Vascular Complications of Marfan Syndrome, Ehlers-Danlos Syndrome, and Loeys-Dietz Syndrome

Vascular Complications of Marfan Syndrome, Ehlers–Danlos Syndrome, and Loeys–Dietz Syndrome

David Bergqvist

Inheritable connective tissue disorders have in common defects in collagen or elastin within the medial layer of the vascular wall causing loss of structural integrity, degeneration, aneurysmal development, and, as a final consequence, rupture of the wall with or without an underlying aneurysm or dissection.

Three connective tissue abnormalities are of particular interest: Marfan syndrome, Ehlers–Danlos syndrome, and Loeys–Dietz syndrome. They are rare diseases, but because they can lead to vascular catastrophes, it is important that vascular surgeons have a basic knowledge about patients who have these syndromes (Table 1). The final diagnosis should be based on molecular genetic testing, in that many signs and symptoms have various degrees of penetrance, making differential diagnosis sometimes difficult.

TABLE 1

Comparative Aspects of Connective Tissue Disorders with Vascular Complications

Syndrome	Sex	Heredity	Prevalence per 100,000	Life Expectancy (Years)	Gene Defect (Mutation)	Aneurysm	Occlusion	Arterial Location
Marfan	M = F	Autosomal dominant	20–30	30–35	Fibrillin-1	++++	0	Aortic root Thoracoabdominal aorta
Ehlers–Danlos	M = F	Autosomal dominant	2–3	45–50	COL3A1	+++	0	Visceral vessels Abdominal aorta
Loeys–Dietz	M = F	Autosomal dominant	Rare	25–30	TGFBR1 TGFBR2	+++	0	Thoracoabdominal aorta Aortic root Tortuosity

Marfan Syndrome

Marfan syndrome is an autosomal dominant disorder with complete penetrance, but there are great variations with individual organ involvement. It is caused by mutations in the gene coding for fibrillin-1, FBN1, which is localized on chromosome 15q21.1. Microfibrils, especially in the aortic wall, are weakened and are associated with defects in the collagen microarchitecture, causing a loose braiding of collagen ribbons. Using an ultrasound phase-locked echo-tracking system, it has been shown that the aorta in Marfan syndrome has increased stiffness.

Affected Organ Systems

Several organ systems are affected in Marfan patients.

Cardiovascular System

Aneurysms occur in the ascending aorta involving at least the sinuses of Valsalva; this is a major criterion. Another major criterion is dissections of the ascending aorta. There may be mitral valve prolapse and calcification of the mitral annulus, dilatation of the pulmonary artery, and dilatation or dissection of the descending and/or abdominal aorta. The risk of dissection increases with the size of the aorta, and in female patients it is also increased in pregnancy. Premature death in Marfan syndrome is predominantly caused by complications involving the aortic root and the thoracic aorta.

Skeletal System

Pectus carinatum or excavatum is a major criterion. Long arms, positive wrist and thumb sign, pes planus, and spondylosis or spondylolisthesis are other major criteria. Minor criteria are joint hypermobility, high-arched palate, and various facial features.

Ocular System

Ectopia lentis is a major criterion, whereas flat cornea, increased axial length of the orbital globe, and hypoplastic ciliary muscle are minor criteria.

Other Signs

Spontaneous pneumothorax, skin striae, and tendency to hernia are minor criteria.

Treatment

A key question is the timing of aortic root surgery to prevent expansion, with dissection and aortic regurgitation. An aortic dilatation beyond 50 mm has been one indication for surgery, but there have been attempts to construct nomograms, where the individual patient’s aortic diameter can predict the necessity of surgery. Composite graft replacement of the aortic root is the procedure of choice, the patient being on cardiopulmonary bypass. Often the coronary arteries have to be revascularized. As an alternative, various types of external wrapping or support have been used to decrease the expansion rate, but the success of such wrapping is open for discussion.

In the case of mitral valve insufficiency a mechanical prosthetic valve is usually inserted, and in the case of abdominal aortic aneurysm, conventional aneurysmal repair is undertaken. Endovascular repair may be considered. The development of endovascular devices with branches and even valves probably decrease the requirement of open surgery for aortic arch and valve repairs. Marfan syndrome is a progressive connective tissue disorder, and thus there is often need for various redo procedures, some patients having several separate interventions.

On the basis of small studies, β-blockade has been recommended to retard aortic root dilatation. A recent meta-analysis of six studies, however, concluded that β-blockade gave no clinical benefit in patients with Marfan syndrome. Only one of the six studies was randomized, though. Another suggestion has been to treat with angiotensin-converting enzyme (ACE) inhibitors, and a third suggestion is treatment with losartan (angiotensin II type of receptor antagonist).

Prognosis

The prognosis depends on the severity of cardiovascular complications, aortic dissection being the most common cause of premature death. Early diagnosis and timely surgery prolong survival, and the average life expectancy has increased to around 70 years. With increasing age, another threat is myocardial dysfunction with heart failure and cardiac arrhythmias.

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Tags: Current Therapy in Vascular and Endovascular Surgery

Aug 25, 2016 | Posted by admin in CARDIOLOGY | Comments Off

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