Article Text

Download PDFPDF

Congenital heart disease in adult patients
Aortopathies in adult congenital heart disease and genetic aortopathy syndromes: management strategies and indications for surgery
  1. Joey M Kuijpers1,2,
  2. Barbara JM Mulder1,2
  1. 1 Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
  2. 2 Netherlands Heart Institute, Utrecht, The Netherlands
  1. Correspondence to Barbara JM Mulder, Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; b.j.mulder{at}amc.uva.nl

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Learning objectives

  1. Review the epidemiology, histology, pathophysiology and genetics of congenital heart disease-associated aortopathies and genetic aortopathy syndromes.

  2. Review and describe

    1. appropriate imaging strategies for diagnosis and follow-up

    2. appropriate pharmacotherapeutic strategies and indications for aortic surgery

    3. considerations relevant to pregnancy

    4. considerations relevant to sports participation in patients with congenital heart disease-associated aortopathy or a genetic aortopathy syndrome.

Introduction

Progressive proximal aortic (ie, aortic root and ascending aortic) dilatation is frequently found in adults with unrepaired or repaired congenital heart disease (CHD). With the growing number of patients with adult CHD (ACHD), physicians increasingly find themselves challenged with the management of proximal aortic dilatation in this heterogeneous patient population. Data on the natural history of CHD-associated aortic dilatation, including risk of dissection, rupture and aortic insufficiency, are scarce. These issues, essentially informing decisions regarding surveillance, pharmacotherapy and surgery, are better defined for genetic aortopathy syndromes, particularly Marfan syndrome (MFS). Moreover, histopathological similarities between CHD-associated and MFS-associated aortopathies have been found.1

This review outlines CHD–associated thoracic aortic dilatation, with special focus on management and indications for surgery. Genetic aortopathy syndromes, including MFS, are addressed as these also require cardiologic follow-up of the proximal aorta. Moreover, data from studies in patients with MFS may inform management of proximal aortic dilatation in the setting of other diseases and syndromes. International guidelines on aortic disease,2–4 ACHD5 6 and valvular heart disease7 are complementary with respect to management of CHD-associated aortic dilatation, and the proposed management represents an integration of these guidelines.

The thoracic aorta

The thoracic aorta is subdivided into the root, ascending aorta, arch and descending aorta (figure 1). Aortic diameter is dependent on age and body size, the latter accounting for generally larger diameters in men. The aorta is considered dilated when its diameter exceeds the upper limit of established normal values, and aneurysmal when it is ≥1.5 times this limit (table 1).8 Normal ascending aortic growth rate is ~1.5  mm per decade in adults.9

Figure 1

Thoracic aortic anatomy (image by Roy van Leeuwen, graphic designer).

Table 1

Normal aortic root and ascending aortic diameters, absolute and indexed to body surface area and height, stratified by gender (adapted from Muraru et al) 8

Genetic aortopathies

Marfan syndrome

MFS, an autosomal-dominant disorder variably involving the cardiovascular, skeletal and ocular systems, skin and dura mater results from mutations in the fibrillin-1-encoding FBN-1 gene. Incidence is 1:3000–5000 individuals.6 Life-expectancy, averaging ~45 years in the pre-open-heart surgery era (with the majority of deaths from aortic dissection or rupture), has increased to ~70 years due to surgical and medical advancements.10 Aortic dilatation, found in 60%–80% of patients, usually starts at the root but often extends distally later in its natural course.11

Histopathology and pathophysiology

MFS aortopathy is characterised by elastic laminar fragmentation, vascular smooth muscle cell (VSMC) loss and extracellular mucoid material accumulation in the aortic wall media. This ‘cystic medial necrosis’ is also found in dilated/dissected aortas of other aetiologies and the ageing aorta but is more extensive in MFS.12

The pathophysiology of MFS aortopathy probably involves reduced fibrillin-1 functionality in the aortic wall. Fibrillin-1 anchors VSMCs to elastic laminae in the medial extracellular matrix (ECM). Deficient functional fibrillin-1 causes VSMC dissociation, inducing elastolytic matrix metalloproteinase (MMP) expression. Resultant elastic laminar fragmentation, ECM disruption and VSMC apoptosis impair aortic wall structural integrity and elasticity.13 Evidence suggests fibrillin-1 additionally sequesters and stabilises transforming growth factor (TGF)-β in latent complexes.14 In fibrillin-1-deficient mice, typical aortic wall damage was associated with increased TGF-β activity and was prevented by administration of TGF-β antibodies or angiotensin II type 1 receptor blockers (ARB; TGF-β signalling down-regulators).15

Natural history

Aortic root growth rate is greater than normal, averaging 0.4–0.5 mm/year. A subset of patients shows faster growth (~1.5 mm/year), associated with greater dissection risk.16 17 Risk for dissection or death increases steeply at proximal aortic diameters ≥50 mm (1.33%/year vs 0.33%/year with diameters 45–49 mm).18 Other risk factors for dissection include family history of dissection and pregnancy.2 3 After aortic root surgery, the aorta distal to the repair site remains at risk for dilatation and dissection.11 19

