Heart, Lung and Circulation
Volume 17, Issue 5 , Pages 357-363, October 2008

Management of the Ascending Aorta in Patients with Bicuspid Aortic Valve Disease

  • Michael P. Vallely, PhD, FRACS

      Affiliations

    • The Baird Institute, Sydney, Australia
    • Corresponding Author InformationCorresponding author. Tel.: +61295502350.
    • ,
  • Christopher Semsarian, PhD, FRACP

      Affiliations

    • Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia
    • Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
    • Central Clinical School, Faculty of Medicine, University of Sydney, Sydney, Australia
    • ,
  • Paul G. Bannon, PhD, FRACS

      Affiliations

    • The Baird Institute, Sydney, Australia
    • Central Clinical School, Faculty of Medicine, University of Sydney, Sydney, Australia
    • Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital, Sydney, Australia

Received 14 September 2007; received in revised form 5 December 2007; accepted 23 January 2008.

Article Outline

Bicuspid aortic valve (BAV) disease is the most common form of congenital heart disease, affecting 1–2% of the population. Only 20% of patients will maintain normal valve function throughout their life and more than 30% of patients will develop serious morbidity. It is a highly heritable condition, with transmission likely to be autosomal dominant. Patients with BAV have a 10-fold risk of aortic dissection when compared to the normal population. Management of BAV associated aortopathy represents a significant clinical challenge.

Keywords: Bicuspid aortic valve, Aortic dissection

 

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Introduction 

Bicuspid aortic valve (BAV) disease occurs in 1–2% of the population.1, 2 It is the most common form of congenital heart disease, compared to 0.8% for all other forms combined, and also results in more morbidity than all other congenital heart disease combined.3, 4 BAV may be sporadic or familial, with a 4:1 male predominance.5

More than 35% of patients with BAV will develop serious complications including aortic dissection, endocarditis, aortic stenosis and aortic regurgitation requiring valve replacement.6 In patients older than age 15 years having aortic valve replacement, more than 50% of them will have BAV disease.7, 8

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Pathophysiology 

Bicuspid aortic valves are the result of abnormal aortic cusp formation during valvulogenesis. Adjacent cusps fuse to form a single aberrant cusp, larger than its counterpart, yet smaller than two normal cusps combined. The leaflets are usually oriented right to left with the true commissures oriented anterior and posterior. There can be significant morphological variability in the BAV.9, 10 Most commonly the right and left coronary leaflets comprise the larger fused leaflet and the non-coronary leaflet is separate with true commissures. The coronary arteries usually arise in front of the cusp with a raphe.6, 11 Bicuspid valves are likely to be the result of a complex developmental process, not simply the fusion of two normal cusps. Congenital aortic valve malformations may reflect a continuum of pathology. Unicuspid valves may represent a more severe form of bicuspid disease. This is reflected by earlier onset of aortic valve related symptoms and an 18-fold increased risk of aortic dissection when compared to case-matched controls.6, 12 Endocardial cushion defects and neural crest abnormalities may contribute to the severity of valvular and aortic complications in these patients.13

Only 20% of patients with a congenitally bicuspid aortic valve will maintain a normally functioning valve throughout life.1 More than 30% of patients will develop serious morbidity throughout their life. Patients may develop progressive calcification and stenosis. BAV disease is the major cause of pure aortic stenosis in most series.3, 14 Patients may develop pure regurgitation with or without infection (40–60% of severe aortic regurgitation in the BAV population is secondary to infective endocarditis).8 Thirty percent of patients with a BAV will develop endocarditis in their lifetime.3, 15 A bicuspid valve is present in 7–13% of unselected cases of aortic dissection.16, 17 Importantly, aortic dissection usually occurs in the presence of a normally functioning bicuspid aortic valve, having a 9–12-fold increased risk of Stanford Type A aortic dissection.18

Bicuspid aortic valves have a heterogenous presentation that is age related. While some patients will present early with symptoms of aortic valve disease (angina, dyspnoea and syncope) many patients will remain asymptomatic until late in life.19 Paediatric patients tend to present with aortic stenosis or endocarditis. Young adults present with pure aortic regurgitation, with or without endocarditis. There may be a subset of young patients with aortic regurgitation that may be at higher risk for aortic complications, including aortic root dilatation.20 Middle age adults present with aortic dilatation and/or aortic dissection or aortic stenosis. Elderly patients present with aortic stenosis.12

