Controversies in Aortic Dissection and Aneurysmal Disease

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The demographic characteristics of the patient population are summarized in the Table. The outcome data of the included articles are summarized in eAppendices in the Supplement. There were no randomized clinical trials identified. From the 20 studies, there were 19 single-center studies and 1 dual-center study.

Three studies were prospective, while the remaining 17 studies were retrospective. Blinding was not used in any of the studies. The mean length of follow-up ranged from 2. Eleven studies used echocardiogram as the mode of imaging for follow-up, 8 used computed tomography as the preferred mode of imaging, and 1 used fluoroscopy.

The mean SD age of the study patients was The mean range initial aneurysm size among 13 studies was The pooled annual growth rate for mixed valve type was 0. The combined effect estimate for annual growth rate for all studies was 0. Fourteen studies reported the incidence of elective aortic surgery during follow up, 12 studies reported incidence of aortic dissection or rupture, and 13 studies reported the incidence of all-cause mortality over follow-up periods that ranged from 2.

The linearized rate of composite outcome, including aortic dissection, aortic rupture, and all-cause mortality, was 2. The linearized all-cause mortality rate was 1. Furthermore, using the isolated TAV group as the reference, there were no significant associations between the valve types and the composite outcome isolated BAV group coefficient, 0. In this study, we sought to explore the natural history of AsAA and to compare outcomes based on valvular phenotype. However, because all except 2 studies followed thoracic aortic management guidelines for ascending aortic repair when patients met criteria for surgical intervention, the true natural history of AsAA across the size spectrum was not examined; instead, we reported on the growth rate; the incidence of aortic repair, dissection, and rupture; and all-cause mortality of AsAA followed in the real-world clinical setting.

The growth rate of the moderately dilated aorta is low, and differences do exist between the different valves types, with large intragroup variation as well Figure 2. For patients with TAV only, the pooled mean annual growth rate was only 0. However, this difference was not statistically significant. In both groups, the annual growth rates reported by Davies et al 10 1. The low mean growth rate may have implications for appropriate time interval between imaging studies for follow-up of patients with moderately dilated ascending aorta. Current guidelines suggest annual or biannual imaging for patients with AsAA.

The result of the meta-analysis supports this proposition; however, there are a lack of consistent data that inform the timing in which more frequent follow-up is required. Interestingly, there was a significant difference in the pooled mean annual growth rate between the mixed valve type group and the nonspecified valve type group 0. This may represent the inclusion of genetic conditions in the nonspecified valve type group that was not specifically stated within the inclusion and exclusion criteria of the studies, and therefore was not excluded from the systematic review. There was also significant interstudy variation in all outcomes examined.

There was a nonsignificant trend toward higher rate of elective aortic repair in studies reporting on patients with BAV only compared with patients with TAV only However, similar to the data for growth rate, the incidences of elective ascending aortic surgery in the TAV group and BAV group reported by Davies et al 10 again appeared to be outliers at Notably, the rate of composite outcome reported by Davies et al is higher not only when compared with reports with similar initial aneurysm diameter, but also when compared with the rate reported by Joyce et al, 7 which included patients who were considered nonoperative with an aneurysm size of more than 5.

Factors associated with annual growth rate not only varied significantly but were often contradictory between studies; therefore, meaningful statistical analysis evaluating their association with outcomes could not be performed. While 3 studies 8 , 17 , 19 identified baseline aortic diameter as a factor associated with increased growth rate, 4 studies 13 , 14 , 18 , 24 found that baseline aortic diameter was not associated with aortic dilatation, and 2 studies 12 , 16 reported higher annual aortic growth rate with lower baseline aortic diameter.

One study 10 found that aortic stenosis is associated with higher annual aortic dilatation, while another 17 found aortic regurgitation to be associated with higher growth rate.

Thoracic aortic aneurysm: How to counsel, when to refer

Another study 26 determined that valvular dysfunction is not associated with faster aortic dilatation. Renal failure and female sex were identified as being associated with faster annual growth rate in 2 separate studies, 14 , 16 while anticoagulation and statin medication use were found be associated with a lower growth rate. Coady et al 27 and Vapnik et al 15 demonstrated that size was the most important factor associated with acute dissection or rupture; however, most other studies did not report aneurysm size at aortic dissection or rupture, and comparison was therefore not possible.