Other genetic aortopathies

Genetic disorders associated with aortopathy include the autosomal dominant vascular Ehlers-Danlos,20 21 Loeys-Dietz22 23 and aneurysms-osteoarthritis syndromes,24 25 the chromosomal defect Turner syndrome26 and non-syndromic familial thoracic aortic aneurysms and dissection.27–29 Aortic complications may occur at smaller diameters than in MFS, although data are sparse due to the low prevalence of these syndromes. Genetic and clinical features relevant to their diagnosis, and recommendations for the management of associated aortopathies are presented in table 2.

Table 2

Non-Marfan genetic aortopathies: genetics, clinical features, diagnosis and management of the aorta

CHD-associated aortopathy

Bicuspid aortic valve

Bicuspid aortic valve (BAV), affecting 0.5%–2% of the population with a male predominance of ~3:1,30 results from fusion of the right and left coronary cusps (>70%), right and non-coronary cusps (10%–20%) or left and non-coronary cusps (5%–10%) of the aortic valve.2 Aortic coarctation (CoA) is present in ~7%, in association with right-left fusion phenotype. General mode of inheritance is autosomal dominant with incomplete penetrance. However, the male predominance and association with Turner syndrome suggest X-linked inheritance30: several gene mutations with differing modes of inheritance may underlay BAV.31 While valve stenosis and insufficiency are the predominant complications, proximal aortic dilatation is found in 50%–87% of adult patients.17 32 33 Dilatation is generally greatest at the ascending aorta and often also involves the root and/or arch (figure 1). BAV-associated aortic dilatation probably results from an interplay between altered transvalvular haemodynamics and an intrinsic aortopathy.30

Histopathology and pathophysiology

The histopathological findings (‘cystic medial necrosis’, increased MMP activity, reduced fibrillin-1) are similar to MFS.1 30 34 A heritable syndrome incorporating BAV and familial aortopathy is evidenced by increased incidence of aortic dilatation among BAV patients’ first-degree relatives with normal valves.35 Several observations suggest a causative role for abnormal haemodynamics: the histological abnormalities often show predilection toward the area of increased shear stress induced by eccentric transvalvular flow.36 Moreover, different fusion types are associated with distinct transvalvular flow directions and distinct dilatation patterns: right-left fusion is usually associated with root and/or ascending aortic dilatation, and right non-coronary fusion with dilatation extending toward the arch.37 38 Furthermore, midline flow is associated with normal aortic diameters.38

Natural history

Ascending aortic growth rates range from 0.3 to 2.0 mm/year, while ~40% of patients show stable diameters over several years,17 32 33 emphasising heterogeneity within the BAV population. Factors associated with increased growth, including greater baseline diameter,39 valvular dysfunction17 33 39 and aortic stiffness,40 are inconsistently found, complicating risk stratification. Dissection incidence is 3.1 cases per 10 000 person-years, 8.4 times the risk in the age-matched population.39 Dissections occur at similar diameters as in degenerative aneurysms (ie, those related to atherosclerotic risk factors).41

Aortic coarctation

CoA accounts for 5%–8% of all CHD.5 6 Presence of BAV in ~60% and similar aortic wall abnormalities between these anomalies suggests they represent separate manifestations of an inherited aortopathy.1 42 Indeed, CoA is a generalised arteriopathy with impaired elasticity and functionality of the precoarctation vasculature that persists after–even early–repair.1 43 44 Associated risk of late morbidity, including aortic dilatation, dissection and rupture, necessitates continued follow-up after repair. The CoA site itself remains an area of concern, with chance of re-CoA, dilatation and rupture, a discussion of which is beyond the scope of the present review.5 6

In retrospective series of adults after surgical CoA repair, aneurysm formation was found in ~14%,42 45 and dissection or rupture in ~2.5%.42 Postcoarctectomy ascending aortic growth rate is greater in ‘complex’ CoA (ie, associated with BAV, ventricular septal defect (VSD), hypoplastic aortic arch or increased left ventricular mass), compared with isolated CoA.46 A recent study found that advancing age and concomitant BAV independently predicted aortic complications, while age at repair, repair type, residual or re-CoA and hypertension did not.42

Conotruncal defects

Conotruncal defects—tetralogy of Fallot (ToF) and pulmonary atresia with VSD (PA+VSD), double outlet right ventricle, truncus arteriosus and transposition of the great arteries (TGA)—are characterised by abnormalities of the ventricular outflow tracts and great vessels. Literature on associated aortopathy is scarce and focuses mainly on ToF/PA+VSD and TGA. While thoracic aortic dilatation is common after repair of conotruncal defects—with aortic wall abnormalities similar to MFS1—dissection risk is low, with only a few reported cases in ToF47–50 and TGA patients.51 Moreover, a population-based study covering ~100% of hospitalisation in Texas over 13.5 years found no association between conotruncal defects and risk for aortic dissection: 10.5 cases per 100 000 conotruncal patient-years (vs 10/100 000 patient-years in the reference population).52