The nature of the valve lesion is different between patients. Importantly, the severity of the aortic disease is different according to the type of valve lesion. Patients with pure aortic incompetence have a higher rate of sinus dilatation than patients with stenotic disease.21 This group of patients represents approximately 15% of patients with BAV disease.1

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Genetics and Bicuspid Aortic Valve Disease 

Several family-based studies have shown that BAV disease, either alone or in combination with other cardiovascular malformations, can be inherited in families, and is therefore likely to have a genetic basis. Most family studies suggest inheritance is autosomal dominant, i.e. there is a 50% chance an affected person with BAV passing on the disease to his/her offspring.

In an echocardiography study of 50 patients with known BAV disease, Cripe et al. screened 309 patients (including relatives). Seventy-four patients (24% prevalence; 89% inheritance) had a BAV. Ninety-seven patients (31% prevalence) had a BAV and/or other congenital cardiac anomaly (74% inheritance). BAV disease was almost entirely genetic in this population with a pattern of inheritance suggestive of autosomal dominant transmission with variable penetrance.5

The specific genetic basis of BAV and the associated aortopathy has not been identified. Several family-based studies have identified chromosomal regions linked to disease without identification of the causative gene to date. In a genetic study of 10 families with BAV and aortic aneurysms, Goh et al. demonstrated linkages to chromosome 15 in 9 out of the 10 families.22 Most recently, Martin et al. have also identified three additional chromosomal loci (5, 13 and 18) linked to BAV associated with other cardiovascular malformations (but not aortopathy).23 More recently, McKellar et al. identified NOTCH 1 variants in 10% of patients with BAV and thoracic aortic aneurysms compared to only 2% of patients with TAV and thoracic aortic aneurysms.24

Collectively, based on family and genetic studies to date, the screening of at least first-degree and possibly second-degree relatives of patients with BAV disease should be considered.5

Bicuspid aortic valve disease is usually an isolated defect. However, 20–50% of patients will have an additional cardiovascular anomaly.25 Fifty percent of patients with coarctation of the aorta, and 30% with an interrupted aortic arch will have a BAV.26 Up to 30% of patients with an isolated VSD or Turner's syndrome will have a BAV.27 Bicuspid pulmonary valve disease is common and has implications for the Ross procedure.28, 29 Coronary anomalies are common (short left main coronary artery, 90% left dominant coronary anatomy) and have implications for surgery.30 Patients with congenital left ventricular outflow tract obstruction (Shone's complex and others) are likely to have relatives with BAV disease.31

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BAV Disease and the Aorta 

The exact cause of BAV disease remains unknown. It is clearly a complex developmental process rather than just a case of simple cusp fusion. Cardiac cushion deformities may affect the valve cusps, the aortic root and the ascending aorta. Neural crest abnormalities, deficiencies in endothelial derived nitric oxide synthase (eNOS), fibrillin-1 deficiencies and increased matrix metalloproteinase (MMP) levels and activity have all been implicated in the development of BAV disease and associated aortic abnormalities.6

The natural history of aortic rupture is clearly related to the size of the aorta. Elefteriades and co-workers have produced several articles showing increased rupture rates of the ascending aorta with aortic dimensions greater than 60mm.32 In a more recent article from the same authors, the natural history of patients (n=514) with ascending aortic aneurysms (>35mm) and tricuspid (n=451; 86.6%) or bicuspid aortic valves (n=70; 13.4%) were followed. Patients with BAV had higher growth rates (1.9mm per year) than patients with TAV (1.3mm per year). A significantly greater percentage of patients with BAV (78.8%) underwent replacement of their ascending aorta than patients with a TAV (44.8%; p<0.0001). The BAV patients were significantly younger than the TAV patients (48.9 vs. 63.1 years). BAV related aortic stenosis was a negative predictor for adverse aortic events.33

