Aneurysmal dilatation of the aortic sinuses of Valsalva — beyond Marfan syndrome: a single centre experience and review of the literature

Abstract

Aneurysmal dilatation of the aortic sinuses of Valsalva has been most extensively documented in the setting of aortopathies, particularly Marfan syndrome. On the other hand, there is limited data in the literature about congenital sinus of Valsalva aneurysms outside this context. For the purpose of this review, we carried out a literature search on aneurysmal dilatation of the sinuses of Valsalva in Marfan syndrome, and compared this with congenital sinus of Valsalva aneurysms, also including data from a case series from our institution. In conclusion, there are differences in management of aortic dilatation in Marfan syndrome and congenital sinus of Valsalva aneurysms. Though less well-recognised, congenital aneurysms are often associated with significant morbidity and mortality and timely intervention is necessary.

Keywords

sinus of Valsalva aneurysms / Marfan syndrome / aortic dissection

Introduction

The aortic root is the segment of the aorta lying between the aortic valve and the sinotubular junction. The spaces lying between the three bulges in the aortic wall and the luminal surface of the aortic valve cusps constitute the sinuses of Valsalva (SoV). Two of these sinuses, most commonly the ones adjacent to the pulmonary valve, give rise to the right and left coronary arteries and are thus named the right and left coronary sinuses respectively. The third sinus is usually referred to as the non-coronary sinus. The sinuses of Valsalva are intrapericardial and lie in close proximity to all four cardiac chambers, the atrial and ventricular septa and the atrioventricular node [ 1].

Aneurysmal dilatation of the aortic root results from weakening of the aortic wall and can be due to congenital or acquired conditions. Congenital aneurysmal dilatation is seen in connective tissue disorders, which affect the elastic tissue, like Marfan syndrome, as well as in conjunction with a number of congenital heart defects, predominantly ventricular septal defects and bicuspid aortic valve. Acquired aneurysms can result from weakening of the aortic sinus walls by infection related to endocarditis on the aortic valve, inflammatory conditions like Behcet’s disease and syphilitic aortitis or trauma [ 2].

The clinical manifestations of SoV aneurysmal dilatation range from the entirely asymptomatic cases, which are detected incidentally during cardiac imaging, to patients who manifest with severe hemodynamic compromise due to rupture or dissection, which in turn is associated with a high mortality rate. Whereas aortic root dilatation at sinus level in the setting of aortopathies, particularly Marfan syndrome, is well-known and extensively studied, there is limited data in the literature regarding SoV aneurysms outside this context.

This review follows on from our published work on congenital SoV aneurysms [ 3]. In this series, we utilized data from the echocardiography and histopathology databases at the Royal Brompton Hospital. We included all cases of documented asymmetrical aneurysmal dilatation of at least one coronary sinus of Valsalva, with or without rupture or dissection, from about 1200 histopathology specimens and all ruptured SoV aneurysms detected on around 8000 digital adult echocardiograms between 2004 and 2012. We excluded symmetric aortic root dilatation involving all 3 sinuses and aneurysmal aortic dilatation of any type in patients with a confirmed diagnosis of Marfan syndrome. Clinical details and information on procedures and surgery were obtained from case notes.

Prevalence

The prevalence of Marfan syndrome is quoted at 2-3 per 10 000 [ 4]. It is however less clear what proportion of patients with Marfan syndrome have aortic root involvement. Congenital SoV aneurysms were first described by Hope et al. in 1839 [ 5]. As most documentation in the literature is in the form of case reports or surgical series, it is difficult to establish their true prevalence. They were found in 0.15%-3.5% of patients undergoing open heart surgery and in 0.09% of 8138 autopsy subjects [ 2]. They are commoner in men and in Eastern compared to Western countries [ 6- 8]. The right coronary sinus is the most commonly involved, followed by the non-coronary sinus [ 2, 9].