Aortic dilatation in ToF (~10% of all CHD)6 has been found on fetal echocardiography. It mainly involves the root but may extend to or predominantly affect the ascending aorta.53 Its pathogenesis likely involves prerepair aortic volume overload—right ventricular outflow obstruction with right-to-left shunting—and an intrinsic aortopathy.1 Indeed, Niwa et al 54 found aortic dilatation was associated with pulmonary atresia (rather than stenosis) and longer shunt-to-repair interval (ie, greater and more prolonged aortic volume overload). Aortic root dilatation was found in 7%53−15%54 of adults after repair at relatively old age (on average >5 years53 and >10 years54). Importantly, repair in infancy (age <1 year), currently common practice, has been associated with normalisation of root diameters during childhood.55 Root dilatation may thus less frequently affect future adults with ToF. Three of four reported dissections occurred at aortic diameters >70 mm,47–49one at 53 mm.50

TGA patients are at increased risk for aortic dilatation, after both atrial baffle (Mustard/Senning)56 and arterial switch operations (ASO).57 58 Proximal aortic dilatation after atrial baffle procedures seldom leads to complications, with only one reported dissection after the Mustard operation.51 The ASO, standard treatment since the late 1980s, involves translocation of the aorta and pulmonary artery above the sinus level: the pulmonary root and valve remain in situ as the neo-aortic root and valve. Neo-aortic root dilatation is found in 50%–65% of patients a long period after ASO, at least moderate aortic insufficiency in 3%–15%.57–59 Ascending aortic diameters are generally normal. After ASO in early childhood, neo-aortic growth persists through early adulthood, without stabilisation over time.60 However, significant aortic insufficiency and valve and/or root surgery are rare in long-term follow-up after ASO (~5% at 15 years). No neo-aortic dissection or rupture has been reported to date.57–60 Given the relative infancy of the ASO, very-long-term outcomes are currently unavailable.

After truncus arteriosus repair, a dilated aortic root has been found in the majority of patients, although need for reoperation was rare and no dilatation-related complications occurred.61

Other CHD and postoperative states

After the Ross procedure—replacement of the aortic valve and/or root with a pulmonary autograft—autograft dilatation is common. Dilatation is related to preoperative aortic insufficiency and free-standing root replacement (as opposed to subcoronary implantation). Need for reoperation, mainly indicated for neo-aortic dilatation, is ~20% at 12 years.62 At least four dissections in dilated autografts have been reported.63 Propagation of dissection is often limited by the suture lines, possibly improving prognosis relative to native aortic-root dissection. However, dissection may be asymptomatic due to its limited size and autograft denervation, thus going undetected while risk of rupture of the weakened autograft is increased.64

Hypoplastic left heart syndrome (HLHS)—hypoplasia of left ventricular structures and proximal aortaand other univentricular physiologies are preferably treated with three-stage palliative surgery. Stage 1 (Norwood procedure) involves aortic replacement (root) and reconstruction (ascending aorta, arch) using pulmonary homograft material. Stages 2 (Glenn) and 3 (Fontan) create bidirectional and total cavopulmonary connections, respectively. After HLHS palliation, progressive dilatation and reduced distensibility of the neo-aortic root, ascending aorta and arch are found.65 Neo-aortic insufficiency was present in 61% of patients at a median of 9 years after Norwood but was rarely greater than mild.66 Root dilatation requiring surgical intervention and neo-aortic dissection are probably rare, with only a few cases67–69and one70 reported case, respectively. Moreover, aortic dissection is an uncommon cause of death long-term after Fontan palliation: in 261 patients with various underlying defects followed for a median of 12 years after Fontan surgery, aortic dissection was the cause of only one of 76 deaths.71

Management

General considerations

Imaging

Guidelines on aortic disease provide important considerations for aortic imaging.2 3 Measurement of maximal aortic diameter is most accurate perpendicular to its longitudinal axis (figure 2A), while asymmetric root dilatation—particularly relevant to MFS—is best assessed on short-axis views (figure 2B).72 For serial imaging, standardised measurement at defined anatomic locations and the same timepoint during the cardiac cycle is important.8 Transthoracic echocardiography (TTE) generally adequately visualises the aortic valve, root and proximal ascending aorta, but not the more distal segments. Transoesophageal echocardiography may provide an alternative in patients with poor acoustic windows but is semi-invasive, while CT and MRI provide better assessment and allow aortic diameter measurement perpendicular to the centreline. Multidetector CT provides high-resolution images in a short acquisition time, but ionising radiation exposure makes CT less favourable for young patients and routine monitoring. MRI, not associated with ionising radiation, is the preferred method, especially for serial imaging in young patients, despite longer acquisition times.2 3 Thresholds for surgery are generally based on leading-edge-to-leading-edge diameter measurements (2–4 mm larger than inner-edge-to-inner-edge measurements).8 If a thoracic aortic aneurysm is found, the entire aorta should be assessed for other affected segments (CT/MRI).

