Few studies have explored the influence of sex and gender on cardiovascular events among MFS patients. Initial reports of peripartum ascending aorta dissection or rupture suggested that women with MFS might face a higher risk of aortic dilation and events. However, subsequent publications have consistently shown that men exhibit more aggressive aortic manifestations, with a higher occurrence of aortic events (including type A and B dissection and aortic surgery), typically at a younger age than women.18–20 Further studies on genotype/phenotype correlations suggest that the observed sex differences are unrelated to specific genotype.21,22

The pathophysiological mechanisms underlying these differences remain incompletely understood, making it currently impossible to disentangle the effects of sex from gender. However, a few experimental studies using FBN1 mutant mouse models have suggested a protective role for elevated estrogen levels,23 which have been inversely related to aortic diameters, growth, and fragmentation of aortic wall elastic lamellae. This effect may be mediated by the inhibition of proteoglycan deposition and reduction in collagen and matrix metalloproteinase expression.

Less information is available about the impact of sex and gender on cardiovascular involvement in other syndromic and nonsyndromic HTAD. In LDS associated with TGFBR1 variants, male sex has been reported to be a risk factor for adverse aortic events. Conversely, female LDS patients with TGFBR2 variants experience a higher occurrence of type A dissections at diameters <45mm compared with men.12 Despite these findings, the underlying cause of this sex disparity remains elusive. Additionally, while male LDS patients with TGFB2 variants seem to have a higher aortic risk, there is no evidence of sex or gender differences in LDS patients carrying SMAD3 variants.24 In vEDS, male sex has been related to higher mortality due to vascular complications compared with women, especially among the youngest patients.25

In nonsyndromic HTAD patients carrying an ACTA2 variant, adverse aortic events were more prevalent in men than in women; however, the median age at the first event did not differ between sexes, and the type of aortic dissection (A vs B) was unaffected by sex.24 Sex or gender differences have not been reported in nonsyndromic HTAD attributed to SMAD3, MYLK, MYH11 and LOX, although studies on these genes are limited.24

Pregnancy in women with HTAD increases the risk of aortic complications compared with the general population and to the nonpregnant period.26–28 Type A dissections during pregnancy mostly occur in patients unaware of their MFS diagnosis,26,29 highlighting the critical importance of diagnosis and prepregnancy counseling. Type B dissections can occur in diagnosed patients, and their onset remains unpredictable.26,28,29 Furthermore, MFS women with prepartum aortic diameters between 40 and 45mm demonstrated stable aortic dimensions throughout pregnancy.26 Importantly, outside the peripartum period, MFS women who have ever been pregnant do not exhibit an increased aortic risk compared with those who have never been pregnant.26,30 Limited information exists on pregnancy-related risks in LDS,31,32ACTA233 and vEDS.34 The risk is likely higher in these syndromes than in MFS, especially in vEDS, which includes not only aortic but also nonaortic vascular complications and uterine rupture. Specialized prepregnancy counseling and shared decision-making are advised in women with HTAD who are planning pregnancy.

A diagnosis of HTAD can affect patients’ functional, mental, and social well-being.35,36 Although there is a growing body of literature examining quality of life (QoL) in MFS patients,37,38 studies on LDS and vEDS remain scarce.35,39,40 Most studies, typically based on patient-reported outcome measures, indicate that QoL is generally impaired in these patients,35,37–39 especially in women.36 Several socioeconomic factors, such as lower income and educational level,41,42 unemployment,36,41,42 and limited social support,42 have been associated with decreased QoL in MFS. This highlights the importance of assessing QoL alongside socioeconomic status to gain insights into the overall well-being of HTAD patients. Assessments should encompass symptom burden, functional status, psychological well-being, social and occupational functioning, treatment adverse effects, health care utilization, and patient satisfaction to enhance the understanding and management of HTAD.10

A sedentary lifestyle is a known cardiovascular risk factor in the general population, but evidence of its effects on HTAD is scarce. Similarly, the impact of physical exercise on the progression of aortic diameters and the risk of acute aortic syndrome in HTAD patients is unclear, preventing health care professionals from recommending exercise to these patients. However, 2 studies in murine models have suggested a potential benefit of low- to moderate-intensity aerobic exercise, which may reduce aortic elastin fiber fragmentation and growth.43,44

Few studies have focused on evaluating the impact of physical exercise on aortic structure and function in HTAD patients. Recent data on children and young adults with MFS suggest that daily physical activity, such as walking 10 000 steps a day, limits aortic root growth,45 and 2 studies have evaluated exercise rehabilitation programs in MFS.46,47 However, larger cohort studies are needed to validate these findings, and to ultimately guide more precise recommendations.

European clinical practice guidelines currently recommend that patients with HTAD avoid high- or very high-intensity exercise, as well as contact and power sports, even in the absence of aortic dilation.48 In contrast, skill sports, mixed sports, and low-intensity endurance sports are not considered risky, even in patients with moderate aortic dilation (40-45mm) or previous proximal aorta replacement.

