Loeys–Dietz syndrome pathology and aspects of cardiovascular management: A systematic review

Abstract

Loeys–Dietz syndrome is an autosomal dominant genetic disorder which is associated with significant and often crucial vascular manifestations. This review is aimed to examine current evidence on pathophysiology and management of Loeys–Dietz syndrome in current era. A comprehensive electronic search was done to identify the articles that discussed all the aspects of Loeys–Dietz syndrome, combined key words and Medical Subject Headings (MeSH) terms were used. Relevant articles have been summarized in each relevant section. Loeys–Dietz syndrome is an autosomal dominant genetic disorder which has combined and multi-systemic manifestations. The increased breakdown of extracellular matrix predisposes an individual to developing aneurysms in the aortic tree which is undoubtedly the most significant complication of this disorder. Understanding the pathophysiology and natural history of Loeys–Dietz syndrome and regular surveillance is important to plan prophylactic interventions to prevent life-threatening aortic emergencies which can be fatal. Loeys–Dietz syndrome is an aggressive genetic condition that predisposes an individual to the development of life-threatening aortic aneurysms. Our understanding of Loeys–Dietz syndrome remains ever-changing and it is likely that the knowledge regarding its diagnosis and treatment will become more clearly defined in the coming years with deeper genetic studies.

Keywords

Aorta Loeys–Dietz aortic pathology

Introduction

Loeys–Dietz syndrome (LDS) is an autosomal dominant genetic disorder, characterized by a variety of clinical manifestations, namely the triad of tortuous arteries and aortic aneurysms, hypertelorism, and a bifid uvula or cleft palate.¹ The syndrome lies on a continuum which highlights its varying clinical course amongst sufferers. Until recently, classification of LDS consisted of two types which was based on its corresponding gene mutation (TGFBR1 and TGFBR2, respectively). Type 1 LDS mainly leads to craniofacial anomalies whereas these are largely absent in type 2, the latter having a more cutaneous involvement causing increased susceptibility to bruising, abnormal scarring, and transparent skin.² However, owing to the difficulty in ascertaining a subtype based on clinical features, the classification of the disease based on the type of gene mutation alone is a recommended approach. This classification has been updated to reflect the discovery of other genes which are detailed below. The presence of craniofacial features is linked to worsening aortic disease.² Due to this being predominantly a disorder of connective tissue, skeletal abnormalities such as craniosynostosis, scoliosis, pectus deformities, and talipes equinovarus are frequently observed.^1,3 Patients are also more likely to have amplified immune responses leading to features of atopy and gastrointestinal inflammation.⁴ However, the most concerning feature of LDS is its aggressive vascular disease progression marked by increasing aortic dilatation which inherently leads to a greater risk of acute aortic events.

Patients usually present in childhood, with a diagnosis based on a combination of the clinical manifestations, family history, and confirmation of specific genetic mutations. Due to the syndrome being part of a close family of connective tissue disorders, there may be diagnostic difficulty owing to the shared characteristics observed between LDS type 1 and Marfan syndrome (MFS) and LDS type 2 and Ehlers–Danlos syndrome. This is important in terms of management and prognosis as the initial clinical series demonstrated that median survival was lower in LDS (37 years) compared to MFS (70 years) and Ehlers–Danlos (48 years) syndrome.¹ Furthermore, patients with LDS are at risk of aortic dissections even at aortic diameters not normally known to cause such an event.¹ Favourably, LDS patients had a significantly less fatal complication rate post-surgery than those with Ehlers–Danlos syndrome (1.7% versus 45%).¹ Therefore, accurate genetic testing is clearly necessary in order to establish the correct diagnosis, especially when the phenotype shows a degree of overlapping with the aforementioned genetic disorders.

Due to the fatal nature of LDS if left untreated, there has been substantial research regarding the management of the condition. At present, there is no definitive cure and a multi-disciplinary approach involving cardiovascular surgeons, radiologists, and genetic counsellors is warranted. As with every newly described disorder there is a great deal of information that has yet to be discovered and present knowledge will naturally change following the results of future studies and novel therapies. Despite this, the current literature has advocated certain management options. This paper will review the management of patients with LDS, with a focus on prophylactic and acute intervention, endovascular repair, and joint thoracoabdominal aneurysm repair.

Methods and materials

Search strategy

A comprehensive literature search was done on PubMed, SCOPUS, Cochrane database, Google Scholar, and OVID to identify articles that discussed LDS, its pathophysiology and management of aortovascular aspect of LDS. This was done in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.⁵ Key words used were ‘Loeys-Dietz syndrome’, ‘LDS’, ‘Connective tissue disorder’, ‘Outcomes’, ‘aortovascular management’, ‘LDS pathophysiology’, ‘Vascular and connective tissue’, ‘LDS and aorta’, ‘Aortic syndrome and LDS’. The search terms were used as key words and in combination as MeSH terms to maximize the output from literature findings. A staged literature search was done, whereby a separate literature search was performed for each section within this article and all the relevant studies were identified and summarized separately. Papers that reported on many aspects of LDS were described in numerous sections of this review. The relevant articles are cited and referenced within each section separately. No limits were placed on publication time or language of the article. All the relevant articles were identified and screened by three authors; the results are summarized in a narrative manner within the text of this review.