Figure 2

Aortic MRI images in a patient with Marfan syndrome. (A) Long-axis view of the thoracic and abdominal aorta, with aortic diameter measurements at multiple anatomic locations (lines). (B) Short-axis view of the aortic root, with diameter measurements between the right coronary cusp (RCC) and left coronary cusp (LCC), and the right and left coronary cusps to the non-coronary cusp (NCC).

Risk factor management and medical therapy

Blood-pressure control is indicated in all patients with thoracic aortic dilatation.2 General blood-pressure targets are recommended in the absence of connective tissue disease. Prophylactic pharmacotherapeutic strategies to reduce aortic growth have been studied mainly in MFS: data to support selection of such agents stem largely from studies in MFS (wbelow).2 3

Surgical management

Thoracic aortic aneurysms are generally treated by surgical replacement of the affected segment using a tube graft. Symptomatic aneurysms (chest/back pain, compression of adjacent structures, aortic regurgitation) are associated with poor outcome and should prompt consideration of surgery. In asymptomatic patients, the indication for prophylactic surgery weights the long-term risk for dissection against the one-time risks associated with surgery. Proximal aortic diameter, an important determinant of long-term dissection risk, is the main criterion for the decision regarding surgery (table 3). While absolute aortic diameter may imperfectly predict dissection (in a large registry of type A dissections, 60% occurred at diameters below the surgical threshold)73 absolute surgical thresholds perform well in preventing aortic root dissection in MFS.74 Diameter indexed to body size (maximal aortic diameter by body surface area (BSA)75 or maximal aortic cross-sectional area by patient height)76 may be more reliable in patients of short stature. Moreover, assessments of other factors, particularly increased aortic stiffness (associated with greater aortic diameter (growth) in both MFS77 and CHD)40 78  could aid patient risk stratification.

Table 3

Recommended indications for prophylactic aortic surgery for asymptomatic aortic root and/or ascending aortic aneurysms

Defect-specific considerations

Marfan syndrome

Patients with MFS require lifelong regular (annual) follow-up in a specialist centre.6

Diagnosis relies on the Ghent criteria, which put increased weight on the cardinal features—aortic root aneurysm and ectopia lentis—and genetic testing in a recent revision.79

Imaging surveillance should include at least yearly imaging of the aortic root and ascending aorta. TTE generally suffices. MRI (or CT) of the entire aorta should be performed at diagnosis, repeated every 5 years (normal diameter beyond root) or annually (aneurysmal aorta beyond root),2 3 6 and continued after aortic root surgery.10 19 The proposed imaging strategy is presented in figure 3.

Figure 3

Imaging surveillance of the aorta in patients with Marfan syndrome. *If visualisation of aortic root and ascending aorta is inadequate, MRI (or CT) should be employed. mo, months; SoV, sinuses of Valsalva; STJ, sinotubular junction; TTE, transthoracic echocardiography.

Familial screening including TTE of first-degree relatives is indicated. If the proband has an FBN-1 mutation, genetic screening of first-degree relatives with imaging of relatives with FBN-1 mutations provides an alternative strategy.2–4 The same strategy applies to other familial thoracic aortic aneurysm syndromes (table 2).

Pharmacotherapy, including blood-pressure control (systolic blood pressure target <120 mm Hg) and prophylactic pharmacotherapy is indicated in all patients with MFS. β-blockers are routine practice in most centres,2 3 6 although aortic growth-rate reduction is inconsistently found and reduced aortic complication-risk cannot be concluded from available data.80 81 ARBs are an emerging prophylactic treatment option. In the first two randomised trials in patients with MFS, losartan—often against background β-blockers —reduced aortic dilatation rate compared with open-label controls.82 83 Later trials found no differences in dilatation rate or risk of adverse events between losartan and atenolol,84 85 and no effect of losartan on top of maximal β-blockers on dilatation rate.86 Multiple randomised trials of ARBs in MFS are underway. A proposed meta-analysis of all relevant trials should allow more definitive conclusions about the effect of ARBs and β-blockers on aortic disease in MFS.87 Without conclusive evidence favouring either β-blockers, ARBs or a combination may provide appropriate prophylaxis. Medical treatment should be continued after aortic surgery.88