In our center’s series [ 3], we identified a total of 12 cases of congenital SoV aneurysms during the 8-year period under study. Eight cases were detected on echocardiography and 4 cases were identified among the histopathology specimens. These numbers might be somewhat higher than quoted in the general literature in view of the fact that our center offers an adult congenital heart disease service and the histopathology department is a specialist center for referral of heart specimen from sudden cardiac deaths. In line with the trends in the literature, we had a predominance of male cases (7/12) and the right coronary sinus was the most commonly involved (9/12), followed by the non-coronary sinus in 6 cases. Table 1 summarizes the details of these 12 patients, with case numbers in the text corresponding to it [ 3].

Etiology and histopathological characteristics

Marfan syndrome is an autosomal dominant connective tissue disorder caused by a mutation in the FBN-1 gene on chromosome 15q21 that codes for the extracellular matrix glycoprotein fibrillin-1. Over one thousand mutations in this gene have been identified to date. Up to 25%-30% of cases are the result of de novo mutations in the absence of a family history of the condition. The diagnosis of Marfan syndrome is based on clinical and genetic findings as outlined in the revised Ghent Criteria of 2010 [ 4]. Aneurysmal dilatation of the sinuses of Valsalva, defined as a Z score for the aortic root at the level of the sinuses of≥2 in patients over the age of 20 years (or Z score of≥3 in patients under age 20) is one of the major diagnostic criteria and also represents a main source of morbidity and mortality in these patients.

Congenital SoV aneurysms are often associated with other congenital cardiac defects, in particular ventricular septal defects (VSD), mostly perimembranous or doubly-committed, and bicuspid aortic valve. Sinus of Valsalva aneurysms have also been described in patients with Klippel-Feil syndrome [ 10, 11], cutis laxa [ 12], Treacher-Collins syndrome [ 13] and Takayasu’s arteritis [ 14]. This was reflected in our case series cohort with 5/12 patients having a concomitant congenital cardiac defect — two cases with a bicuspid aortic valve, two with a VSD and one with a history of resected subaortic stenosis. Another patient had Klippel-Feil syndrome [ 3].

Histologically, the aortic wall in Marfan syndrome shows fragmentation, disorganisation and loss of elastic lamina and replacement by material consisting of glucosaminoglycans [ 15]. Erdheim termed these changes “cystic medial necrosis” [ 16]. Though these changes are at times considered to be pathognomonic of Marfan syndrome, such degeneration of the aortic medial layer is evident in other forms of thoracic aneurysms. In fact, 3 of the cases of congenital SoV aneurysms from our series had cystic medial degeneration of the aortic wall on tissue histology. Cystic medial degeneration was widespread in cases 1 and 2, while in case 12, these changes were restricted to the sinuses of Valsalva, with the other sections of the aorta being histologically normal. In case 9, histology of sections from the aneurysm showed thinning of the wall with diffuse replacement of elastin by fibromyxoid connective tissue, while sections from the uninvolved aorta were normal. Histological information was also available for 2/7 patients (cases 4 and 5) who underwent surgical repair. In case 4, sections of the right coronary sinus of Valsalva aneurysm showed it to be lined by dense collagen with focal calcification and Lambl excrescence formation. Sections of the aortic wall away from the aneurysm showed focal disorganisation of the elastic layers with an increase in smooth muscle cells. In case 5, the fistulous connection resulting from the ruptured non-coronary sinus of Valsalva into the right atrium consisted of fibrous tissue at one end of which was a cystic nodule lined with histiocytes. Sections of aortic wall showed focal nodular medial and subintimal fibrosis but no cystic medial degeneration [ 3]. Figs. 1 and 2 below are postmortem images from cases 2 and 9 respectively.

Clinical presentation

Dilatation of the aortic root in Marfan syndrome often involves all three sinuses though the extent to which each sinus is involved can vary. More extensive involvement of the aorta can also be seen, and in some instances, there can be aneurysmal dilatation of other segments of the aorta with sparing of the sinuses [ 4]. Aneurysmal dilatation of the sinuses is not in itself a cause for symptoms and most cases are detected on routine echocardiographic assessment of patients who are being investigated for, or have been confirmed to have, Marfan syndrome. However, studies have shown that there is a correlation between the severity of aortic root dilatation and the risk of aortic dissection and/or rupture [ 17, 18]. Aortic dissection classically manifests clinically with acute severe chest pain that often radiates to the interscapular region and which can migrate as the dissection extends. Further clinical manifestations depend on the extent of dissection and associated end-organ involvement from extension of the dissection into branches of the aorta. Aortic dissection and/or rupture can also result in hemopericardium which can lead to cardiac tamponade which is often fatal if not treated promptly [ 19].