Inclusion and exclusion criteria

Studies were included if they have discussed LDS and management of aortovascular aspect of LDS. Exclusion criteria were editorials, consensus documents, and commentaries.

Data extraction

All the relevant articles were identified and screened by two authors and any disagreements were resolved through team consensus or vote. Data were also extracted by two authors and was validated by the third author. The results are tabulated and then summarized in narrative manner in each section of this review.

Statistical analysis

It was not possible to conduct an appropriate meta-analysis because there were not enough research data amongst the studies on this subject.

Results

A total of 15 articles were selected for inclusion in this systematic review after screening (Figure 1). The characteristics of these included studies are summarized in Table 1.

Figure 1.

PRISMA chart of the literature search. LDS: Loeys–Dietz syndrome.

Table 1.

Summary of included articles.

Author	Country	Study type	Key findings
Aftab et al.⁶	USA	Retrospective	– No operative deaths in patients undergoing elective surgery (VSRR and Bentall).
Beaulieu et al.⁷	USA	Retrospective	– No reports of technical failures or perioperative complications in the endovascular group.Perioperative morbidity in those undergoing open repair was 11.8%. (Endovascular repair (23.5%), open repair (76.5%)).
Cleuziou et al.⁸	Scotland	Case Report	– 11 year old patient with LDS underwent successful VSRR.
Edelman et al.⁹	Australia	Case Report	– Initial endovascular management was successful in a 31 year old male patient with LDS.
Hughes¹⁰	N/A	Narrative Review	– Early and aggressive surgery is essential and well tolerated in LDS patients that are typically of a young age. – A VSRR technique is preferred for root replacement when feasible, as well as preventing late type A dissection.
Iba et al.¹¹	Japan	Retrospective	– Six patients who underwent elective surgery with VSRR had no major complications during hospital stay.
Jondeau et al.¹²	Worldwide	Retrospective	– Study recommends prophylactic surgery to be undertaken at an aortic diameter of 45 mm (males) and 40 mm (females) in those with TGFBR2 mutation/severe extra aortic features.
Loeys et al.¹	USA	Prospective	– Surgical intervention should be considered in children once the aortic diameter exceeds the 99th percentile for age and body surface area and once the diameter of the aortic valve annulus reaches 18 mm. – LDS patients who did not undergo surgical intervention died earlier.
Neri et al.¹³	Italy	Case Report	– Thoracic endovascular repair successfully excluded the aortic aneurysm. – A novel open hybrid approach was adopted leading to the successful repair of an 80 mm TAAA.
Patel et al.¹⁴	USA	Retrospective	– VSRR is a safe and reliable procedure for younger patients with LDS and has low risk of mortality, need for reintervention, and valve failure. – Recommendation that surgery should be performed on a child once the aortic annulus is greater than 20 mm so that adult-sized prosthesis can be accommodated.
Patel et al.¹⁵	USA	Retrospective	– 86.5% of patients who had VSRR as had subsequent reimplantation. Overall, 2.5% (2/79) of patients died peri-operatively (both had VSRR) and 24.7% (19/77) of patients required further intervention (VSRR (80.0%) and Bentall (20.0%)).
Rankin et al.¹⁶	USA	Case Report	– A 29 year old female with LDS recovered successfully after undergoing total aortic replacement.
Wang et al.¹⁷	USA	Case Report	– Endovascular repair was performed successfully on a male LDS patient who suffered from recurrent asymptomatic left femoral–popliteal aneurysms.
Williams et al.¹⁸	USA	Case Report	– Total aortic replacement was performed successfully on a 29 year old female with LDS.
Williams et al.¹⁹	USA and Belgium	Retrospective	– No operative or hospitalized deaths occurred. One patient required a permanent pacemaker after a complication following Bentall procedure (VSRR (18.3%) and Bentall (7.0%)).

LDS: Loeys–Dietz syndrome; TAAA: thoracoabdominal aortic aneurysm; TGFBR2: transforming growth factor (TGF) beta-receptor 2; VSRR: valve-sparing root replacement.

LDS is an autosomal dominant genetic disorder which has combined and multi-systemic manifestations. The increased breakdown of extracellular matrix (ECM) predisposes an individual to developing aneurysms in the aortic tree which is undoubtedly the most significant complication of this disorder. Understanding the pathophysiology and natural history of LDS and regular surveillance is important to plan prophylactic interventions to prevent life-threatening aortic emergencies which can be fatal.

Genetics

The primary genetic defect causing LDS was initially thought to be solely from heterozygous mutations in the genes encoding transforming growth factor (TGF) beta-receptor I (TGFBR1) and II (TGFBR2), discovered in 2005 (Figure 2).²¹ Since then, there have been findings of other genes implicated in the phenotypic spectrum of LDS such as SMAD2/3 and TGFB2/3. Much research has been carried out with regards to the initial genes. The type of gene, whether TGFBR1 or TGFBR2, has no bearing on the clinical severity of the disease although it is almost certain that the carrier will develop at least some of the clinical features in the future (nearly 100% positive predictive value).

Figure 2.

Diagram outlining TGFB/SMAD signalling pathway. Source: Reprinted from Dolivo et al.²⁰ SBE: Smad Binding Element; SMAD2/3: TGFβ: transforming growth factor beta.