Prophylactic aortic surgery is indicated at proximal aortic diameters ≥50 mm, as risk of dissection or rupture increases steeply from that diameter onward.18 A lower diameter threshold may be considered with additional risk factors, including rapid growth, family history of dissection, desired pregnancy and severe aortic or mitral regurgitation.2–4 6 Concerning rate of growth, the 2010 American guidelines3 and 2014 Canadian position statement4 for thoracic aortic disease recommend considering surgery in all patients with rates ≥5 mm/year, regardless of absolute diameter. The 2014 European guidelines for aortic diseases2 and 2010 European guidelines for grown-up CHD6 recommend a diameter threshold of 45 mm be considered in patients with MFS with a growth rate ≥3 mm/year, on repeated measurements using the same technique, measured at the same aortic level, with side-by-side comparison and confirmed by another technique (eg, CT or MRI). Concerning desired pregnancy, the 2014 European guidelines for aortic diseases2 recommend considering surgery at aortic diameters ≥45 mm, and the 2010 American guidelines3 at diameters ≥40 mm. As pregnancy is generally well tolerated with root diameters <45 mm, the authors concur with the former.89 These surgical recommendations and considerations are presented in table 3. Increased aortic tortuosity and higher circulating TGF-β levels have been associated with faster aortic root growth and dissection or aortic surgery.90 91 These factors may aid future risk stratification. Considerations regarding management of non-MFS genetic aortopathies are set out in table 2.

Bicuspid aortic valve

Diagnosis of BAV and associated aortic dilatation may be (incidentally) made on TTE. Given the heterogeneity in pathogenesis30 31 and natural history17 32 33 of BAV aortopathy and the existence of distinct phenotypic subtypes,37 38 an individualised approach to surveillance and treatment may be required.

Imaging surveillance should include aortic root and ascending aortic echocardiography. MRI (or CT) is indicated if TTE is inadequate, and in case of diameters ≥45 mm and/or growth >3 mm/year. Follow-up frequency depends on aortic diameter, growth rate and family history (figure 4).2 7

Figure 4

Imaging surveillance of the aorta in patients with bicuspid aortic valve. *If visualisation of aortic root and ascending aorta is inadequate or dilatation extends beyond field of view, MRI (or CT) should be employed. mo, months; TTE, transthoracic echocardiography.

Familial screening (TTE) of first-degree relatives for BAV and/or ascending aortic dilatation is recommended by guidelines.2–4 7 BAV indeed meets important criteria for screening: it is asymptomatic and not readily diagnosed during routine care, echocardiography can reliably identify the defect, effective treatment is available and early intervention can improve outcome.92 However, we recognise that such screening would put a heavy burden on institutional resources and is thus likely not feasible in clinical practice. While the feasibility and appropriate timing of screening remain debatable, patients should be counselled about the hereditary nature of the disease and the increased risk of cardiovascular morbidity in first-degree relatives.

Pharmacotherapy with β-blockers is general practice in BAV-associated aortic dilatation. Given the histopathological similarities with MFS, ARBs may provide an alternative. Systematic evaluation of these agents in BAV patients is lacking, but a randomised trial (ClinicalTrials.gov identifier NCT01202721), evaluating the safety and efficacy of atenolol and telmisartan in BAV aortopathy, is currently ongoing.

Prophylactic aortic surgery is recommended at aortic root/ascending aortic diameters ≥50 mm in older guidelines, including the 2010 American guidelines for thoracic aortic disease.3 5 More recent guidelines, including the 2014 European guidelines for aortic diseases, advocate a more individualised approach incorporating the presence of risk factors: rapid growth, hypertension and desire for pregnancy (no risk factors present: surgical threshold ≥55 mm, risk factors present: ≥50 mm).2 7 Concerning rate of growth, the 2010 American guidelines for aortic disease recommend considering surgery at rates ≥5 mm/year, regardless of absolute diameter in all patients.3 The 2014 European guidelines recommend a lower diameter threshold for surgery of 50 mm at rates ≥3 mm/year (on repeated measurements using the same technique, measured at the same aortic level, with side-by-side comparison and confirmed by another technique),2 while the 2014 American guidelines for valvular disease recommend this lower threshold at rates ≥5 mm/year.7 Of note, the 2014 European guidelines on aortic diseases include CoA as a risk factor for dissection in BAV, recommending a surgical threshold of 50 mm in its presence.2 The authors find the association between CoA and increased risk insufficiently demonstrated in literature and would not recommend this lower threshold for surgery. As BAV patients undergoing isolated aortic valve replacement (AVR) remain at risk for aortic complications, concomitant prophylactic aortic replacement may be considered at lower diameters (≥45 mm).2–4 7 In a landmark study, 15-year freedom from aortic surgery or complications was 43% in those with aortic diameters of 45–49 mm at AVR, and 81% in those with diameters of 40–44 mm.93 Concomitant ascending aortic replacement in those with diameters ≥45 mm is safe and may prevent aortic complications and reoperations.94 These surgical recommendations and considerations are presented in table 3.

