predicting adverse events than mid-ascending aortic dilatation (P=0.087). Short stature posed as a serious risk factor. The dedicated risk curves for the aortic root and the mid-ascending aorta revealed hinge points at 5.0 and 5.25 cm, respectively. Conclusions The natural histories of the aortic root and mid-ascending aorta are uniquely different. Dilation of the aortic root imparts a significant higher risk of adverse events. A diameter shift for intervention to 5.0 cm for the aortic root and to 5.25 cm for the mid-ascending aorta should be considered at expert centers.

Aortic Delamination-A Possible Precursor of Impending Catastrophe.

Aortic diameter is a powerful predictor of adverse aortic events, such as aortic rupture or dissection, forming the basis of prophylactic surgical repair criteria. Limited evidence is available regarding the association of aortic wall thickness (AWT) with these adverse aortic events. We present the case and surgical video of a 73-year-old man with chest pain and an increased AWT, who underwent ascending aortic repair and deep hemiarch placement under deep hypothermic circulatory arrest. Surgical pathology demonstrated evidence of aortic delamination and medial separation, indicative of an impending dissection. The patient recovered uneventfully, and his chest pain ultimately resolved after open repair. In this patient, increased AWT was felt to be the precursor to a potential aortic catastrophe.

Is Aortic Z-score an Appropriate Index of Beneficial Drug Effect in Clinical Trials in Aortic Aneurysm Disease?

Aortic Z-score (Z-score) is utilized in clinical trials to monitor the effect of medications on aortic dilation rate in Marfan (MFS) patients. Z-scores are reported in relation to body surface area and therefore are a function of height and weight. However, an information void exists regarding natural, non-pharmacological changes in Z-scores as children age. We had concerns that Z-score decrease attributed to "therapeutic" effects of investigational drugs for Marfan disease connective tissue diseases might simply reflect normal changes ("filling out" of body contour) as children age. This investigation studies natural changes with age in Z-score in normal and untreated MFS children, teasing out normal effects that might erroneously be attributed to drug benefit. (1) We first compared body mass index (BMI) and Z-scores (Boston Children's Hospital calculator) in 361 children with "normal" single echo exams in four age ranges (0 to 1, 5 to 7, 10 to 12, 15 to 18 years). Regression analysis revealed that aging itself decreases ascending Z-score, but not root Z-score, and that increase in BMI with aging underlies the decreased Z-scores. (2) Next, we examined Z-score findings in both "normal" and Marfan children (all pharmacologically untreated) as determined on sequential echo exams over time. Of 27 children without aortic disease with sequential echos, 19 (70%) showed a natural decrease in root Z-score and 24 (89%) showed a natural decrease in ascending Z- score, over time. Of 25 untreated MFS children with sequential echos, 12 (40%) showed a natural decrease in root Z-score and 10 (33%) showed a natural decrease in ascending Z-score. Thus, Z-score is over time affected by natural factors even in the absence of any aneurysmal pathology or medical intervention. Specifically, Z-score decreases spontaneously as a natural phenomenon as children age and with fill out their BMI. Untreated Marfan patients often showed a spontaneous decrease in Z-score. In clinical drug trials in aneurysm disease, decreasing Z-score has been interpreted as a sign of beneficial drug effect. These data put such conclusions into doubt.

Natural history of descending thoracic and thoracoabdominal aortic aneurysms.

OBJECTIVES: Elucidating critical aortic diameters at which natural complications (rupture, dissection, and death) occur is of paramount importance to guide timely surgical intervention. Natural history knowledge for descending thoracic and thoracoabdominal aortic aneurysms is sparse. Our small early studies recommended repairing descending thoracic and thoracoabdominal aortic aneurysms before a critical diameter of 7.0 cm. We focus exclusively on a large number of descending thoracic and thoracoabdominal aortic aneurysms followed over time, enabling a more detailed analysis with greater granularity across aortic sizes. METHODS: Aortic diameters and long-term complications of 907 patients with descending thoracic and thoracoabdominal aortic aneurysms were reviewed. Growth rates (instrumental variables approach), yearly complication rates, 5-year event-free survival (Kaplan-Meier), and risk of complications as a function of aortic height index (aortic diameter [centimeters]/height [meters]) (competing-risks regression) were calculated. RESULTS: Estimated mean growth rate of descending thoracic and thoracoabdominal aortic aneurysms was 0.19 cm/year, increasing with increasing aortic size. Median size at acute type B dissection was 4.1 cm. Some 80% of dissections occurred below 5 cm, whereas 93% of ruptures occurred above 5 cm. Descending thoracic and thoracoabdominal aortic aneurysm diameter 6 cm or greater was associated with a 19% yearly rate of rupture, dissection, or death. Five-year complication-free survival progressively decreased with increasing aortic height index. Hazard of complications showed a 6-fold increase at an aortic height index of 4.2 or greater compared with an aortic height index of 3.0 to 3.5 (P < .05). The probability of fatal complications (aortic rupture or death) increased sharply at 2 hinge points: 6.0 and 6.5 cm. CONCLUSIONS: Acute type B dissections occur frequently at small aortic sizes; thus, prophylactic size-based surgery may not afford a means for dissection protection. However, fatal complications increase dramatically at 6.0 cm, suggesting that preemptive intervention before that criterion can save lives.