It was first thought that either gene could cause both LDS types I and II; however, it is now thought that TGFBR1 and TGFBR2 target LDS type I and II separately.²² Moreover, the mutations arise de novo in three-quarters of patients with only one-quarter being passed on from an affected parent.⁵ SMAD3 mutations were first attributed to aneurysmal-osteoarthritis syndrome; however, they have now established themselves as a contributory element in the development of type III LDS. Similarly, TGFB2 mutations give rise to type IV and a combination of SMAD3 and TGFB3 results in type V. It is therefore apparent that the genetics behind this disease is more complex than initially thought. Interestingly, the aneurysmal effects of LDS are typically less pronounced in those who are susceptible to TGFB2/3 mutations and these mutations also show less penetrance. Different gene mutations give rise to extra-aortic features to varying degrees, for example those with TGFB3 do not have the characteristic arterial tortuosity whilst patients harbouring the SMAD3 mutation have been dealt an unfortunate hand with all manifestations of the disease present, according to comparisons drawn by one study.²³

TGF-beta signalling plays a significant role in vital cellular processes such as embryogenesis, tissue homeostasis, cell differentiation, inflammation, and vascular remodelling. Genetic mutations cause enhanced signalling of the TGF-beta pathway which subsequently leads to dysregulation in the processes that maintain vascular integrity. This potentiates ECM degradation and increases susceptibility to aortic dilatation and dissection as well as the other clinical features found in patients with LDS.²⁴ Histological analysis of aortic vasculature demonstrates abnormalities in the tunica media and greater collagen deposition.²

Imaging and surveillance

Two-thirds of LDS patients will reveal an aortic root aneurysm at baseline investigations and nearly all will show features of root dilatation. An additional one-fifth will already have had an aortic dissection once diagnosis has been established.² Therefore, the importance of early diagnosis, genetic counselling, and cardiovascular intervention for this syndrome cannot be emphasized enough due to its early mortality if left untreated (mean age at death being 26 years) and the increased incidence of complications such as uterine rupture in pregnancy.¹

Active surveillance of aortic root aneurysms will determine the rate of dilatation and the urgency to operate, especially with reported cases of dissection at relatively small aortic diameters (mean of 46 mm).¹ Unique to LDS, there have been cases of alarmingly fast aortic dilatation at >1 cm/year which highlights the importance of regular surveillance scans.²⁵ This, combined with the propensity for aneurysm dissection to suddenly occur in an otherwise asymptomatic patient, clearly demonstrates the need for established surveillance guidelines. To date, there are no official criteria for imaging at-risk or identified patients with LDS although certain cardiovascular organizations, such as the American Heart Association, have defined imaging guidelines for those with thoracic aortic aneurysms including patients with LDS. These guidelines recommend whole body imaging in all patients with LDS at diagnosis and six monthly afterwards.²⁶ MacCarrick et al.⁴ also set surveillance criteria and proposed further imaging on a yearly basis after diagnosis with subsequent imaging guided by rate of disease progression and severity.

Computerized tomography angiography (CTA) or magnetic resonance angiography (MRA) of the entire arterial tree is paramount as approximately 50% of LDS type 1 patients will have an aneurysm in the vessels distal to the aortic root.² Furthermore, 3D reconstruction of the arteries using these imaging modalities is of particular benefit to those with mutations in the TGFBR1/2, TGFB2, and SMAD3 genes as they show a higher susceptibility to arterial tortuosity.²³ It is important to highlight the fact that tortuosity is not a risk factor for aneurysm development although increased tortuosity of vertebral arteries has been linked with adverse cardiovascular outcome in children and young adults.⁴ These imaging modalities will also provide additional information regarding the tortuous arterial vessels in the head and neck, another hallmark of LDS. The decision to use CTA or MRA is influenced by several factors. Whilst both offer a highly detailed capture of the aorta and branch artery involvement, CT scanning is more readily available (beneficial in the acute setting), is not prevented by metallic implants or pacemakers, and has a shorter imaging duration whereas MRI scanning obviates the need for iodinated contrast or radiation.²⁶

Prophylactic surgery

Asymptomatic patients with evolving thoracic aneurysms, especially in those with LDS, should be periodically imaged to assess the rate of expansion so that timely surgical intervention can be performed. The decision to operate is based on a variety of factors such as aneurysm size, rate of growth, extent of extra-aortic features, family history, and genotype.^1,21 The European Society for Vascular Surgery (ESVS) and European Society of Cardiology (ESC) have both suggested thresholds for elective surgical intervention in patients with LDS. The ESVS suggests that patients should be considered for surgery if they have aortic root diameters of >40 mm, descending thoracic aortic diameters of >50 mm, and/or accelerated growth of the aneurysm at a rate of >5 mm/year.²⁷ The ESC recommends operating on patients once ascending aorta diameters reach ≥42 mm.²⁸ A large, international multicentre study carried out by Jondeau et al.¹² recommends prophylactic surgery to be performed at an aortic diameter of 45 mm in males and 40 mm in females who carry the TGFBR2 mutation or in patients who display a higher degree of extra-aortic features. In children, surgical intervention should be considered once the aortic diameter surpasses the 99th percentile for age and body surface area and as soon as the aortic valve annulus reaches 18 mm.¹ These criteria are not absolute and it is important to consider the fact that patients may experience aortic dissections at diameters lower than these thresholds, especially in those who have the TGFBR2 mutation.^1,12 Therefore, it may be sensible to offer prophylactic surgery in patients with diameters <40 mm. Early surgery may be justified in LDS due to a younger patient population who are generally able to withstand such a complex intervention.¹⁰ The degree of craniofacial abnormalities also correlates with the extent of aortic disease so that surgery may be offered to those with a more severe form of LDS type I as a means of prophylactic surgery.²⁸