Progressive dilatation of the sinuses can also lead to functional aortic regurgitation, which in turn can result in symptoms of breathlessness and gradual decline in exercise capacity. Isolated aneurysmal sinus dilatation is not usually associated with clinical signs. In the presence of aortic regurgitation, there can be an early diastolic murmur along the lower left sternal edge, and, with progressive left ventricular dilatation, the apex beat can be displaced. Aortic dissection and/or rupture are often associated with tachycardia and hypotension, especially if associated with hemopericardium, and clinical deterioration can be rapid [ 19].

The symptoms associated with congenital sinus of Valsalva aneurysms are very varied and depend on the size of the aneurysm, the sinus/es involved, and the presence and severity of any associated rupture. As mentioned earlier, the right coronary sinus is the one most frequently affected followed by the non-coronary sinus [ 2]. Small non-ruptured SoV aneurysms are often asymptomatic and are diagnosed incidentally during echocardiographic imaging. Large aneurysms can cause symptoms by impinging on adjacent cardiac structures. Aneurysms arising from the right or left coronary sinuses can lead to stretching of the adjacent coronary artery and result in ischemia, infarction and cardiac arrhythmias [ 14, 20, 21]. Right ventricular outflow tract obstruction has also been reported [ 22, 23]. In our case series, there was only one patient with an unruptured SoV aneurysm (case 12 in Table 1) and he died suddenly, probably from cardiac ischemia and/or arrhythmia from stretching of the adjacent right coronary artery.

Frequently, the first manifestation of a SoV aneurysm follows rupture. Most commonly, ruptures occur into the right ventricle or the right atrium and result in the acute development of a large-volume left-to-right shunt. In such instances, patients usually present with symptoms of worsening heart failure and are often found to have a new continuous murmur on praecordial auscultation [ 24]. Rupture of the aneurysm into the pericardial space can also occur, resulting in hemopericardium and tamponade and is associated with a high mortality.

In our case series, worsening heart failure symptoms from aneurysm rupture was the commonest clinical manifestation (seen in 5 cases), followed by sudden death, mainly from aortic dissection/aneurysm rupture with associated hemopericardium (3 cases). One patient had an out of hospital cardiac arrest secondary to dissection. Only 2 cases of 12, or 16.7%, were entirely symptom free from their ruptured aneurysm. All patients with a ruptured aneurysm had a continuous murmur on cardiac examination [ 3]. The clinical manifestations of our patient cohort are summarized in Table 1.

Imaging

Transthoracic echocardiography is the main imaging modality for the diagnosis and follow-up of aneurysmal dilatation of the sinuses of Valsalva. It has the benefits of being non-invasive, relatively inexpensive and easily accessible. Measurements of the aorta should always be made parallel to the plane of the aortic valve. By convention, measurements should be taken at end-diastole and should include the thickness of one aortic wall (“leading edge to leading edge” technique). In the case of aortopathies like Marfan syndrome, it is advisable that the aortic root diameter is also compared to normal values for the patient’s age and body surface area by means of Z-score calculation [ 25]. Consistency in measuring the aortic root is of utmost importance during serial echocardiographic monitoring of patients with known aortic root dilatation, as the rate of growth and the absolute diameters are important parameters on which clinical decision-making relies. Measurements of the proximal ascending aorta from a parasternal long-axis view, transverse arch and proximal descending aorta from the suprasternal view and abdominal aorta from a subcostal view should also be made [ 26]. Two-dimensional echocardiography and color Doppler interrogation of the aortic valve to exclude or quantify the severity of any associated aortic regurgitation should also be performed. Assessment of the mitral valve and ventricular function are also important in Marfan syndrome in view of the association with mitral valve prolapse and cardiomyopathy. Transesophageal echocardiography can have provided better imaging of the aorta in cases of suspected aortic dissection [ 26].

