Degenerative Aneurysm of the Ascending Aorta

Aneurysms of the ascending aorta are often caused by cystic medial degeneration (cystic medial necrosis). Histologically, necrosis and disappearance of muscle cells in the elastic lamina, and cystic spaces filled with mucoid material are often observed. Although these changes occur more often in the ascending aorta, they may affect any portion or the entire aorta. These changes weaken the arterial wall, which dilates and forms a fusiform aneurysm. The aortic root may be involved in this pathologic process, and in patients with Marfan syndrome, the aneurysm usually begins in the aortic sinuses. A large proportion of patients with aortic root aneurysms do not fulfill the criteria of diagnosis of Marfan syndrome, but the gross appearance of the aneurysm and the histology of the arterial wall may be indistinguishable from that of Marfan syndrome. These cases are referred to as forma frusta of Marfan syndrome. Patients with aortic root aneurysms are usually in their second or third decade of life when the diagnosis is made. Other patients have relatively normal aortic roots but develop ascending aortic aneurysms. These patients are usually in their fifth or sixth decade of life. Finally, certain patients have extensive degenerative disease of the entire aorta and develop the so-called mega-aorta syndrome with dilation of the thoracic and abdominal aorta.

Ascending aortic aneurysms tend to increase in size and eventually rupture or cause aortic dissection. The transverse diameter of the aneurysm is the most important predictor of rupture or dissection. In a study by Coady and associates¹⁰ of 370 patients with thoracic aneurysms (201 ascending aortic aneurysms), during a mean follow-up of 29.4 months, the incidence of acute dissection or rupture was 8.8% for aneurysms less than 4 cm, 9.5% for aneurysms of 4 to 4.9 cm, 17.8% for 5 to 5.9 cm, and 27.9% for those greater than 6 cm. The median size of the ascending aortic aneurysm at the time of rupture or dissection was 5.9 cm.

The growth rates of thoracic aneurysms are exponential.¹⁰ In the Coady study, the growth rate ranged from 0.08 cm/yr for small (<4-cm) aneurysms to 0.16 cm/yr for large (8-cm) aneurysms.¹⁰ The growth rates for chronic dissecting aneurysms were much higher than for chronic nondissecting aneurysms. Other studies found greater annual growth rates than the Coady group.^11,12 In addition, the growth rates for aortic root aneurysms may be different from those of ascending aortic aneurysms.

Most patients with aortic root or ascending aortic aneurysms are asymptomatic, and the aneurysm is usually found during routine chest radiographs, which show a widened mediastinum.¹³ Tracheal and esophageal displacement may be observed in the posterolateral view of the chest radiographs. Approximately one third of the patients complain of vague chest pain.¹³ In patients with a massive ascending aortic aneurysm, signs of superior vena cava obstruction may be present. If aortic insufficiency is present, there may be cardiac enlargement and the physical findings associated with it. The diagnoses of aortic root and ascending aortic aneurysm can be confirmed by echocardiography.

Transesophageal echocardiography is the best diagnostic tool to study aortic root aneurysm and the mechanism of aortic insufficiency. The echocardiographer should obtain information on each component of the aortic root, and particularly the aortic cusps. The number of cusps, their thickness, the appearance of free margins, and the excursion of each cusp during the cardiac cycle must be carefully observed. The coaptation areas of the cusps should also be investigated in multiple views and Doppler imaging recorded. Information regarding the morphologic features of the aortic sinuses, sinotubular junction, and ascending aorta is also important. The diameters of the aortic anulus, aortic sinuses, sinotubular junction, and ascending aorta should be obtained in multiple views. The lengths of the free margins of the cusps should be estimated if possible. The mechanism of aortic insufficiency can often be determined by transesophageal echocardiography. Dilation of the sinotubular junction is a common cause of aortic insufficiency in patients with ascending aortic aneurysm and normal aortic cusps. Dilation of the aortic anulus and of the sinotubular junction is usually the cause of aortic insufficiency in patients with aortic root aneurysm. Although fenestrations in the cusps are not easily seen with echocardiography, a regurgitant jet in a commissural area is suggestive of fenestration.

Computed tomography (CT) with intravenous contrast enhancement permits accurate evaluation of the extent and size of the aneurysm. Three-dimensional imaging techniques can provide additional information on the extensiveness and type of aneurysm (e.g., fusiform or saccular).

Magnetic resonance imaging (MRI) provides even more information than CT scanning because it visualizes the arterial wall and surrounding structures with greater contrast. In addition, it has been increasingly used in the diagnosis and management of patients with heart diseases.¹⁴ Magnetic resonance angiography (MRA) is replacing contrast angiography.¹⁵

Marfan Syndrome

Marfan syndrome is an autosomal dominant, variably penetrant, inherited disorder of the connective tissue in which cardiovascular, skeletal, ocular, and other abnormalities may be present to variable degrees. The prevalence is estimated to be around 1 in 5000 individuals. It is caused by mutations in the gene that encodes fibrillin-1 (FBN1) on chromosome 15. This is a large gene (approximately 10,000 nucleotides in the mRNA), and identification of the mutation is a complex task. More than 1000 mutations in FBN1 have been identified. The phenotype is highly variable because of varying genotype expression.