Surgical intervention in the elective setting

Due to its relatively low complication rate at high-volume centres, elective surgery usually consists of performing an aortic valve-sparing root replacement (VSRR) which also obviates the need for post-operative anticoagulation (Figure 3). Several studies have been carried out to evaluate outcomes after prophylactic aortic surgery in patients with LDS. Aftab et al. recently reviewed 53 patients with LDS and demonstrated the safety of surgical repair in this patient cohort. There were no operative deaths after elective surgery, of which 57.6% (19/33) of these patients had VSRR.⁶ Similarly, Iba et al.¹¹ observed favourable outcomes in his review of 16 patients with LDS, where all six patients who had elective surgery did not suffer from any operative mortality. Patel et al.¹⁵ reviewed all patients with LDS at John Hopkins and found that 82.3% (65/79) of patients underwent an aortic root replacement, of which 80% (52/65) were valve-sparing. Overall, 2.5% (2/79) of patients died peri-operatively (both patients had VSRR operations) and 24.7% (19/77) of patients required further intervention. Despite LDS patients tolerating surgery well, there still remains a high rate of reintervention with two studies highlighting repeat operations in 33 and 10% of patients, respectively.^12,19 This study highlights the successful outcomes in this patient cohort whilst demonstrating the necessity for close surveillance post-operatively. Furthermore, surgeons have successfully performed total aortic replacements and recommend this approach as a means of combating the inevitable progression of the disease to the remaining aorta and the risk of a life-threatening aortic dissection.¹⁸,³⁰

Figure 3.

VSRR (a) remodelling, (b) reimplantation. Source: Reprinted from Beckerman and Chen.²⁹

By comparison, the valve replacement procedure first described by Bentall and De Bono³¹ has become well established in the field of aortic aneurysm repair and is performed more often than VSRR (Figure 4). The American Heart Association Guidelines recommend either procedure whereas the European Guidelines appear to favour VSRR if the patient has normal valve function.²⁶ A systematic review by Harky et al. compared VSRR to composite root replacement from 12 papers. Whilst the composite group had shorter aortic cross-clamp and bypass times, the hospital mortality rate was higher in this group (P = 0.002).³²

Figure 4.

Schematic representation of Bentall procedure.

Although challenging, surgical outcomes in selected paediatric patients with LDS have proven to be beneficial with one study stressing the importance of early intervention after its successful VSRR in an 11 month old infant.⁸ Patel et al.¹⁴ also reviewed the outcomes of LDS in children and found that VSRR was a safe and reliable procedure with no operative mortality and lower risk of reintervention than in adults. There have been also reports of thoracoabdominal aortic repair prior to VSRR in children although there still remains questions regarding when to operate and correct graft length in a developing child.³³ For example, Patel et al.¹⁴ recommend performing surgery in a child when the aortic annulus reaches 20 mm so that it can accommodate an adult-sized graft. Many complex decisions are to be made with regards to paediatric aneurysm repair and operative intervention must be timely, taking into account aneurysm diameter, rate of dilatation, and the function of the native valve. Certainly, there are advantages to employing valve-sparing techniques as this precludes the need for anticoagulation and lessens the risk of valve degradation over time. Nonetheless, the literature provides examples of young patients who have demonstrated successful outcomes with both the Bentall and aortic valve-sparing techniques.³⁴

As well as surgery, education about lifestyle changes is essential in the prophylactic management of LDS. For example, patients must avoid contact sports and should perform moderate physical activity, ensuring they do not exert themselves to failure. Optimizing treatment with prophylactic beta-adrenergic and angiotensin receptor blockade has also been proven to slow the rate of aneurysm progression as well as decrease the likelihood of post-operative aortic complications in patients with MFS, a finding which can be extrapolated to LDS.^35,36 Compared to the management of acute dissection, the decision to operate on a healthy, asymptomatic patient with a growing aneurysm is a difficult one to make. Nevertheless, elucidating the family history and offering baseline vascular investigations should be mandatory in those presenting with typical features of LDS to prevent diagnostic delay and ensure appropriate management.

Surgical intervention in the acute setting

Acute aortic syndrome (AAS) encompasses a triad of aortic disease processes, including aortic dissection, intra-mural haematoma, and penetrating aortic ulcer, that have the ability to cause significant haemodynamic compromise or death in the emergency setting.³⁷ These conditions usually have similar presentations and radiological findings hence are diagnosed at the time of operation. Stanford type A dissections represent a surgical emergency and require immediate discussion with the cardiothoracic team, whereas uncomplicated type B dissections can be managed medically by maintaining a low blood pressure and enforcing exercise restrictions.