Echocardiography is the imaging modality that initially detects the majority of SoV aneurysms, with Bricker et al. quoting that 90% (159 of 177) of SoV aneurysms reported in separate case reports in the literature were first diagnosed on transthoracic echocardiography [ 2]. On two-dimensional echocardiography, aneurysms are usually described as having a “wind-sock” appearance. The origin of the aneurysm and its relation to adjacent structures can also be demonstrated. Rupture of the aneurysm into a cardiac chamber is seen on color Doppler as a turbulent jet. Spectral Doppler interrogation of the jet shows a high-velocity continuous shunt across the cardiac cycle, which helps distinguish this from a ventricular septal defect, which is usually characterized by a high-velocity jet predominantly in systole. With large ruptures, Doppler interrogation in the descending aorta can also demonstrate diastolic flow reversal. Echocardiography is also helpful in looking for associated congenital cardiac abnormalities, particularly ventricular septal defects and bicuspid aortic valve.

Electrocardiogram-gated contrast computed tomography (CT) and magnetic resonance imaging (MRI) can provide more detailed delineation of the anatomy of sinus of Valsalva aneurysms and their relation to surrounding structures [ 2]. The European Society of Cardiology Guidelines on the Management of Grown-up Congenital Heart Disease (2010) recommends a CT or MRI on every patient with Marfan syndrome [ 26]. Both modalities have the added benefit of being able to image the entire length of the aorta to exclude aneurysmal dilatation away from the aortic root. They are also often required in the acute setting in patients suspected to have an aortic dissection, especially where the dissection flap starts distal to the aortic root, making it difficult to detect on echocardiography.

Echocardiography represented the main diagnostic imaging modality for detection of SoV aneurysms and associated complications in the 8 live patients in our case series. Additional diagnostic imaging modalities were only required in 2 cases — a transesophageal echocardiogram and cardiac CT in patient 3 (Figs. 3 and 4 below) and a cardiac MRI in case 6.

Management

While the management of aortic root dilatation in the context of Marfan syndrome has been well-defined, the optimal management of sinus of Valsalva aneurysms is less clear.

The management of aortic root dilatation in Marfan syndrome can be broadly subdivided into non-invasive and surgical management [ 27]. Regular echocardiographic assessment is necessary to assess increase in aortic root dimensions and establish the rate of growth. A yearly echocardiogram is advised in patients with stable aortic root diameters below 4.5cm; more frequent monitoring, usually at 6-monthly intervals is recommended when the sinuses are over 4.5cm in diameter [ 26, 27]. A baseline cardiac MRI is also recommended and then should be repeated every 5 years in stable patients with aneurysm formation restricted to the root but more frequently when the dilatation extends beyond the root [ 26].

Certain drugs are thought to help slow down the rate of increase in aortic root dimensions and improve survival, though the publications in the literature are conflicting. A number of publications support the beneficial effect of β-blockade in Marfan syndrome [ 28, 29], with Shores et al. showing a reduction of aortic root enlargement and associated complications (including aortic regurgitation and aortic dissection) both in adolescents and adults treated with propranolol [ 29]. On the other hand, a meta-analysis by Gersony et al. statistically analyzed 6 studies and concluded that there is no evidence that β blockers are of clinical benefit in Marfan patients [ 30]. More recently, angiotensin II receptor blockers (ARBs) have been investigated for their potential benefit in slowing down aortic root dilatation through their antagonistic effect to transforming growth factor β [ 31]. Following a multicenter randomized-controlled trial using losartan versus no additional treatment, Groenink et al. concluded that losartan reduces the rate of aortic root dilatation in adults with Marfan syndrome as assessed on MRI [ 32]. The effects of another ARB, irbesartan, on aortic root dilatation are currently being studied in the UK in the AIMS trial [ 33]. Medications need to be continued even after successful aortic root replacement to protect the remaining sections of the aorta. Patients need to have their blood pressure controlled very strictly, aiming for a systolic blood pressure under 120mmHg (and less than 110mmHg in case of history of aortic dissection) [ 26]. Marfan patients should be advised against aerobic exercise at maximal capacity, contact sports, competitive sports and, most importantly, isometric exercise. Affected individuals of child-bearing age also need to receive genetic counselling in view of the 50% chance of having affected offspring. It is also important to perform screening of all family members of patients with a confirmed diagnosis of Marfan syndrome [ 26].