Current guidelines for surgical thresholds for AsAA are based largely on expert consensus and retrospective observational studies with inconsistent data. In contrast, treatment guidelines for abdominal aortic aneurysm AAA are founded on extensive data and are widely accepted by the surgical community. This study has a number of limitations. First, this is a meta-analysis of studies that included a heterogenous population with different initial mean aortic diameters, variable lengths of follow-up, and different imaging methods, which may introduce variability into the combined effect estimates.

Second, most studies focused on a specific outcome of the natural history of AsAA, and information on all outcomes was not available in all studies. There were insufficient data available to perform analysis for factors associated with growth rate, the rate of composite outcome, or aortic size at acute aortic events.

Third, more than half of the articles included were published prior to and therefore may not represent contemporary medical management of this disease. Fourth, there might be confounders that are not adjusted for in the studies included. The growth rate of the moderately dilated ascending aorta is low. The risk of dissection, rupture, and death also remains low. However, these results require cautious interpretation as a large number of patients in the studies who met guideline criteria for intervention underwent elective aortic surgery.

More robust natural history data from prospective studies or randomized clinical trials are necessary to better inform clinical decision making in patients with ascending aortic disease. Published: August 24, Author Contributions: Dr Guo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Critical revision of the manuscript for important intellectual content: Appoo, Saczkowski, Smith, Ouzounian, Gregory, Herget, Boodhwani.

Thoracic aortic aneurysm: How to counsel, when to refer

Conflict of Interest Disclosures: None reported. Home Issues Specialties For Authors. All Rights Reserved. Download PDF Comment. Figure 1. View Large Download. Incidence of Elective Ascending Aortic Surgery. Twenty-five year outcomes following composite graft aortic root replacement. J Card Surg. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol. J Am Coll Cardiol. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis in clinical trials.

Control Clin Trials. Transformations related to the angular and the square root. Ann Math Stat. Aneurysms of the thoracic aorta: a clinical study with special reference to prognosis. Unoperated thoracic aortic aneurysms: survival rates of the patients and determinants of prognosis. Intern Med. Progression rate of ascending aortic dilation in patients with normally functioning bicuspid and tricuspid aortic valves. Am J Cardiol. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann Thorac Surg. A prospective study of growth and rupture risk of small-to-moderate size ascending aortic aneurysms.

J Thorac Cardiovasc Surg. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Effects of statin therapy on ascending aorta aneurysms growth: a propensity-matched analysis.

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Int J Cardiol. Eur J Cardiothorac Surg. Characteristics and outcomes of ascending versus descending thoracic aortic aneurysms. Risk of aortic dissection in the moderately dilated ascending aorta. Natural history of moderately dilated tubular ascending aorta: implications for determining the optimal imaging interval.

Stability of ascending aortic dilatation following aortic valve replacement. Ectasia of the ascending aorta at the time of aortic valve surgery: replace or relax? Ital Heart J. PubMed Google Scholar. Natural history of a dilated ascending aorta after aortic valve replacement. Circ J. Aortic expansion rate in patients with dilated post-stenotic ascending aorta submitted only to aortic valve replacement long-term follow-up. Management of dilated ascending aorta during aortic valve replacement: valve replacement alone versus aorta wrapping versus aorta replacement.

Changes in size of ascending aorta and aortic valve function with time in patients with congenitally bicuspid aortic valves. When to operate on the bicuspid valve patient with a modestly dilated ascending aorta. Incidence of aortic complications in patients with bicuspid aortic valves. Predictors of ascending aortic dilation in bicuspid aortic valve disease: a five-year prospective study. Am J Med. What is the appropriate size criterion for resection of thoracic aortic aneurysms?

We propose more aggressive surgical approaches toward the BAV with root phenotype. The underlying cause of the incorrect formation of the aortic valve remains relatively uncertain; however, evidence suggests that BAV is a genetic disorder. BAV exhibits an increased prevalence in first-degree relatives of affected individuals Martin et al. The familial clustering suggests an autosomal dominant pattern of inheritance with reduced penetrance Martin et al. There are both single and multiplex affected families, which indicates there may be multiple means of inheritance for BAV Martin et al.

Chromosomal regions of interest for BAV include 18q, 5q, and 13q Martin et al. Despite these probable chromosomal regions, approximately genes are encoded amongst the three novel loci Martin et al. Despite the establishment of the heritability of BAV, the genes yielding the pathology of the aortic valve remain largely undetermined. BAV consists of a variety of morphologies and depending on which cusps are fused, blood flow patterns are impacted, which can affect the aorta in various ways. The most prominent fusion is observed between the left and right coronary cusps, followed by the right and non-coronary cusps, and very few between the left and non-coronary cusps Bissel et al.