The clinical features of Marfan syndrome were thought to be caused by weaker connective tissues resulting from defects in fibrillin-1, a glycoprotein and principal component of the extracellular matrix microfibril. This concept was inadequate to explain the overgrowth of long bones, osteopenia, reduced muscular mass and adiposity and craniofacial abnormalities often seen in Marfan syndrome.¹⁶ Dietz and colleagues^16,17 showed in experimental mice with Marfan syndrome that many findings are the result of abnormal levels of activation of transforming growth factor β (TGF-β), a potent stimulator of inflammation, fibrosis, and activation of certain matrix metalloproteinases, especially matrix metalloproteinases 2 and 9. Excess TGF-β activation in tissues correlates with failure of lung septation, development of a myxomatous mitral valve, and aortic root dilation in mice.¹⁸ This combination of structural microfibril matrix abnormality, dysregulation of matrix homeostasis mediated by excess TGF-β, and abnormal cell–matrix interactions is responsible for the phenotypic features of Marfan syndrome.^16–18 Ongoing destruction of the elastic and collagen lamellae and medial degeneration result in progressive dilation of the aortic root, as well as in a predisposition to aortic dissection from the loss of appropriate medial layer support. Loss of elasticity in the media causes increased aortic stiffness and decreased distensibility.¹⁹

The diagnosis of Marfan syndrome is made on clinical grounds, and it is not always simple because of the variability in clinical expression (Table 67-1). A multidisciplinary approach is needed to diagnose and manage patients afflicted with this syndrome. The presence of major criteria in two separate systems and involvement of a third (minor or major) are needed to establish the diagnosis.²⁰

Table 67–1 Diagnostic Criteria^∗ for Marfan Syndrome (See text)

∗ The presence of major criteria in two separate systems and involvement of a third (minor or major) are needed to establish the diagnosis of Marfan syndrome.

The most common cardiovascular features are aortic root aneurysm and mitral valve prolapse. These anatomic abnormalities may cause aortic rupture, aortic dissection, aortic insufficiency, and mitral insufficiency.

Mitral valve prolapse is age dependent and more common in women. It is caused by myxomatous degeneration of the mitral valve apparatus, which is present in up to 80% of patients with Marfan syndrome, but only 25% of them develop mitral insufficiency. The posterior mitral anulus is grossly dilated in patients with mitral insufficiency, and it is often displaced posteriorly.²¹ The mitral anulus may also become heavily calcified and display a horseshoe appearance on radiographs.

The dilation of the aortic root is often progressive, and the rate of expansion, which varies somewhat, is usually less than 1 or 2 mm/yr. Shores and colleagues¹² randomized 70 patients with Marfan syndrome into propranolol-treated and placebo groups. The growth rates of the aortic root aneurysms in untreated patients were slightly more than three times those of patients who received β-adrenergic blockage. This study has been the scientific basis to treat these patients with a beta-blocker agent. Calcium antagonists and angiotension-converting enzymes have also been reported as effective in delaying aortic dilation, but at present, beta-blocker remains the drug of choice.²²

Aortic dissection is rare in patients with aortic root aneurysm of less than 50 mm, unless they have a family history of aortic dissection. The dissection in most patients starts at the level of the sinotubular junction (Stanford type A aortic dissection). In approximately 10% of patients, it starts just beyond the left subclavian artery (Stanford type B aortic dissection). Without surgery, most patients with Marfan syndrome die in their third decade, from complications of aortic root aneurysm such as rupture, aortic dissection, or aortic insufficiency.^23,24

Patients with Marfan syndrome should be followed at regular time intervals. Doppler echocardiography is the best diagnostic tool for monitoring changes in the mitral valve and aortic root. Patients with an aortic root greater than 40 mm should be followed with echocardiographic measurements twice yearly. MR images of the remaining thoracic and abdominal aorta should also be obtained when indicated.

Pregnancy in women with Marfan syndrome has two potential problems: the risk of having a child who will inherit the disorder and the risk of acute aortic dissection during the third trimester, parturition, or the first postpartum month. Offspring have a 50% risk of inheriting the syndrome. The risk of aortic dissection is less known, but it appears to be low in patients with normal aortic root and cardiac function.²⁵