Aortic coarctation

All patients with CoA require at least two-yearly follow-up at a specialised ACHD centre.6

Imaging surveillance (preferably MRI) for CoA-site assessment and aortic diameter follow-up should be performed at ≤5-year intervals, depending on baseline pathology.5 6 45 Assessment of aortic arch geometry may be incorporated: a more acutely angulated shape causes increased pulse wave reflection and is associated with increased aortic wall shear stress, stiffness and dilatation.95 More frequent imaging may be appropriate in its presence.

Pharmacotherapy and prophylactic aortic surgery are not included in specific guideline recommendations for aortic dilatation in patients with CoA without BAV. The close association between these anomalies imply strategies established for BAV may be appropriate (table 3).5 6

Tetralogy of Fallot

All patients with ToF require periodic follow-up—generally annual, but less frequent in those with minimal haemodynamic disturbance—at a specialised ACHD centre, including TTE. Guidelines focus on follow-up and management of the right ventricular outflow tract but do recognise the occurrence of aortic root dilatation and aortic regurgitation.5 6

Imaging surveillance (TTE) should include aortic valve and root assessment. Periodic MRI is indicated in all patients, with frequency based on pathology found.

Pharmacotherapy and prophylactic aortic surgery are not included in guideline recommendations. Progression of aortic root dilatation is generally slow. Aortic surgery is rarely indicated and generally performed for aortic regurgitation.53 54 Data concerning the (un)natural history of aortic dilatation in these patients are lacking. While there are no reports suggesting increased risk of aortic dissection or rupture at diameters <55 mm, data to establish specific surgical thresholds for patients with ToF are lacking (table 3).

Transposition of the great arteries

Adult TGA patients require at least annual follow-up at an ACHD centre.5

Imaging surveillance is indicated in all TGA patients, with TTE follow-up of the (neo-)aortic valve and root particularly in post-ASO patients.5 Assessment of arch geometry may be incorporated: acute angulation is associated with aortic dilatation.96

Prophylactic surgery after ASO has been recommended for neo-aortic root dilatation ≥55 mm, based on recommendations for degenerative aortic root aneurysms.5 While there are no reports suggesting increased risk of neo-aortic dissection or rupture at diameters <55 mm, data to establish specific surgical thresholds for post-ASO patients are lacking (table 3). Neo-aortic root operations are safe, despite technical challenges imposed by complex anatomy,97 but are uncommon up to 15 years after ASO.57 58

Other CHD and postoperative states

Neo-aortic root diameters should be regularly monitored after the Ross procedure, as dilatation and need for reoperation are common.62 While neo-aortic root dilatation and regurgitation after palliation (Norwood/Fontan) of univentricular physiologies have little impact on outcome, periodic (MRI) follow-up of the aorta is warranted.65

Periodic follow-up is warranted in all patients with ACHD.5 6 When aortic dilatation is noted, regular follow-up of aortic diameter, with frequency based on severity and growth rate, are recommended. Aortic rupture and dissection are rare, with no evidence of increased risk at diameters ≤55 mm. Thus, diameter thresholds for prophylactic proximal aortic replacement as recommended for degenerative aneurysms may be appropriate, although data to establish specific thresholds are lacking (table 3).3 5

Pregnancy

Haemodynamic changes and hormone-induced aortic-wall weakening make pregnancy a period of increased risk for women with aortopathy. Risk of dissection is highest in the third trimester and peripartum period.3 In MFS, pregnancy is variably associated with increased aortic growth.89 98 Dissection risk may be increased, especially in those not receiving adequate preventative measures, but is low at aortic diameters <45 mm.89 99 Thus, proximal aortic diameter ≥45 mm should be a reasonable threshold for prophylactic surgery in MFS women contemplating pregnancy, in agreement with European guidelines2 (American guidelines advise aortic a diameter >40 mm as a threshold for prophylactic surgery).3 Risk is reportedly high in Loeys-Dietz22 and vascular Ehlers-Danlos syndrome,100 but data on pregnancy in non-MFS genetic aortopathies (table 2) are scarce. Pregnancy has not been associated with increased aortic growth rate or complication risk in BAV.101 In a large series of pregnancies in patients with repaired CoA, pregnancy was well tolerated, and no aortic dissection or rupture occurred. The effect of pregnancy on aortic diameter was not assessed.102 A systematic review of 2491 pregnancies in patients with CHD reported no aortic complications, suggesting pregnancy-associated aortic complications are rare.103 The main recommendations concerning the management of the proximal aorta in case of (desire for) pregnancy are presented in box 1.3 4 104

Box 1

Recommendations for the management of pregnancy (wish) in patients with aortopathy

  • PREGNANCY (WISH)

  • Counselling

    • Women with aortic dilatation and/or genetic aortopathy contemplating pregnancy should be counselled about the risk for aortic dissection and the hereditary nature of the disease. Pregnancy should be discouraged if aortic diameter has reached the threshold for prophylactic surgery (table 3). Prepregnancy aortic surgery should be considered*

