Surgery of the Aortic Root and Ascending Aorta

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 approximately 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 messenger RNA), 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 FBN1, 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. Dietz and colleagues 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. 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. 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.

The main features of Marfan syndrome include disproportionate long bone overgrowth, ectopia lentis and aortic root aneurysm. Diagnosis is not always simple, and a multidisciplinary approach is needed to diagnose and manage patients with this autosomal dominant disorder. In 1996, a panel of experts developed the “Ghent criteria” for the diagnosis of Marfan syndrome. Table 67-1 shows the original Ghent criteria, which contain a set of “major” and “minor” manifestations in various organs including cardiovascular, ocular, skeletal, pulmonary, dura mater, and skin. The presence of major criteria in two separate systems and involvement of a third (minor or major) was needed to establish the diagnosis of Marfan syndrome. Using these criteria, a high proportion of patients diagnosed as Marfan are found to have FBN1 mutations. However, some manifestations contained in the Ghent criteria are age dependent, and there are patients with skeletal abnormalities and ectopia lentis without aortic root aneurysm, even in the presence of FBN1 mutations. Experts in this area got together again and developed a “Revised Ghent Nosology for the Marfan Syndrome” ( Box 67-1 ) which emphasizes aortic root aneurysm, ascending aortic dissection and ectopia lentis.

The most common cardiovascular features of Marfan syndrome 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 is 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 annulus is grossly dilated in patients with mitral insufficiency, and it is often displaced posteriorly. The mitral annulus can 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 colleagues 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 β-blocker agent. Calcium antagonists and angiotension-converting enzymes have also been reported as effective in delaying aortic dilation, but at present, β-blocker remains the drug of choice. A prospective randomized clinical trial showed that losartan is effective in reducing the rate of aortic root dilation in patients with Marfan syndrome, and it reduces the rate of dilation of the arch after aortic root replacement. The combination of losartan with a β-blocker was more effective in preventing dilation of the aortic root than β-blocker alone in a small, randomized trial in children.

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). Surgery of the aortic root is recommended when the transverse diameter of the aortic sinuses reaches 50 mm. In patients with family history of dissection, surgery should be considered when the diameter reaches 45 mm. 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. In approximately 10% of patients, the dissection starts just beyond the left subclavian artery (Stanford type B aortic dissection).

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. MRI of the remaining thoracic and abdominal aorta should also be used 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.

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, and on the severe end, there is a complex phenotype in which aortic dissection or rupture commonly occurs in childhood. 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. 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.

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 can 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. Afflicted 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. 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 suggested in any young person 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.

Bicuspid aortic valve, the most common of these malformations, occurs in 1% to 2% of the population. Movahed and colleagues 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 ; 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. The raphe extends from the mid portion of the cusp to the aortic annulus, and its insertion in the aortic root is at a lower level than the other two commissures. Bicuspid aortic valves with two cusps and two sinuses are uncommon and called “type 0”; the most common type is with one raphe and is called “type 1,” and finally with two raphes is “type 2.” Types 1 and 2 can be subclassified according to the fused cusps: left-right is the most common form (a raphe in between the left and right cusps). Abnormal origin of the coronary arteries and circumflex artery dominance are common in patients with bicuspid aortic valve.

Normally functioning bicuspid aortic valves may last the patient's lifetime. Others become stenotic by the fourth or fifth decade of life. Aortic insufficiency can also occur, and it is often associated with dilated aortic annulus. 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. These patients are at risk of developing chronic degenerative aneurysms of the ascending aorta and type A aortic dissection.