Increased Virulence of Descending Thoracic and Thoracoabdominal Aortic Aneurysms in Women.

BACKGROUND: This study evaluates sex differences in the natural history of descending thoracic and thoracoabdominal aortic aneurysms (DTTAAs). METHODS: In all, 907 patients with descending thoracic and thoracoabdominal aortic sizes greater than 3 cm were retrospectively reviewed. Growth rate estimates were performed utilizing an instrumental variables approach. Yearly complication rates as a function of aortic size were computed. RESULTS: There were 615 men (67.8%) and 292 women (32.2%) treated between 1990 and 2018, with mean aortic diameters of 4.1 ± 1.4 cm and 4.8 ± 1.6 cm, respectively (P < .001). The mean growth rate of DTTAAs was 0.17 cm per year in men and 0.25 cm per year in women (P < .001), increasing with increasing aneurysm size. Dissection, rupture, or aortic death or the combination of the three occurred at double the rate for women compared with men (5.8% vs 2.3% per year for the combined endpoint). Diameter of DTTAA greater than 5 cm was associated with 26.3% (male) and 33.1% (female) average yearly rates of the composite endpoint of rupture, dissection, and death (P < .05). The probability of fatal complications (rupture and death) increased sharply at 5.75 cm in both sexes. Between 4.5 and 5.75 cm, there was another hinge-point of higher probability of fatal complications among women. CONCLUSIONS: Women diagnosed with DTTAA fare worse. Faster aneurysm growth and higher rates of dissection, rupture, and aortic death are apparent among women. Current guidelines recommend surgical intervention at 5.5 to 6 cm for DTTAAs without sex considerations. Our findings suggest that increased virulence of DTTAA in women may indicate surgery at a somewhat smaller diameter.

Discrepancies in Measurement of the Thoracic Aorta: JACC Review Topic of the Week.

Clinicians often encounter discrepant measurements of the ascending aorta that impede, complicate, and impair appropriate clinical assessment-including key issues of presence or absence of aortic growth, rate of growth, and need for surgical intervention. These discrepancies may arise within a single modality (computed tomography scan, magnetic resonance imaging, or echocardiography) or between modalities. The authors explore the origins and significance of these discrepancies, revealing that some "truth" usually underlies all the discrepant measurements, which individually look at the ascending aorta with different perspectives and dimensional definitions. The authors conclude with a practical "question and answer" section that addresses common specific issues in interpretation and management of patients in the real-world setting.

Ascending Aortic Length and Risk of Aortic Adverse Events: The Neglected Dimension.

BACKGROUND: Little information is available regarding the longitudinal changes of the aneurysmal ascending aorta. OBJECTIVES: This study sought to outline the natural history of ascending thoracic aortic aneurysm (ATAA) based on ascending aortic length (AAL) and develop novel predictive tools to better aid risk stratification. METHODS: The ascending aortic diameters and lengths, and long-term aortic adverse events (AAEs) (rupture, dissection, and death) of 522 ATAA patients were evaluated using comprehensive statistical approaches. RESULTS: An AAL of ≥13 cm was associated with an almost 5-fold higher average yearly rate of AAEs compared with an AAL of <9 cm. Two AAL "hinge points" with a sharp increase in the estimated probability of AAEs were detected between 11.5 and 12.0 cm, and between 12.5 and 13.0 cm. The mean estimated annual aortic elongation rate was 0.18 cm/year, and aortic elongation was age dependent. Aortic diameter increased 18% due to dissection while AAL only increased by 2.7%. There was a noticeable improvement in the discrimination of the logistic regression model (area under the receiver-operating characteristic curve: 0.810) due to the introduction of aortic height index (AHI) (diameter height index + length height index). The AHIs <9.33, 9.38 to 10.81, 10.86 to 12.50, and ≥12.57 cm/m were associated with a âˆ¼4%, ∼7%, ∼12%, and ∼18% average yearly risk of AAEs, respectively. CONCLUSIONS: An aortic elongation of 11 cm serves as a potential intervention criterion for ATAA, which is even more reliable than diameter due to its relative immunity to dissection. AHI (including both length and diameter) is more powerful than any single parameter in this study.

Medical management of aortic disease in Marfan syndrome.

Marfan syndrome (MFS) is a hereditary disorder with numerous pathophysiological effects, some specifically creating elastic dysfunction in cardiovascular organs. Aortic dilatation, dissection and rupture are major concerns in the management of MFS patients. Predilection to form aneurysms is an indication for prophylactic medical management of thoracic aortic aneurysm disease in these patients. The current guidelines describe ß-blockers as the standard of care with angiotensin receptor blockers (ARBs) emerging as an equal, if not better alternative. We elaborate current evidence for and against different medical regimens used for the medical management of MFS patients.