Several cardiovascular risk factors, such as ageing, obesity,49 hypertension, diabetes, and dyslipidaemia; 11,50,51 as well as lifestyle characteristics, such as smoking,11 have been related to the presence and progression of ascending aortic aneurysms. As a result, current clinical guidelines10,11 recommend controlling modifiable risk factors. Specifically, the most recent guidelines10 advise aiming for a systolic blood pressure of ≤ 129mmHg (≤ 120mmHg if tolerated), a diastolic blood pressure of ≤ 79mmHg, and low-density lipoprotein cholesterol levels of ≤ 55mg/dL. They also emphasize the importance of optimizing diabetes treatment and smoking cessation in patients with aortic aneurysms, but specific recommendations for HTAD patients are lacking.

Despite promising studies on the role of certain serum biomarkers52,53 in assessing aortic risk in MFS patients, these biomarkers have yet to be integrated into clinical practice due to the need for larger, more comprehensive studies to support their use. Nevertheless, this area of research holds significant promise and potential clinical utility.54

The shape of the diseased aorta is more intricate than previously thought, exhibiting not only a transverse growth but also elongation and more complex geometric alterations. Ascending aortic length has been identified as a risk factor for dissection in patients with ascending aortic aneurysms of all etiologies,59 with lengths greater than 11cm predicting adverse aortic events beyond diameter. In addition, aortic tortuosity has been linked to an increased risk of aortic events, including type B dissection, in MFS patients.6,60

Of note, vascular involvement in these patients extends beyond the aorta. In patients with MFS, LDS, or vEDS, increased vertebral artery tortuosity has been associated with a poorer aortic prognosis.61 Moreover, while uncommon in MFS, aortic branch aneurysms have been associated with a higher risk of aortic growth, even after adjusting for aortic diameter.2

Understanding and monitoring changes in aortic geometry and extraaortic vascular features could provide valuable insights into overall cardiovascular involvement in patients with HTAD and may aid in the stratification of aortic risk.

Precision in measuring aortic diameter growth rates is crucial due to its pivotal role in patient management. Nonetheless, current assessments of aortic dimensions are subject to various sources of variability, affecting their reproducibility.62 Although reproducibility for aortic diameter measurements has been reported as excellent for both CCT and CMR,17,63,64 systematic studies on growth rate reproducibility are lacking.65 Only 2 studies have reported limited reproducibility of manual growth rate measurements on CCT and CMR angiography, especially in the aortic root.66,67 Such variability is expected due to potential inaccuracies in both baseline and follow-up diameter measurements, as well as comparisons of nonequivalent segments. Moreover, manual assessment restricts the number of levels at which aortic diameters are assessed, typically relying on predefined anatomical landmarks for reference. This limitation, combined with the failure of manual assessment to accurately capture aortic geometry in 3 dimensions, could lead to risk misestimation.

To address these limitations, various strategies have been proposed. Methods based on aortic segmentation have demonstrated excellent accuracy and reproducibility for measuring both tubular aorta68–71 and aortic root72 diameters. Aortic diameter growth can be further evaluated by applying deformable image registration to serial CCT67,73 or CMR66 angiography, enabling the calculation of 3D aortic diameter and growth maps (figure 2) with limited observer dependence.66,67

Figure 2.

Aortic geometry mapping in a patient with Marfan syndrome. A: baseline aortic mesh and aortic root plane with detected commissures in green. B: diameter maps and aortic root diameters at baseline and follow-up. C: growth rate map and root growth from automatically computed diameters.

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In patients with aortic disease, including MFS, image registration-based measurements of aortic growth rates have proven to be substantially more reproducible than the current standard, both in the aortic root and in the tubular aorta.66,67 Notably, when applied to CCT angiography, the reproducibility at 6 months of follow-up was comparable to that achieved by manual assessment at 3 years of follow-up, opening the possibility of a shorter follow-up period for the assessment of growth.67 Moreover, the maximum rate of aortic growth is rarely located at the level of the pulmonary artery bifurcation, a typical anatomical landmark,67 and does not always occur at the site of maximum diameter.73,74 This highlights the usefulness of mapping 3D growth to estimate risk. Therefore, accurate local assessment of aortic growth can improve clinical management and enhance the understanding of aneurysm physiopathology.74 However, the precise value of this method in assessing the risk of aortic events in HTAD patients has yet to be determined.