Loeys-Dietz syndrome

Mutations in the genes encoding TGF-β receptors 1 and 2 have been found in association with a continuum of clinical features. On the mild end is a presentation similar to that of the Marfan syndrome, or familial thoracic aneurysm and dissection,^26,27 and on the severe end, there is a complex phenotype in which aortic dissection or rupture commonly occurs in childhood.²⁸ This complex phenotype is characterized by the triad of hypertelorism, bifid uvula (or cleft palate), and generalized arterial tortuosity with widespread vascular aneurysm and dissection. This phenotype has been classified as Loeys-Dietz syndrome.²⁹ Affected patients have a high risk of aortic dissection or rupture at an early age and at relatively small aortic diameters. CT angiograms should be obtained from the head to the pelvis. Surgery is recommended for adults when the aortic root exceeds 4 cm or the descending thoracic aorta exceeds 5 cm. If the craniofacial features are severe in children, surgery is recommended when the aortic root Z-score is greater than 3, or when the expansion is greater than 0.5 cm in 1 year.³⁰

Ehlers-Danlos Syndrome

The Ehlers-Danlos syndrome encompasses a group of heterogeneous connective tissue disorders that involve the skin and joints and cause hyperelasticity and fragility of the former and hypermobility of the latter. It may also involve the cardiovascular system. Vascular Ehlers-Danlos syndrome is a rare autosomal dominant inherited disorder of the connective tissue resulting from mutation of the COL3A1 gene encoding type III collagen.³¹ Affected individuals are prone to serious vascular, intestinal, and obstetric complications. These problems are rare during infancy but occur in up to 25% of affected persons before the age of 20 years and in 80% before the age of 40. Median survival is 48 years. Spontaneous rupture without dissection of large- and medium-caliber arteries such as the abdominal aorta and its branches, the branches of the aortic arch, and the large arteries of the limbs accounts for most deaths. Intestinal perforation, usually involving the colon, is less often fatal. Pregnancy is a high risk for women with this syndrome. Aortic root dilation was present in 28% in a series of 71 patients with Ehlers-Danlos syndrome.³² Aortic dissection is uncommon.

As with many rare diseases, delayed or incorrect diagnosis can lead to inadequate or inappropriate management. Diagnosis is based on clinical findings including specific facial features, thin translucent skin, propensity to bleeding, and rupture of vessels or viscera. Diagnosis can be confirmed by biochemical assays showing qualitative or quantitative abnormalities in type III collagen secretion, or by molecular biology studies demonstrating mutation of the COL3A1 gene. Varied molecular mechanisms have been observed with different mutations in each family. No correlation has been established between genotype and phenotype. Diagnosis should be suspected in any young person presenting with arterial or visceral rupture or colonic perforation. There is currently no specific treatment for this syndrome.

Bicuspid Aortic Valve Disease

Congenital aortic valve malformations include a phenotypic continuum of unicuspid valves (severe form), the various types of bicuspid aortic valves (moderate form), tricuspid valves (normal), and the rare quadricuspid valves.³³

Bicuspid aortic valve, the most common of these malformations, occurs in 1% to 2% of the population. Movahed and colleagues³⁴ recently reviewed 24,265 patients who had echocardiograms performed for various clinical reasons, and 1742 echocardiograms obtained by screening teenage athletes in Southern California, and found a prevalence of bicuspid aortic valves of 0.6% in the large cohort and 0.5% in the smaller one. Males are affected more than females at a ratio of 4:1. There is a relatively high incidence of familial clustering, which suggests an autosomal dominant inheritance with reduced penetrance.^35,36 However, it remains unproved that bicuspid aortic valve is an inherited disorder. Patients with bicuspid aortic valve usually have three aortic sinuses and two cusps of different sizes. The larger cusp, usually the one attached to the interventricular septum, contains a raphe, which probably represents an incomplete commissure. Bicuspid aortic valves with two cusps and two sinuses are far less common than bicuspid aortic valves with two cusps and three sinuses. Most patients with bicuspid aortic valves have a dominant circumflex artery and a small right coronary artery. Normally functioning bicuspid aortic valves may last the patient’s lifetime. Others become stenotic by the fourth or fifth decade of life. Aortic insufficiency may also occur, and it is often associated with dilated aortic anulus.³⁷ It is more common in younger patients, and it results from the prolapse of one cusp, usually the one that contains the raphe.

Both bicuspid and unicuspid aortic valves are often associated with premature degenerative changes in the media of the wall of the aortic root and ascending aorta.^38,39 These patients are at risk of developing chronic degenerative aneurysms of the ascending aorta and type A aortic dissection.⁴⁰

Atherosclerosis

Atherosclerosis of the ascending aorta and transverse arch is a common cause of stroke.^41,42 Sometimes, atherosclerosis can cause extensive calcification of the aortic root, ascending aorta, and transverse arch, which is often associated with coronary artery disease, stenosis of one or both coronary arteries orifices, and aortic valve stenosis. Extensive calcification of the ascending aorta is clinically described as “porcelain” aorta.^43,44

Atherosclerotic aneurysms of the ascending aorta are uncommon. They are more common in the abdominal aorta and to a lesser degree in the descending thoracic aorta. Atherosclerosis often causes irregular and saccular aneurysms of the ascending aorta rather than the more fusiform shape of those caused by degenerative disease of the media.