Comparison of Quality of Life Perceived by Patients with Bioprosthetic versus Mechanical Valves after Composite Aortic Root Replacement.

OBJECTIVE: To assess whether postoperative quality of life (QOL) for composite aortic root replacement patients differs according to whether it is based on the use of mechanical valves or bioprosthetic valves. METHODS: The study included 146 consecutive patients who underwent composite aortic root replacement at our institution from January 2010 to April 2014 with bioprosthetic (34.9%, n = 51) and mechanical (65.1%, n = 95) valves. Patient-perceived QOL was measured by administering the Short Form (SF)-36v2 Health Survey and a series of supplemental questions to further evaluate valve-specific differences. Final survey participation (n = 121) included 82.9% of the qualifying patients, and involved 76.5% (39/51) of those with bioprosthetic valves and 86.3% (82/95) of those with mechanical valves. Reasons for not completing the survey included 5 expired patients (3.4%), 1 lost due to a language barrier (0.7%), 6 who refused to participate (4.1%) and 13 who were lost to follow-up (8.9%). The mean follow-up time was 32 months (range 4-56 months). RESULTS: Patients in the bioprosthetic valve group were older (mean age 67.5 ± 13.6 years) and included more females (25.6% or 10/39) than those in the mechanical valve group (mean age 56.6 ± 12.0 years; 11.0% or 9/82 were female). No significant differences were found between the bioprosthetic and mechanical valve groups for any QOL aspects scored by the SF-36v2 survey. All 8 domains and 2 summary scales comprising the QOL evaluation were above national norms calculated using gender- and age-matched, norm-based scoring for a standard national average of 50. The supplemental questions indicated satisfaction with each valve type despite characteristics that were of concern to patients. In the mechanical valve group, 90.2% (74/82) reported that the audible valve click was not troublesome, 85.4% (70/82) that taking a blood thinner regularly did not affect daily life and 81.7% (67/82) that blood testing for anticoagulation therapy was not troublesome. CONCLUSIONS: Receiving a tissue or a mechanical valve does not directly affect postoperative QOL. Answers to supplemental questions suggest that prior concerns with mechanical valves do not affect patients in the commonly anticipated negative manner. The preconception of a heavy QOL burden for mechanical composite grafts is contradicted by this study.

Aortic dissection associated with penetration of a spinal pedicle screw: a case report and review of the literature.

A 30-year-old male underwent a corrective posterior instrumented spinal fusion for scoliosis. Six years later, he was found to have an aortic dissection after aortic penetration of a spinal pedicle screw. We review the literature, including diagnostic modalities, and treatment decision-making for this unusual complication.

Medical treatment for thoracic aortic aneurysm - much more work to be done.

A 45 year old executive presents to your office for risk assessment after learning that his sister required an ascending aortic aneurysm repair. He is a well-informed man, concerned about his personal risk for aortic disease, and undergoes a cardiac screen which reveals a dilated ascending aortic aneurysm, measuring a maximal diameter of 4.4 cm. His aortic valve is tricuspid. He is non-Marfanoid and asymptomatic. He realizes that he does not yet meet guideline criteria for aortic surgery, but he is also cognizant of the fact that he is approaching the cut-off for surgical intervention. He wishes to minimize his future risk of aortic rupture, dissection and aortic expansion and seeks your input. Should 'medical treatment' should be employed at this stage? Is there sufficient basis to initiate any form of pharmacotherapy? Would you start a beta-adrenergic receptor blocker, an angiotensin receptor blocker, a matrix metalloproteinase inhibitor (doxycycline), or a statin to reduce his aortic risk for rupture, dissection or need for surgical repair? Does your clinical decision match evidence from existing data? Our paper will address these issues among other questions relevant to the role of medical therapy for thoracic aortic disease.

Do ß-Blockers Really Work for Prevention of Aortic Aneurysms?: Time for Reassessment.

Since 1994, when a small 70-patient study seemed to demonstrate that ß-blocker treatment could help prevent aortic aneurysms in patients with Marfan syndrome, ß-adrenergic-blocking drugs have been increasingly believed to reduce the progression of aortic aneurysms in the general population with aortic disease. This literature review examines the scientific evidence of this treatment and questions whether ß-blocker treatment for aortic aneurysms should continue to be uniformly recommended. Five separate clinical trials studying the effects of ß-blockade therapy in patients with Marfan syndrome are analyzed, in addition to four other clinical trials studying the effects of ß-blockade therapy in patients without Marfan syndrome. The analysis suggests that the scientific evidence for ß-blocker treatment is unconvincing, because ß-blockade therapy fails to consistently reduce aortic aneurysm growth in patients with or without Marfan syndrome. It is alarmingly clear that prospective, multicenter clinical trials are greatly needed to test the efficacy of this now conventional therapy in a more robust scientific fashion.