BAVs are associated with many clinically serious abnormalities, including aortic valve insufficiency and stenosis as well as aortic dilation and dissection. We provide an overview of the heterogeneity of BAV, and the associated complications to improve treatment. BAV with root phenotype TAA [aortic root dilation and aortic insufficiency AI ] should be treated more aggressively surgically; and less aggressively if the aortic root is not involved. Articles were limited to those written in English.

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Additionally, references from key articles were manually searched in a backward cumulative fashion for additional articles. NOTCH1 functions in both familial and sporadic BAV and is crucial during cardiac valve formation that promotes epithelial—mesenchymal transition Kostina et al. For example, disruption of Notch signaling in transgenic mice is correlated with faulty neural crest cells patterning as well as unequal aortic valve leaflets with bicuspid-like morphology and aortic arch abnormalities characterized by disorganized aortic wall histology with dispersed vascular smooth muscle cells Broberg and Therrien, A study that detected a novel heterozygous sequence variation found that the mutation was present in all affected family members with BAV but absent from the unaffected family members Qu et al.

GATA5 plays an essential role in cardiac morphogenesis and aortic valve development Nemer et al. Due to its high expression in endocardial cushions of both the outflow tract and the atrioventricular canal, GATA5 became a candidate gene for congenital heart diseases, more specifically BAV, and mutations in GATA5 have been associated with an increased susceptibility to BAV, but the specific detailed molecular mechanism needs to be further researched. Despite the awareness of candidate genes for the heritability of BAV, the specific genetic basis underlying BAV remains largely unknown.


The involvement of many genes adds to the heterogeneity of the population of patients with BAV. In addition to the genetic source leading to the formation of BAV, the complications of BAV could also be associated with genetics. Taken together, it is clear that BAV is not a simple Mendelian trait but an accumulation of complex traits Ellison et al. The different phenotypes of valvulopathy in BAV patients also reflect the heterogeneity of this patient population.

In all age groups, BAV underlies the majority of cases of aortic valve disease Martin et al. The most common complication of BAV is valvular stenosis followed by valvular insufficiency Pachulski and Chan, Studies have suggested a correlation between BAV phenotype and the valvular complications that develop. Hahn et al. Compared to the normal population, there is a significantly higher rate of dilation of the proximal aorta in patients with BAV Della Corte et al. Della Corte et al.

Aortic aneurysm commonly involves aortic root, ascending aorta, and aortic arch in clusters Fazel et al. Researchers suggest two theories for the cause of aneurysms in patients with BAV: the hemodynamic theory and the aortopathy theory. Upon pairing patients with TAVs and BAVs based on sex and degree of AI, stenosis, or combined aortic valve disease, the patients with BAV were considerably younger due to the earlier onset of valvular disease and had significant aortic dilation at all levels compared to the matched patients with TAVs Keane et al.

Matching patients with TAVs and BAVs with similar degrees of valvular abnormalities reduces the effect of valvular lesions on hemodynamics and more accurately assesses the BAV Keane et al. The exact molecular and cellular pathways involved in BAV aortopathy remain unknown.

However, MMP-2 matrix metalloproteinase-2 has been identified as a key molecular modulator and a circulation biomarker of aortic dilation in patients with BAV. An increase in MMPs, enzymes that process or degrade the extracellular matrix, is associated with the development of aortic aneurysms Ikonomidis et al. Therefore, an increase in collagen turnover and a decrease in collagen cross-linking may be a factor in the formation of aneurysms in patients with BAVs Broberg and Therrien, The pathological hallmark of TAA is medial degeneration; therefore, smooth muscle cells SMCs; key component of the medial layer function in this pathology Milewicz et al.

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  • On the other hand, the SMCs differentiated from paraxial mesoderm, modeling the descending thoracic aorta, have normal expression of contractile protein, including MYH11 and contractile function Jiao et al. Similar to the valvulopathy, BAV subtype exhibits a correlation to the location of aortic dilation. Hope et al. BAVs compared to TAVs and different subtypes of BAV alter the hemodynamic blood flow through the valve, diversely impacting the aorta, leading to different locations of dilation.