However, aortic dissection can (and often does) occur in patients with aortic dimensions well under 60mm. Type A aortic dissection is a catastrophic event, with a 75% two-week mortality without surgical treatment.34 However, the surgical management of acute type A dissection is improving. Recent Australasian data has shown dramatic improvements in the surgical management of acute type A dissection. Surgical mortality in the early 1970s was greater than 50%, whilst mortality after 2000 has reduced to 11%.35 This data compares very favourably with recent data from the International Registry of Acute Aortic Dissection which reports surgical mortality varying from 7% to 30% between surgeons and surgical centres.34, 36

In an autopsy study of patients with Type A aortic dissection Neri et al. examined 220 patients including 94 patients with a connective tissue disorder including BAV disease (mean aortic diameter, 41.8mm) and 126 without a connective tissue disorder (mean aortic diameter, 41.3mm). The authors demonstrated that aortic dissection occurred in one third of patients with a normal aortic diameter. Fifty-seven percent of patients had an aortic diameter greater than 40mm and only 10% of patients had a true aneurysm. The authors concluded that dissection super-imposing on near-normal aortic size might be an expression of functional wall changes other than dilatation.37

In an echo series of 139 patients with aortic dissection, Epperlein et al. demonstrated that 5/79 (6.3%) of patients with Type A dissection had a BAV, representing a nine-fold risk on the normal population. In contrast only 1/60 (1.7%) of the patients with a Type B dissection had BAV. This is highly suggestive that BAV may affect the ascending aorta preferentially.17

There are two broad theories as to the cause of aortic dilatation in patients with aortic valve disease. The first of these theories is that ascending aortic dilatation may be a consequence of blood flow turbulence. This is thought to disturb vascular endothelial cells, which leads to apoptosis and atherosclerosis in the aortic wall causing aortic dilatation.38 However, there is a growing body of evidence that suggests a common pathogenic mechanism underlying both bicuspid valve formation and its associated aortopathy. This evidence includes:

(1)Patients with haemodynamically normal BAV have larger aortic root and ascending aorta diameters than patients with normal tricuspid aortic valves.39

(2)BAV patients exhibit more histological abnormalities including cystic medial necrosis and apoptosis in the ascending aorta media than patients with tricuspid aortic valves.40

(3)A reduced extracellular matrix components and increased matrix degradation enzymes in the aorta of BAV patients.41, 42

(4)BAV disease has high heritability with determination being almost entirely genetic.5

(5)Ascending aortic dilatation can occur even after the valve is replaced, which is in contrast to patients with a tricuspid valve who demonstrate reduction in aortic size over time after replacement of their haemodynamically significant valve.43

Greater than 50% of patients with BAV will demonstrate aortic dilatation. In an echocardiography study, Gurvitz et al. compared 76 children with BAV to 41 normal controls. Aortic root dilatation was significantly increased in patients with BAV disease (with and without haemodynamically significant lesion aortic stenosis or regurgitation) when compared to the control group.44 In another echocardiography study, Ben-Dor et al. compared the ascending aorta of 88 patients with degenerative, rheumatic or bicuspid aortic stenosis to a group of control patients. Patients with BAV aortic stenosis had significantly larger ascending aortas than the other groups.45

In a large echocardiography-based series of 41,000 patients from the University of Pennsylvania (patients with aortic root pathology such as endocarditis and Marfan's syndrome were excluded), patients with BAV disease (118 after exclusions) were compared to the matched (for age and severity of the valve lesion) tricuspid valve controls. The degree of aortic dilatation in the BAV group was out of proportion to the severity of the valvular lesion.39

In an echocardiography-based study of 68 patients with BAV disease, with and without haemodynamically significant valvular lesions, Ferencik examined progressive dilatation of the aortic annulus, sinuses, sino-tubular junction and the proximal ascending aorta. Progression of aortic dilatation was independent of the presence of valvular dysfunction. The proximal ascending aorta showed an increased rate of dilatation when compared to the other sites. Therefore, it would appear that the proximal aorta is most vulnerable to dilatation in BAV disease and the proximal ascending aorta is the site of most type A dissections.46 This study has significance when examining the merits of replacing the whole aortic root or just the ascending aorta in patients with BAV disease.