Type A aortic dissections, if unoperated, has a high mortality rate of 50% within 48 h.²⁸ In LDS, it has been established that there is a greater propensity for aortic dissection with 20% of patients being diagnosed after aortic dissection has occurred.² Furthermore, the aortic aneurysms can occur at relatively small diameters.¹ Indeed, there have been reports of dissections at initial aortic diameters of 41 mm (23 year old female) and 42 mm (15 year old male), both patients requiring urgent surgical repair after failure of aggressive beta-blockade.^30,38 After all, the use of antihypertensives in patients with LDS is a temporary measure and will not reverse the malignant progression of the vasculopathy. As LDS is becoming more widely recognized, the literature suggests that total aortic replacement will become an established treatment method in both the prevention and treatment of patients presenting with AAS, especially due to the fact that these patients will likely require distal aortic operations in the future.^10,16,18 Aftab et al.⁶ reported 81.8% of patients who required multiple operations following a type 1 dissection, suggesting that a more aggressive total arch and/or root replacement at the time of aortic dissection would be more appropriate, a recommendation also held by Patel et al.³⁹ Growth of an aneurysm within the aortic dissection may also occur hence the need for regular imaging follow-up, with MacCarrick et al.⁴ recommending surveillance at 1, 3, 6, and 12 months then annually.

The operative technique for acute type A aortic dissection (ATAAD) can vary considerably from aortic root repair to total aortic arch replacement in highly selected individuals.⁴⁰ One study examined the short-term and midterm outcomes after VSRR and Bentall operations in 135 patients presenting with ATAAD, and found that operative mortality was lower in those who had VSRR compared to the Bentall group (3% versus 13%).⁴⁰

Role of endovascular stenting

Thoracic endovascular aneurysm repair (TEVAR) of both acute and uncomplicated type B aortic aneurysms has been widely discussed in the literature as a less invasive approach compared to conventional open repair, with TEVAR demonstrating less mortality, shorter hospital stay, and earlier return to normal activity.^41–43 However, the role of endovascular repair in patients with connective tissue disorders remains controversial. The ESC and European Association for Cardio-Thoracic Surgery (EACTS) issued a statement regarding their position on TEVAR in the management of connective tissue disease, overall recommending the open approach unless the patient meets specific criteria for TEVAR.⁴⁴ In patients with LDS, open repair is recommended over TEVAR as the latter may cause progressive aneurysm development at the landing/fixation zones of the native aorta or ongoing perfusion of the false lumen, resulting in graft failure.^6,13 The tortuous arteries that are characteristic of the genetic condition also make for a more challenging endovascular repair. As a result, endovascular repair is only advocated if the stent-graft devices are positioned within pre-existing grafts from previous vascular surgery. This was the case in one study which successfully performed a hybrid procedure involving both open and endovascular techniques in a 29 year old female with LDS.¹⁸ Furthermore, another series revealed that 23.5% (4/17) of operations were performed via an endovascular approach in nine patients with LDS who had enlarging descending aortic aneurysms.⁷ All of the endovascular interventions were well tolerated compared to 11.8% perioperative morbidity in those who had open repair. A large meta-analysis comprising of 12,399 patients were analysed by Ultee et al.⁴⁵ who concluded that there was a decline in mortality following the introduction of endovascular techniques for ruptured thoracic aortic aneurysms.

Given the ability for aneurysms to develop in areas distal to the aortic arch, there needs to be careful analysis of the whole arterial tree when imaging patients with LDS. Endovascular repair has been successfully performed on a gentleman with LDS who had recurrent asymptomatic left femoral–popliteal aneurysms.¹⁷ The stent lasted six years and reintervention was required due to the malignant nature of disease progression instead of treatment failure. Further studies demonstrated technical success with endovascular repair of internal mammary, bilateral iliac artery, and intracranial aneurysms, with excellent short-term results ranging from five months to two years.^46–48

It is clear that there is a role for endovascular repair in patients with LDS in the management of both aortic and peripheral aneurysms.^9,13,17 Ultimately, endovascular repair should be considered only in selected patients (those who have landing zones in previously sited grafts, are unable to tolerate open repair, or as a ‘bridging’ method until patients can be transferred to a centre that performs open repair) as recommended by ESC and EACTS and it seems more sensible to consider both the endovascular and open approach as complementary rather than antagonistic. Indeed, there are now cases of hybrid procedures involving both operative techniques. More studies with longer follow-up need to be performed in order to provide more definitive endovascular guidelines for these complex patients.

Management of thoracoabdominal aneurysms

Thoracoabdominal aortic aneurysms (TAAAs) represent a significant technical challenge and open repair is associated with a myriad of post-operative complications including renal failure, myocardial infarction, cerebrovascular events, and death.²⁷ The type of surgical intervention depends on the location of the aneurysm as initially classified by Crawford, with TAAAs from connective tissue diseases likely to fall under type II (aneurysms in the descending aorta up to the aortic bifurcation). It is therefore unsurprising that type II TAAAs are associated with higher mortality and complications. The mortality rates for open TAAA repair are variable, with one study demonstrating a 30-day mortality rate of 19.2 and 48.4% for elective and emergency repair whilst others have observed 30-day and one-year mortality rates of 2.8–8.2 and 11–16.5%, respectively.^49,50 Moulakakis et al.⁵¹ performed a systematic review and meta-analysis on the outcomes for open thoracoabdominal repair and found the pooled mortality rate to be 11.3%. Endovascular and hybrid techniques are becoming increasingly popular as a way to operate in octogenarians with significant co-morbidities who may be unfit for open repair. Indeed, the endovascular approach is known to have fewer post-operative complications but the trade-off is that these patients are likely to be met with more reinterventions further down the line.^52,53 Benrashid et al.⁵³ compared hybrid with open repair and, despite the former containing more elderly and frail patients, the in-hospital operative mortality was similar in both groups (9.9% versus 7.1%, P = 0.59). Similarly to endovascular repair, the hybrid repair group were subject to more reinterventions than open repair, primarily due to endoleak (12.3% versus 1.2%, P = 0.004).⁵³ Open repair is still ranked as the gold-standard by some authors, with Corvera et al.⁵⁴ recently advocating this approach given the low mortality, decreased reintervention rate, and good long-term survival in their analysis of patients who had repair of chronic TAAAs post aortic dissection.