  • Pharmacological treatment

    • Strict blood-pressure control is indicated

    • Start β-blocker therapy in women with genetic aortopathy syndrome, aortic dilatation and/or (history of) type B aortic dissection

    • Angiotensin receptor blockers/ACE inhibitors are contraindicated: switch to β-blockers as soon as contraceptives are stopped

  • Imaging

  • Prepregnancy

    • MRI (or CT) imaging of the entire aorta advisable

  • During pregnancy

    • Aortic root/ascending aortic dilatation and/or genetic aortopathy syndrome: transthoracic echocardiography per 4–8 weeks

    • Dilatation beyond distal ascending aorta: MRI (without gadolinium)

  • Aortic surgery

  • Prepregnancy

    • Prophylactic: aortic diameter =threshold for surgery (table 3)*

  • During pregnancy

    • Indications: type A dissection; type B dissection, if complicated by malperfusion or aortic rupture (otherwise, medical treatment with MRI monitoring); prophylactic, aortic diameter =50 mm with rapid growth

    • First/second trimester (=28 weeks), fetus not viable: aortic repair with intensive fetal monitoring

    • Third trimester (=29 weeks), fetus viable: urgent caesarean section directly followed by aortic surgery

  • DELIVERY

  • At centre where cardiothoracic surgery is available

  • Mode of delivery

    • Aortic root/ascending aortic diameter <40 mm: vaginal delivery favoured

    • Aortic root/ascending aortic diameter 40–45 mm: consider vaginal delivery with epidural anaesthesia and expedited second stage (eg, forceps, vacuum delivery) or caesarean delivery

    • Aortic root/ascending aortic diameter >45mm: consider caesarean delivery

  • Timing

    • Consider elective caesarean delivery in Loeys-Dietz syndrome, vEDS or non-syndromic familial thoracic aortic aneurysms and dissections and aortic dilatation

  • *Prophylactic surgery in vEDS is an undesirable option (tissue fragility, bleeding diathesis). In principle, pregnancy is contraindicated.

  • vEDS, vascular Ehlers-Danlos syndrome.

Sports/exercise

The 36th Bethesda Conference produced recommendations concerning competitive sports participation of patients with cardiovascular abnormalities. Specific task forces formulated recommendations for MFS, Ehlers-Danlos syndrome,105 BAV106 and CHD in general.107 The former three are presented in table 4, and we refer to Task Force 2 107 for the latter. No specific recommendations for CHD-associated aortopathy other than BAV exist. Importantly, all patients with thoracic aortic dilatation should avoid strenuous isometric and resistance exercises.4 108 In general, dynamic (endurance) sports are preferable. Task Force 3 provides recommendations regarding aortic regurgitation.106 Of note, the Bethesda Conference recommendations concern competitive sports and thus provide a framework for patient counselling on recreational sports participation: individual advice should be based on intended physical exertion, which should be adequately explored in the consult.

Table 4

Recommendations for competitive sports participation of patients with Marfan syndrome, EDSIV and bicuspid aortic valve

Future perspectives

Effective pharmacological therapies to prevent aortic dilatation in CHD-associated aortopathy and appropriate criteria for prophylactic aortic surgery are needed. Ongoing research has improved our knowledge of the pathophysiology of CHD-associated aortopathy, providing a basis for evaluation of potentially effective pharmacotherapies. However, trials of preventative pharmacotherapy for CHD-associated aortopathy are currently lacking. Given the histopathological similarities with MFS-associated aortopathy,1 completed and presently ongoing trials in patients with MFS87 may provide viable options for pharmacotherapies (particularly β-blockers, ARBs) to be studied in CHD-associated aortopathy. Longitudinal studies should further elucidate the natural history of CHD-associated aortopathy. Guidelines for the timing of prophylactic aortic surgery are currently based on absolute aortic diameter, which is an insufficient predictor of risk for dissection or rupture.73 Indexed diameters may improve identification of patients at risk,75 76 but other predictors, including aortic functional studies,40 77 78 and genetic and/or biochemical90 markers should be explored, and the premise of guidelines updated accordingly.

Summary and conclusions

Progressive aortic root and/or ascending aortic dilatation is frequently found in adults with repaired or unrepaired CHD, particularly in those with BAV, CoA, ToF and TGA after ASO. Routine follow-up of these patients with attention to aortic diameter is necessary. General cardiovascular risk-factor management—including blood-pressure control—is indicated. However, guidelines for the management of CHD-associated aortopathy are either based on expert consensus or lacking, as the pathophysiology and natural history of the disease are largely unknown. These issues are much better defined for the aortopathy associated with MFS, for which evidence-based guidelines are available. Importantly, CHD-associated aortopathy shows histological and functional similarities with MFS. As for MFS, decisions regarding prophylactic surgery are based on absolute aortic diameter and presence of additional risk factors for dissection or rupture. In the absence of evidence-based prophylactic pharmacotherapy, both β-blockers and ARBs may be appropriate in affected patients with CHD, following trials performed in patients with MFS. Future research is necessary to produce evidence-based guidelines for the follow-up and treatment of CHD-associated aortopathy. Completed and ongoing studies in patients with MFS may provide viable options for pharmacotherapeutic strategies to be tested in CHD-associated aortopathy.