Yasuda and co-workers compared patients undergoing aortic valve replacement for aortic stenosis. They demonstrated that patients with tricuspid valves who underwent aortic valve replacement had regression of their aortic dilatation, suggesting that post-stenotic dilatation in this setting has a predominantly haemodynamic pathogenesis. However, patients with BAV disease demonstrated progression of their aortic dilatation, irrespective of whether they had their valve replaced or not. This suggests an intrinsic abnormality of the aortic wall causing aortic dilatation in the BAV group.43

In a similar study by Russo et al., the authors compared 50 patients with BAV (mean aortic diameter, 48mm) undergoing AVR with 50 patients with TAV (mean aortic diameter, 36mm) undergoing AVR. In the BAV group, five patients suffered late aortic dissection and seven patients suffered late sudden death. There were no incidents of late-dissection or sudden death in the TAV group. The authors recommended an aggressive policy of replacing even normal looking ascending aortas in patients with BAV disease.47

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BAV and Other Aortic Anomalies 

The association with other aortic anomalies reflects the continuum of the aortic disease. In a study by Oliver et al. of 235 adults with coarctation, 57% of the patients had a BAV. Thirty-seven patients developed serious aortic complications. The prevalence of aortic complications in the BAV group was 22% compared to only 8% of the patients without a BAV. Aortic complications of BAV account for 86% of ascending aortic aneurysms and 70% of descending aortic aneurysms, with 80% of the patients with aneurysm recurrence at the coarctation repair site having a BAV. The combination of coarctation and BAV may represent a more extensive neural crest origin abnormality. Patients with both conditions co-existing should be treated more aggressively to prevent catastrophic aortic complications.48

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BAV and Marfan's Aortopathy 

Cystic medial degeneration is the pathological entity associated with BAV disease. Pathological observations include fragmentation and loss of elastic fibres, coagulative necrosis of medial smooth muscle, loss of cell nuclei and collapse of elastic lamellae and medial pooling of glycoprotein which leads to intramedial aortic dissection.49

While Marfan's disease has many features in common with BAV disease, there are many differences. Fibrillin-1 deficiency is a common defect. However, there are differences in the expression of the subtypes of MMP enzymes between the two conditions (MMP-2 in BAV, MMP-9 in Marfan's).42 The phenotypic expression is different. Marfan's patients tend to have aortic sinus dilatation, whilst BAV patients demonstrate dilatation above the sinotubular junction.50 Consequently aortic dissection occurs in 40% of patients with Marfan's and only 5% of patients with BAV. However, because BAV is far more common than Marfan's, BAV is the underlying pathology in more cases of aortic dissection.51

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Surgical Options for the Ascending Aorta in BAV Disease 

In the setting of abnormal valve function, aortic valve replacement is indicated. There are several options available to patients with ascending aortic dilatation in the presence of BAV disease. These include:

•Reduction aortoplasty, with or without wrap augmentation.

•Supra-sinus ascending aorta replacement.

•Ascending aorta replacement with sinus resection and remodelling.

•Valve sparing root replacement.

•Aortic root replacement with a valved conduit.
o.Mechanical valve.

o.Stented xenograft.
-Porcine.

-Pericardial.


o.Stentless xenograft.
-Porcine.


o.Allograft.

o.Pulmonary autograft (Ross procedure).


In a study from the Cleveland Clinic of 430 patients with a BAV, the risk of aortic dissection was 12.5% with an aortic size less than 50mm. Patients with Marfan's syndrome and an aortic diameter less than 50mm had a 15% risk of dissection, a rate not dissimilar to those with BAV aortopathy. The authors suggested that if all patients with an aortic diameter greater than 40mm had their ascending aorta replaced then 95% of dissections would be avoided.51

In a prospective study of 35 patients (20 patients with BAV) undergoing aortic valve replacement with aortic diameters greater than 40mm the authors noted that 5 patients had a subsequent aortic event. The recommendation arising from this paper is for all patients undergoing AVR with an ascending aorta greater than 40mm should have their ascending aorta replaced at the same time.52

In a study from Dr. Tirone David's group, 201 patients with BAV disease and ascending aorta less than 50mm undergoing AVR were followed. Patients with an aorta greater than 50mm had their aorta replaced. The study patients were divided into three groups:

(1)Aorta <40mm (normal aorta).