As mentioned previously, LDS can cause relentless progression of aneurysms to the thoracoabdominal aorta and it is not uncommon to detect aneurysms in the renal or iliac arteries. It has also been established that patients who are subject to aortic root replacements (i.e. the majority of patients with LDS) have a risk of triggering downstream thoracoabdominal aneurysm formation. This adds to the aforementioned suggestion that prophylactic total aortic replacements should be the norm in patients who meet the criteria for VSRR. To date, there is a paucity of studies assessing the outcomes of TAAA repair in LDS and results are based on a few case reports. Neri et al.¹³ successfully performed the repair of an 80 mm TAAA in a 25 year old male using a novel hybrid approach. Hashizume et al.⁵⁵ also carried out both open and endovascular TAAA repair in a 41 year old female. Both cases involved a staged repair with an initial TEVAR followed by open repair of the distal aorta. Likewise, another hybrid approach has been trialled on a 29 year old female who required a combination of proximal and thoracoabdominal aortic repair. Inoue et al.³³ and Williams et al.⁵⁶ performed successful total aortic replacements (via open repair) in a 9 year old and 32 year old male who both had extensive thoracoabdominal disease. Despite the few studies in patients with LDS, many studies have assessed the outcomes of TAAA repair in MFS and, given the underlying similarities between the two disorders, it may be appropriate to generalize these findings to LDS.

Genetic counselling

Genetic counselling is the umbrella term used to describe a range of discussions regarding the nature and implications of a genetic disorder so that affected or at-risk individuals can make more informed decisions about their health and family planning. By identifying LDS sooner, through family screening, preventative treatment can be performed in a timely manner. Counselling prior to conception is vital to ensure couples are fully aware of the 50% transmission risk to children (if one parent is affected) and subsequent management options. During pregnancy, prenatal diagnosis of LDS can be achieved by chorionic villus sampling or amniocentesis.⁴ Due to the lack of clear guidelines, an expert consensus has developed recommendations for genetic counselling for patients who have, or are likely to have, a cardiogenetic condition. They propose that in patients with diagnosed thoracic aortic aneurysms, risk factors such as large aortic diameter, positive family history of dissection, and dysmorphic features should be carefully evaluated to determine the presence of an underlying genetic condition.⁵⁷ Indeed, there is an association between a positive family history and subsequent increased risk of aortic dissections amongst family members which highlights the necessity for family screening.⁵⁸

The ESC recommends offering genetic testing to all first-degree relatives of an affected individual who has a confirmed mutation. In those who have no evidence of a mutation, their first-degree relatives who have any of the aforementioned risk factors should be screened.²⁸ Transthoracic echocardiogram (TTE) is the imaging modality of choice for family screening as it is inexpensive and easily accessible. The whole arterial tree should be imaged in patients with LDS as the condition can cause aneurysms in the other areas of the vasculature.² MRI and CT scanning, although both a major radiation risk, should be performed in the initial screening to ensure any aneurysms missed by TTE are detected. With regards to the timeline of screening, the expert consensus suggests an interval of 5 years (or 10 years in stable aneurysms) from the age of 25 years until 65 years. If the affected patient is less than 25 years of age, screening of other family members should start 10 years below the affected patient’s age.⁵⁷

Future research

The relatively recent discovery of LDS combined with its low incidence has caused the disease to become an area of constantly evolving research. For example, there have been numerous advances in the role of genetics, particularly the recognition of SMAD2/3 and TGFB2/3, which facilitates more accurate diagnosis of the LDS subtype and consequently optimizing patient management. There will inevitably be breakthroughs regarding the discovery of genetic mutations in the future which will helpfully broaden the phenotypic spectrum of the disease. Imaging guidelines have been produced which aim to establish a consensus with regards to surveillance screening. Future research should be directed towards establishing clearer and more universal surveillance imaging guidelines due to the malignant progression of aneurysm dilatation. As stressed previously, early detection and consistent surveillance is warranted in order to aid operative decision making. Lastly, aortic operative techniques have been subject to much scrutiny as these are all known to be high-risk, complex procedures. However, the low incidence of LDS means that large studies are difficult to carry out, especially in determining outcomes after ATAAD in LDS patients. The data from ATAAD management does not specifically evaluate outcomes for LDS and more studies are needed to help guide management options in the acute setting.

Conclusion

LDS is an aggressive genetic condition that predisposes an individual to the development of life-threatening aortic aneurysms. Our understanding of LDS remains ever-changing and it is likely that the knowledge regarding its diagnosis and treatment will become more clearly defined in the coming years.

Footnotes

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Amer Harky

References

Loeys

Schwarze

Holm

, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006; 355: 788–798.