    While the fusion subtypes contribute to flow patterns, so do valvular dysfunctions, such as AI and AS. Most frequently, the hemodynamic change in patients with BAV affects the ascending aorta, but not the aortic root Tadros et al. Aortic regurgitation yields higher stroke volumes which causes higher wall tension in the ascending aorta while AS creates a high-velocity jet that increases shear stress on the ascending aorta Tadros et al. Yet, aortic root aneurysms are still frequently seen in BAV patients Schaefer et al.

    This fact supports the idea that aortopathy is the key factor of TAA in patients with BAV, and that patients with root aneurysms may be due to more severe aortopathy and less to hemodynamics.

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    Also, patients with BAV and isolated dilation of the aortic root tend to be younger, are more likely male, and have AI Tadros et al. Taken together, BAV is a heterogeneous disease. Different gene mutations may cause different subtypes of BAV and exhibit different severity of aortopathy, which result in aortic aneurysm in different parts of the aorta root, ascending aorta or arch and at different ages with the contribution of hemodynamic change due to BAV. The criteria of surgical repair of the aneurysm in these two patients should be different. Aortic dissection occurs 5—10 times more often among patients with BAVs than those with TAVs Braverman, , rendering it a potentially lethal disease.

    In patients with BAVs followed prospectively, aortic dissection has been an infrequent event; however, in patients with BAVs aortic dissection occurs an average of one decade earlier than patients with TAVs Braverman, A study of 56 patients with pure AI, who had an isolated AVR found that the subset of patients with a root aneurysm and AI appears to be different than the hemodynamically-triggered aortopathy seen in patients with BAV stenosis and asymmetric dilation of the tubular ascending aorta Girdauskas et al.

    Girdauskas et al. A study by Wang et al. Both Girdauskas et al. Therefore, though it seems that BAV finds itself in the middle of the high risk of patients with MFS and the low risk of patients with acquired valve disease of a TAV, by separating out the distinct populations of BAV, we believe those with the root phenotype root dilation and AI will be closer to those of MFS while those with AS and ascending dilation will be closer to those of the acquired valve disease of the TAV.

    Therefore, it might be reasonable to separate patients with BAV into groups to decide treatment; potentially be more aggressive when treating patients with BAV—with root phenotype AI and root aneurysm. We propose that when evaluating patients, patients can be classified into two separate groups; Cluster A—root phenotype root aneurysm and AI and Cluster B—no root involvement no root aneurysm or AI. While the percentage of patients with Cluster A aortopathy is often less than those with Cluster B, Cluster A aortopathy is associated with a faster diametric growth rate of the ascending aorta Della Corte et al.

    Because patients with Cluster A aortopathy have an increased probability of life-threatening aortic events, such as aortic dissection and rupture, they could fit under the more aggressive guidelines for patients with connective tissue disorders, such as MFS Girdauskas et al. Cluster A BAV malignant form —root phenotype with aortic root aneurysm and AI should be treated more aggressively with surgical resection at 5 cm for asymptomatic patients, as for patients with MFS, while Cluster B BAV benign form without aortic root aneurysm could be treated less aggressively as for patients with a tri-leaflet aortic valve with surgical resection at 5.


    A study by Michelena et al. Schneider et al. While the addition of an aortic root procedure to an AVR increases technical complexity as well as cardio-pulmonary bypass time, Kim et al. However, if surgeons are not familiar with the aortic root procedures, they should refer the case to a high-volume center of performing aortic root procedures to achieve the best outcome. Figure 1. Thoracic aortic aneurysm in BAV, a heterogeneous disease, can be divided into two clusters based on the aortic root involvement. EN and BY substantially contributed to the conception and design of the work, the acquisition, analysis of data for the work; drafted and revised the work critically for important intellectual content; approved the final version to be published; and agree to be accountable for all aspects of the work ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Adamo, L. Surgical threshold for bicuspid aortic valve aneurysm, a case for individual decision-making. Heart , — Bissel, M. Cusp fusion pattern in bicuspid aortic valve disease predicts severity of aortic flow abnormalities. CrossRef Full Text.

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    Braverman, A. Aortic involvement in patients with a bicuspid aortic valve. Heart 97, — Broberg, C. Understanding and treating aortopathy in bicuspid aortic valve.

    Trends Cardiovasc. Della Corte, A. Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve. JACC Cardiovasc. Imaging 6, — Predictors of ascending aortic dilatation with bicuspid aortic valve, a wide spectrum of disease expression.

    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease
    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease
    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease
    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease
    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease
    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease
    Controversies in Aortic Dissection and Aneurysmal Disease Controversies in Aortic Dissection and Aneurysmal Disease

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