Prophylactic surgical aortic root replacement is recommended in those patients with Marfan syndrome and a significant degree of aortic root dilatation. The ESC guidelines recommend prophylactic root replacement when (1) the maximal diameter of the root is≥50mm or (2) the aortic dimensions are between 46 and 50 mm in patients with a family history of dissection or those with severe aortic or mitral regurgitation needing surgery or in those with a rate of aortic dilatation of more than 2 mm/year or in women who want to become pregnant. In the absence of significant aortic regurgitation, a valve-sparing approach is usually recommended [ 26].

The management of SoV aneurysms in non-Marfan patients is much less clearly defined. Most material in the literature consists of either isolated case reports or surgical series relating to the repair of ruptured aneurysms [ 9]. Ruptured aneurysms with large-volume left-to-right shunts should be repaired promptly, either surgically or trans-catheter, to avoid deterioration of clinical symptoms. Because of the serious manifestations documented with unruptured sinus of Valsalva aneurysms, including sudden cardiac death, it would be intuitive to recommend surgical repair of large aneurysms even before they become clinically manifest, also considering the low operative risk quoted by experienced centers [ 9]. Though small unruptured SoV aneurysms can probably be managed conservatively, they still need echocardiographic follow-up to assess for increase in size, signs of rupture or accompanying aortic regurgitation. SoV aneuryms should be looked for specifically in patients with certain congenital heart lesions, particularly ventricular septal defects and bicuspid aortic valve.

All 8 live patients in our case series underwent repair of the SoV aneurysm — 7 had surgical excision of the aneurysm and repair of associated abnormalities and 1 patient (case 6) had percutaneous device closure of the ruptured sinus [ 3]. Of these 8 patients, 7 remain well to date, while 1 patient (case 3) needed aortic valve surgery for significant aortic regurgitation that progressed since his initial surgery.

Conclusions

Aneurysmal dilatation of the sinuses of Valsalva is most often thought of in the setting of aortopathies, with Marfan syndrome being the best characterized to date. However, we hope that this review and the data from our center’s case series helps make clinicians aware of congenital SoV aneurysms as an important, albeit, less common entity. We have shown that they are often associated with an underlying congenital cardiac defect, particularly VSDs and bicuspid aortic valve, and we would advise extra effort to pick up these defects on routine echocardiography. Caution should be taken not to miss the turbulent flow across small ruptured aneurysms particularly in the presence of turbulence across concomitant VSDs.

Because aneurysmal dilatation per se is often associated with no symptoms, we advise close monitoring by cardiac imaging, mainly in the form of serial transthoracic echocardiography. Correct and consistent measurement of the aortic diameter in cases of Marfan syndrome and other aortopathies is of utmost importance. Offline remeasurements on serial studies by the same experienced operator are often useful in instances where there is significant discrepancy in serial readings. Congenital SoV aneurysms that are being managed conservatively should also be imaged regularly to detect significant increases in size, the development of rupture or encroachment onto adjacent cardiac structures. In the absence of guidelines in the literature, we would recommend yearly echocardiographic follow-up for most aneurysms though larger aneurysms or those showing a rapid increase in size might have to be echoed more frequently.

While the correlation between increasing root dimensions and risk of dissection in Marfan syndrome is clearly set out in the literature, there is no data regarding size of congenital aneurysms and risk of complications. The data from our case series shows that the majority of these aneurysms carry a high morbidity, and possibly mortality, and thus we would advise early surgical intervention to resect larger aneurysms, ideally before they become symptomatic. As suggested by our case series, only small-volume chronic aneurysm ruptures are well-tolerated in the long-term. Thus most ruptured aneurysms should be dealt with early to avoid clinical deterioration which can be rapid.

Three of the 12 patients in our series developed acute aortic dissection, which was fatal in 2 cases and resulted in cardiac arrest in the third case. We feel that this highlights another possible complication of non-Marfan aneurysms which carries a high mortality and represents another reason while these aneurysms should not be taken lightly.

Compliance with epthics guideline

Maryanne Caruana, Mary N. Sheppard, and Wei Li all declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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