Van Hemelrijk

Renard

Loeys

The Loeys-Dietz syndrome: an update for the clinician. Curr Opin Cardiol 2010; 25: 546–551.

Kirmani

Tebben

Lteif

, et al. Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome. Am J Med Genet A 2010; 152A: 1016–1019.

MacCarrick

Black

3rd Bowdin

, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med 2014; 16: 576–587.

Moher

Liberati

Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535.

Aftab

Cikach

Zhu

, et al. Loeys-Dietz syndrome: intermediate-term outcomes of medically and surgically managed patients. J Thorac Cardiovasc Surg 2019; 157: 439–450.e5.

Beaulieu

Lue

Ehlert

, et al. Surgical management of peripheral vascular manifestations of Loeys-Dietz syndrome. Ann Vasc Surg 2017; 38: 10–16.

Cleuziou

Eichinger

Schreiber

, et al. Aortic root replacement with re-implantation technique in an infant with Loeys-Dietz syndrome and a bicuspid aortic valve. Pediatr Cardiol 2010; 31: 117–119.

Edelman

Ramponi

Bannon

, et al. Familial aortic aneurysm and dissection due to transforming growth factor-beta receptor 2 mutation. Interact Cardiovasc Thorac Surg 2011; 12: 863–865.

10.

Hughes

GC.

Aggressive aortic replacement for Loeys-Dietz syndrome. Tex Heart Inst J 2011; 38: 663–666.

11.

Iba

Minatoya

Matsuda

, et al. Surgical experience with aggressive aortic pathologic process in Loeys-Dietz syndrome. Ann Thorac Surg 2012; 94: 1413–1417.

12.

Jondeau

Ropers

Regalado

, et al. International registry of patients carrying TGFBR1 or TGFBR2 mutations: results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 2016; 9: 548–558.

13.

Neri

Tommasino

Tucci

, et al. A complex thoracoabdominal aneurysm in a Loeys-Dietz patient: an open, hybrid, anatomic repair. Ann Thorac Surg 2010; 90: e88–e90.

14.

Patel

Alejo

Crawford

, et al. Aortic root replacement for children with Loeys-Dietz syndrome. Ann Thorac Surg 2017; 103: 1513–1518.

15.

Patel

Crawford

Magruder

, et al. Cardiovascular operations for Loeys-Dietz syndrome: intermediate-term results. J Thorac Cardiovasc Surg 2017; 153: 406–412.

16.

Rankin

Braverman

Kouchoukos

NT.

Total aortic replacement in Loeys-Dietz syndrome. Ann Thorac Surg 2009; 87: 1949–1951.

17.

Wang

Kernodle

Hicks

, et al. Endovascular repair of tortuous recurrent femoral-popliteal aneurysm in a patient with Loeys-Dietz syndrome. J Vasc Surg Cases Innov Tech 2018; 4: 156–159.

18.

Williams

McCann

Hughes

GC.

Total aortic replacement in Loeys-Dietz syndrome. J Card Surg 2011; 26: 304–308.

19.

Williams

Loeys

Nwakanma

, et al. Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. Ann Thorac Surg 2007; 83: S757–S763.

20.

Dolivo

Larson

Dominko

Fibroblast growth factor 2 as an antifibrotic: antagonism of myofibroblast differentiation and suppression of pro-fibrotic gene expression. Cytokine Growth Factor Rev 2017; 38: 49–58.

21.

Arslan-Kirchner M, Epplen JT, Faivre L, et al. Clinical utility gene card for: Loeys-Dietz syndrome (TGFBR1/2) and related phenotypes. Eur J Hum Genet 2011;1 9(10): doi:10.1038/ejhg.2011.68.

22.

Takeda

Yagi

Hara

, et al. Pathophysiology and management of cardiovascular manifestations in Marfan and Loeys-Dietz syndromes. Int Heart J 2016; 57: 271–277.

23.

Schepers

Tortora

Morisaki

, et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum Mutat 2018; 39: 621–634.

24.

Jones

Spinale

Ikonomidis

JS.

Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. J Vasc Res 2009; 46: 119–137.

25.

Kuzmik

Sang

Elefteriades

JA.

Natural history of thoracic aortic aneurysms. J Vasc Surg 2012; 56: 565–571.

26.

Hiratzka

Bakris

Beckman

, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease. J Am Coll Cardiol 2010; 55: e27–e129.

27.

Riambau

Bockler

Brunkwall

, et al. Editor’s choice – management of descending thoracic aorta diseases: clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2017; 53: 4–52.

28.

Erbel

Aboyans

Boileau

, et al. 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The task force for the diagnosis and treatment of aortic diseases of the European Society of Cardiology (ESC). Eur Heart J 2014; 35: 2873–2926.

29.

Shimizu H, Yozu R. Valve-sparing aortic root replacement. Ann Thorac Cardiovasc Surg 2011; 17(4): 330–336.

30.

Suh

Kwon

Kim

, et al. A case of near total aortic replacement in an adolescent with loeys-dietz syndrome. Korean Circ J 2012; 42: 288–291.

31.

Bentall

De Bono

A technique for complete replacement of the ascending aorta. Thorax 1968; 23: 338–339.

32.