(2)Aorta 40–45mm.

(3)Aorta 45–50mm.

The authors noted that there was a significantly higher incidence of aortic complications at 15 years in the group of patients with aortas greater than 45mm (>45mm: 43%; 40–45mm: 78%; <40mm: 81% freedom from ascending aortic complications). This correlated with decreased survival in this group.53

Patients with connective tissue diseases that culminate in aortic pathology tend to be younger than those patients with atherosclerotic and/or hypertensive aortic pathology. Elective aortic procedures can be performed with low mortality in these groups. This is highlighted in a study of 675 patients undergoing elective aortic root replacement for Marfan's syndrome related aortic pathology in 10 high-volume aortic centres in North America. The elective mortality was 1.5% (7/455 patients) and the emergent mortality was 11.7% (12/103 patients). The eight-fold increase in mortality in the emergent group highlights the need for preventative surgery.54

Aortic root replacement using the modified Bentall approach with re-implantation of the coronary arteries as buttons is a reproducible procedure with excellent long-term results. In a European study of 72 aortic root replacements performed over 20 years, the authors reported a 0% elective (53/72) 30-day mortality and a 21% emergent (19/72) 30-day mortality. Long-term results included a 91% freedom from death at 16 years with 0% endocarditis, thrombosis, haemorrhage or structural valve deterioration.55 This study clearly demonstrates the benefits of elective surgery and the longevity achievable with a composite graft.

The relative preservation of the sinuses in the BAV aortopathy may indicate that replacement of the ascending aorta with or without sinus remodelling may eliminate the need for a formal aortic root replacement and its associated increased morbidity.51 In a 30-year review (1965–1995) by the Stanford group, patients undergoing treatment for aortic valve disease and aortic aneurysm or aortic dissection (n=390) with ascending aortic replacement (n=255) or aortic root replacement (n=135) were studied. The authors reported improvements in morbidity and mortality associated with aortic surgery in that time (15% for whole series, 7% for last decade). There have been even further improvements in the last decade.

The authors observed no differences in early or late mortality between the two groups. The seven patients in the ascending aorta replacement group who required re-operation for sinus of Valsalva aneurysms were noted to have gross sinus dilatation at the time of their initial operation. In this group of patients, the current recommendation would be to perform an aortic root replacement at the time of the initial operation. The authors also observed no difference in the two groups at early or late follow-up. However, they did recommend sinus resection with preservation of tongues of aorta around the coronary ostia for patients undergoing ascending aortic replacement.56

In a similar, smaller study of 45 patients, Sundt et al. demonstrated no difference in the management of patients with a haemodynamically significant BAV and associated dilated ascending aorta with a composite graft aortic root replacement or a valve and ascending aortic replacement.57

Reduction ascending aortoplasty is a controversial treatment for dilatation of the ascending aorta in the presence of aortic valve disease. In a recent study, the authors examined 68 patients with a mean aortic diameter of 50.9±7mm undergoing reduction aortoplasty. Only 10 patients in the study had BAV disease, which limits the power of the study. The authors suggested that BAV was not a predictor of late aortic events after reduction aortoplasty.58

However, in a recent review article on reduction aortoplasty, Robicsek made two important observations. Firstly, he recommended that the technique not to be used in patients with cystic medial degeneration, which is the pathology of the aortic dilatation seen in patients with BAV disease. Secondly, reduction aortoplasty does not eliminate the risk of type A dissection, that resection and replacement of the ascending aorta virtually does.59 Therefore, we should question the role of reduction aortoplasty in patients with BAV associated aortic dilatation.

Pulmonary autograft (Ross procedure) replacement of the aortic root for aortic root dilatation in the setting of BAV disease remains controversial. The incidence of bicuspid pulmonary valve disease is high in these patients.28 This has implications for long-term valve function and for dilatation of the pulmonary autograft.29 It is a procedure that should be used highly selectively and in high volume, specialised centres.