Key messages

  • Aortic root and/or ascending aortic dilatation is frequently encountered in patients with repaired or unrepaired congenital heart disease (CHD) and is a common feature of certain genetic aortopathy syndromes, including MFS, vascular Ehlers-Danlos syndrome, Loeys-Dietz syndrome and Turner syndrome.

  • The natural history and pathophysiology of CHD-associated aortic dilatation are largely unknown. These issues are much better defined for MFS.

  • CHD-associated aortic dilatation likely results from an intrinsic aortic medial defect, which shows histopathological similarities with that found in MFS.

  • All patients with thoracic aortic dilatation and/or a genetic aortopathy syndrome require periodic follow-up of aortic diameters.

  • Transthoracic echocardiography is the imaging modality of choice for diagnosis and follow-up of aortic root/ascending aortic dilatation. MRI and CT provide better visualisation beyond the proximal ascending aorta. MRI is preferred over CT to minimise iatrogenic radiation exposure.

  • First-degree relatives of patients with a genetic aortopathy syndrome should be screened for the presence of aortic dilatation and/or the genetic defect.

  • The decision regarding prophylactic aortic surgery is based primarily on absolute aortic root/ascending aortic diameter. The diameter threshold for MFS is 50 mm, or 45 mm in the presence of factors increasing risk for dissection/rupture. Lower thresholds may be considered for the other genetic syndromes, based on individual risk profiles. The diameter threshold for prophylactic surgery in BAV is 55 mm, or 50 mm in the presence of risk-increasing factors. For other CHD types, data to establish specific aortic diameter thresholds for prophylactic aortic replacement are lacking; given the low incidence of aortic complications with aortic diameters <55 mm, the threshold of 55 mm established for degenerative aortic aneurysms may be appropriate.

  • Both β-blockers and angiotensin II type 1 receptor blockers (ARBs) have been tested as prophylactic agents to reduce aortic growth rate and the risk for aortic complications in MFS. There is currently no evidence favouring either, and either one (or a combination of both) may provide an appropriate strategy. Given the histopathological similarities with MFS, these agents may be considered as prophylactic therapy in CHD-associated aortopathy.

  • Pregnancy represents a period of increased risk for patients with aortic dilatation and/or a genetic aortopathy syndrome, which warrants adequate counselling and increased aortic surveillance. Especially patients with vascular Ehlers-Danlos and Loeys-Dietz syndrome are considered high-risk patients.

  • Sports and exercise, particularly strenuous isometric and resistance exercise, may increase risk of aortic rupture or dissection. Patients should be adequately counselled regarding the possibilities and restrictions.

Acknowledgments

The authors thank Dr Berto J Bouma for critically reviewing the manuscript.

References

  1. 1.
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9.
  10. 10.
  11. 11.
  12. 12.
  13. 13.
  14. 14.
  15. 15.
  16. 16.
  17. 17.
  18. 18.
  19. 19.
  20. 20.
  21. 21.
  22. 22.
  23. 23.
  24. 24.
  25. 25.
  26. 26.
  27. 27.
  28. 28.
  29. 29.
  30. 30.
  31. w31.
  32. w32.
  33. w33.
  34. w34.
  35. w35.
  36. w36.
  37. w37.
  38. w38.
  39. w39.
  40. w40.
  41. w41.
  42. w42.
  43. w43.
  44. w44.
  45. w45.
  46. w46.
  47. w47.
  48. w48.
  49. w49.
  50. w50.
  51. w51.
  52. w52.
  53. w53.
  54. w54.
  55. w55.
  56. w56.
  57. w57.
  58. w58.
  59. w59.
  60. w60.
  61. w61.
  62. w62.
  63. w63.
  64. w64.
  65. w65.
  66. w66.
  67. w67.
  68. w68.
  69. w69.
  70. w70.
  71. w71.
  72. w72.
  73. w73.
  74. w74.
  75. w75.
  76. w76.
  77. w77.
  78. w78.
  79. w79.
  80. w80.
  81. w81.
  82. w82.
  83. w83.
  84. w84.
  85. w85.
  86. w86.
  87. w87.
  88. w88.
  89. w89.
  90. w90.
  91. w91.
  92. w92.
  93. w93.
  94. w94.
  95. w95.
  96. w96.
  97. w97.
  98. w98.
  99. w99.
  100. w100.
  101. w101.
  102. w102.
  103. w103.
  104. w104.
  105. w105.
  106. w106.
  107. w107.
  108. w108.

Footnotes

  • Competing interests None declared.