The aorta serves not only as a conduit for blood flow but also as a buffer to reduce the pulsatile flow and pressure generated by left ventricular contraction, ensuring a steadier flow rate to peripheral circulation. Aortic elasticity is crucial for cardiovascular function, but it diminishes with age, which in turn affects cardiovascular health.50,75 Basic research demonstrating the underlying structural abnormalities of the aorta in patients with MFS76,77 prompted imaging studies aiming to identify whether these abnormalities were reflected in measurable elastic properties.78,79 Positive findings stimulated further research, particularly with the advent of CMR,80–85 which provides vast possibilities for assessing aortic biomechanics.86 While much attention has focused on MFS, efforts are not limited to this condition.82,87,88

Various stiffness parameters can be assessed using transthoracic echocardiography or CMR. Circumferential strain measures changes in aortic diameter or area throughout the cardiac cycle at a specific aortic level. When normalized by local pulse pressure, it yields aortic distensibility. This measurement is normally obtained via CMR but can also be measured by echocardiography, provided that there is no aortic motion through the imaging plane, and assuming that the aorta is circular. Of note, aortic distensibility measurement should use local pulse pressure, which is rarely available.89 Ascending aorta longitudinal strain evaluates the longitudinal stretch of the proximal aorta during the cardiac cycle due to left ventricular contraction.90,91 Pulse wave velocity, which refers to the velocity of propagation of pressure or flow waves, is typically measured with 2D phase-contrast CMR or tonometry, and can be regionally evaluated with 4D flow CMR. CMR-derived biomechanical descriptors have been validated against ex vivo mechanical tissue properties.92 Additionally, recent studies have linked distensibility with specific genetic loci, supporting their role in predicting cardiovascular outcomes.93,94

Research has consistently demonstrated that patients with MFS have increased aortic stiffness compared with normal controls at all aortic levels,80,81,83,88,95,96 at an early age82,88 and even in the absence of aortic dilation.81,95 This increased stiffness has also been reported in patients with various connective tissue disorders,82 and in patients with LDS87 or Turner syndrome.88 Longitudinal studies in MFS97 and other connective tissue disorders98 indicate a progressive increase in aortic stiffness with age, with rates of change similar to those observed in healthy individuals.98

Remarkably, increased aortic stiffness predicts progressive ascending91,99 and descending aorta dilation,85 need for preventive surgery,82 and adverse aortic events91 in these patients. In MFS, elevated baseline aortic root stiffness, assessed by echocardiography, has been associated with faster aortic root growth, and adverse aortic events at young ages.99 Local descending aorta distensibility by CMR has also been shown to predict colocalized progressive dilation.85 Additionally, CMR-derived proximal aorta longitudinal strain independently predicts aortic root growth rate and adverse aortic events in MFS patients,91 underscoring the importance of measuring the often-neglected longitudinal deformation. In children and young patients with connective tissue disorders, retrospective analyses of CMR revealed lower aortic root strain as an independent predictor of aortic root replacement when excluding root diameter (the primary surgical indicator) from the model.82

Assessing aortic biomechanics provides valuable insights for risk prediction in HTAD patients. Using 4D flow CMR allows for a comprehensive characterization of aortic biomechanics and fluid dynamics, as described in the following section.

Patients with HTAD have distinct hemodynamic profiles throughout the thoracic aorta, which may be related to progressive dilation and dissection.100 Moreover, flow patterns before and after aortic surgery can be used to assess the efficacy of the intervention (figure 3), although no study has yet tested the long-term implications of such evaluations.

Figure 3.

Peak systolic velocity streamlines in a patient with Marfan syndrome before (A) and after (B) prophylactic root replacement. After surgery, higher velocity is observed in the proximal ascending aorta, as well as increased rotational flow at the distal ascending aorta.

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Hemodynamic profiles are characterized by various fluid descriptors. Among the most studied is rotational flow, which can be defined as the coherent rotation of blood flow: this rotation can occur around an axis parallel to the aortic centerline, a physiological feature of blood flow in the thoracic aorta often known as “helical flow,” or perpendicular to it, which is often referred to as “vortex flow.” Vortex flow results in backward flow during systole and has not been reported in healthy individuals. In addition, flow can be characterized by its interaction with the aortic wall. Specifically, wall shear stress (WSS) is the tangential force per unit of wall area exerted by the moving blood on the aortic wall. WSS is a vector, normally reported with its magnitude, which can be decomposed into circumferential (along the aortic circumference) and axial (along the longitudinal direction) components.

In the proximal ascending aorta, patients with MFS have lower axial and magnitude WSS, as well as increased vortexes compared with healthy individuals.101,102 These alterations have been related to local dilation,103 and normalized after surgical exclusion of the dilation.102 Several studies have identified abnormal flow patterns in the proximal descending aorta of MFS patients, consistently showing abnormally low helical flow103 and circumferential WSS,104 especially in the inner part of the proximal descending aorta.101,105 These abnormalities were related to the severity of local dilation,101,105 but were present even in patients without dilation,103 and in young patients,105 suggesting a potential causal relationship with local dilation. Furthermore, these alterations worsened during follow-up105 and were not restored by proximal aorta surgery.100,106 Abnormally intense vortical flow has also been reported in the proximal descending aorta,107 correlating with local diameter.103 However, this flow abnormality was not present in absence of local dilation,103 and was not restored by proximal aortic surgery,102 indicating that it may result from dilation. Longitudinal studies are required to determine whether these abnormalities are associated with future type B aortic dissections.

Notably, only a limited number of studies have measured abnormal flow patterns in other HTAD entities. To our knowledge, only one study has reported flow patterns in LDS, showing similar aortic flow abnormalities as those found in MFS patients.87