A “watch and wait” policy for patients with ascending aortas over 40mm in the setting of BAV disease exposes the patient to the risk of aortic dissection and to re-operative aortic surgery with its high mortality (particularly in the emergent setting).60

Aortic root and ascending aortic replacement after previous cardiac surgery remains a very challenging procedure with a high mortality. In high-volume centres, mortality has improved. In a recent North American series, the authors reported 147 patients who underwent re-operations on the ascending aorta and aortic root with a 5.4% mortality.61 However, this is contrasted with a recent European study of 56 patients undergoing aortic root replacement after previous surgical intervention on the aortic valve, aortic root or ascending aorta. The authors reported an in-hospital mortality of 17% in this series.62

In a recent European study of 73 patients undergoing re-operations on the ascending aorta or aortic root, the elective 30 day mortality was 8% whilst the emergent mortality was 35%.63 In a published series from our unit of patients having aortic root replacements after previous cardiac surgery, we reported an 11% (3/26) 30-day elective mortality with a 100% (6/6) emergent mortality.60 These two studies highlight the disparity between mortality associated with elective and emergent re-operative procedures on the ascending aorta and aortic root. The need for elective first time replacement of the ascending aorta or aortic root or a planned reintervention is vital in ensuring acceptable mortality figures in this group.

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Recommendations for Australian Surgical Practice 

Management of the aorta in bicuspid aortic valve disease remains controversial. Resection of the ascending aorta will eliminate the vast majority of patients from the risk of type A dissection. This risk must of course be balanced against the risk of aortic surgery. Data from the Australian Institute for Health and Welfare suggests that aortic root replacement, even in the elective setting, does not have the same low mortality as we see from the large volume North American units (5.6% vs. 1.5%).54, 64 Therefore, recommendations for the average volume unit in the Australian environment are needed.

The relative sparing of the aortic sinuses in bicuspid aortic valve disease and the proven long-term benefits of replacing the ascending aorta in patients with BAV disease may reduce the necessity of aortic root replacement in this setting.

In terms of clinical evaluation, the growing evidence for a familial genetic basis in BAV disease should warrant a thorough family history to be taken, and consideration of clinical screening of at least all first-degree relatives of the BAV affected patient.

Recommendations for the management of the BAV ascending aorta in the Australian environment are as follows.

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Normal Bicuspid Aortic Valve Function 

Patients with normal bicuspid aortic valve function should undergo ascending aortic replacement with sinus remodelling if the aorta is greater than 45mm in diameter. If the aortic sinuses are abnormal then the patient should undergo an aortic root replacement.

The mechanical valved conduit remains the gold standard for this procedure. However, consideration can be given for xenograft, homograft or valve sparing procedures to avoid Warfarin. Provision for safe re-do surgery, with closure of the pericardium or the use of a pericardial membrane, should be made in this setting.

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Abnormal Bicuspid Aortic Valve Function 

In the setting of abnormal bicuspid aortic valve function requiring aortic valve replacement we would recommend replacement of the ascending aorta if the aorta is greater than 40mm in diameter.

In the setting of normal aortic sinuses then a sinus remodelling ascending aortic replacement should be performed. In the setting of abnormal sinuses, then an aortic root replacement with a valved conduit should be performed.

Consideration should also be given to stratifying patients according to their valve lesion. For example, young patients with pure aortic incompetence have a much higher dissection risk and rate of root aneurysms and consideration should be given to elective root replacement in these patients, irrespective of the dimensions of the ascending aorta.

Endovascular treatment of the descending thoracic aorta in the acute and chronic setting is becoming more increasingly utilised. The role of endovascular techniques in the management of disease in the ascending thoracic aorta remains controversial. With future developments these techniques may become more widely applicable to the management of ascending aortic aortopathy.34

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Conclusion 

Bicuspid aortic valve disease remains a common condition seen in Australian cardiothoracic surgical practice. The associated aortopathy and predisposition to aortic dissection (with or without aortic dilatation) remains a challenging clinical problem.

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PII: S1443-9506(08)00040-1

doi:10.1016/j.hlc.2008.01.007

Heart, Lung and Circulation
Volume 17, Issue 5 , Pages 357-363, October 2008

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