Harky

Fok

Froghi

, et al. Valve-sparing aortic root repair compared to composite aortic root replacement: a systematic review and meta-analysis. J Heart Valve Dis 2017; 26: 632–638.

33.

Inoue

Minatoya

Oda

, et al. Total aortic replacement for a 9-year-old boy with Loeys-Dietz syndrome. Ann Thorac Surg 2016; 101: 1185–1188.

34.

Augoustides

JGT

Plappert

Bavaria

JE.

Aortic decision-making in the Loeys-Dietz syndrome: aortic root aneurysm and a normal-caliber ascending aorta and aortic arch. J Thorac Cardiovasc Surg 2009; 138: 502–503.

35.

Isekame

Gati

Aragon-Martin

, et al. Cardiovascular management of adults with Marfan syndrome. Eur Cardiol 2016; 11: 102–110.

36.

Habashi

Judge

Holm

, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312: 117–121.

37.

Corvera

JS.

Acute aortic syndrome. Ann Cardiothorac Surg 2016; 5: 188–193.

38.

Lee

Fazel

Schwarze

, et al. Rapid aneurysmal degeneration of a Stanford type B aortic dissection in a patient with Loeys-Dietz syndrome. J Thorac Cardiovasc Surg 2007; 134: 242–243, 243.e1.

39.

Patel

Arnaoutakis

George

, et al. Valve-sparing aortic root replacement in Loeys-Dietz syndrome. Ann Thorac Surg 2011; 92: 556–560.

40.

Harky

Bashir

Antoniou

, et al. The changing surgical approach to acute type A aortic dissection. J Vis Surg 2018;4 :151. doi: 10.21037/jovs.2018.07.05.

41.

Stone

Brewster

Kwolek

, et al. Stent-graft versus open-surgical repair of the thoracic aorta: mid-term results. J Vasc Surg 2006; 44: 1188–1197.

42.

Mitchell

Rushton

Jr Boland

, et al. Emergency procedures on the descending thoracic aorta in the endovascular era. J Vasc Surg 2011; 54: 1298–1302.

43.

Biancari

Mariscalco

Mariani

, et al. Endovascular treatment of degenerative aneurysms involving only the descending thoracic aorta: systematic review and meta-analysis. J Endovasc Ther 2016; 23: 387–392.

44.

Grabenwoger

Alfonso

Bachet

, et al. Thoracic endovascular aortic repair (TEVAR) for the treatment of aortic diseases: a position statement from the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2012; 33: 1558–1563.

45.

Ultee

KHJ

Zettervall

Soden

, et al. The impact of endovascular repair on management and outcome of ruptured thoracic aortic aneurysms. J Vasc Surg 2017; 66: 343–352.e1.

46.

Ohman

Charlton-Ouw

Azizzadeh

Endovascular repair of an internal mammary artery aneurysm in a patient with Loeys-Dietz syndrome. J Vasc Surg 2012; 55: 837–840.

47.

Casey

Zayed

Greenberg

, et al. Endovascular repair of bilateral iliac artery aneurysms in a patient with Loeys-Dietz syndrome. Ann Vasc Surg 2012; 26: 107.e5-10.

48.

Levitt

Morton

Mai

, et al. Endovascular treatment of intracranial aneurysms in Loeys-Dietz syndrome. J Neurointerv Surg 2012; 4: e37.

49.

Coselli

LeMaire

Preventza

, et al. Outcomes of 3309 thoracoabdominal aortic aneurysm repairs. J Thorac Cardiovasc Surg 2016; 151: 1323–1337.

50.

Conrad

Crawford

Davison

, et al. Thoracoabdominal aneurysm repair: a 20-year perspective. Ann Thorac Surg 2007; 83: S856–S861.

51.

Moulakakis

Karaolanis

Antonopoulos

, et al. Open repair of thoracoabdominal aortic aneurysms in experienced centers. J Vasc Surg 2018; 68: 634–645.e12.

52.

Oderich

Ribeiro

Reis de Souza

, et al. Endovascular repair of thoracoabdominal aortic aneurysms using fenestrated and branched endografts. J Thorac Cardiovasc Surg 2017; 153: S32–S41.e7.

53.

Benrashid E, Wang H, Andersen ND, Keenan JE, McCann RL, Hughes GC. Complementary roles of open and hybrid approaches to thoracoabdominal aortic aneurysm repair. J Vasc Surg 2016; 64(5):1228–1238. doi:10.1016/j.jvs.2016.04.022.

54.

Corvera

Copeland

Blitzer

, et al. Open repair of chronic thoracic and thoracoabdominal aortic dissection using deep hypothermia and circulatory arrest. J Thorac Cardiovasc Surg 2017; 154: 389–395.

55.

Hashizume

Shimizu

Honda

, et al. Stepwise total aortic repairs with fenestrated endografts in a patient with Loeys-Dietz syndrome. Ann Thorac Surg 2017; 104: e39–e42.

56.

Williams

Wechsler

Hughes

GC.

Two-stage total aortic replacement for Loeys-Dietz syndrome. J Card Surg 2010; 25: 223–224.

57.

Verhagen

JMA

Kempers

Cozijnsen

, et al. Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives. Int J Cardiol 2018; 258: 243–248.

58.

Chou

Mok

SCM

, et al. Positive family history of aortic dissection dramatically increases dissection risk in family members. Int J Cardiol 2017; 240: 132–137.