Family history
Aortic dilation (Z ≥ 2) or dissection
Ectopia lentis
Systemic score (≥7 of 20)
Pathogenic FBN1 mutation
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The diagnosis requires the coexistence of aortic root aneurysm or aortic dissection together with either a pathogenic FBN1 mutation, ectopia lentis, or a positive family history. The remaining cardinal manifestations of Marfan syndrome are incorporated in a systemic score, where a systemic score >7 also contributes to the diagnosis (Table 14.2) [2].
Table 14.2
Scoring of the systemic features
Feature | Score |
|---|---|
Wrist and thumb sign | 3 (wrist or thumb: 1) |
Pectus carinatum deformity | 2 (pectus excavatum or chest asymmetry: 1) |
Hindfoot deformity | 2 (plain pes planus: 1) |
Pneumothorax | 2 |
Dural ectasia | 2 |
Protrusio acetabuli | 2 |
Reduced upper segment/lower segment ratio and increased arm/height without severe scoliosis | 1 |
Scoliosis or thoracolumbar kyphosis | 1 |
Reduced elbow extension | 1 |
Facial features (3/5): dolichocephaly, enophthalmus, downslanting palpebral fissures, malar hypoplasia, retrognathia | 1 |
Skin striae | 1 |
Myopia >3 diopters | 1 |
Mitral valve prolapse (all types) | 1 |
Marfan syndrome considerably overlaps with other heritable connective tissue disorders, such as Loeys-Dietz syndrome, familial ectopia lentis, and Ehlers-Danlos syndrome. The variability in clinical expression and presence of FBN1 mutations in the different fibrillinopathies require a multidisciplinary approach in a Marfan screening center for complete evaluation and counseling.
14.1.2 Clinical Cardiovascular Findings
Mean survival of untreated patients was about 40 years in historic series. Prognosis and premature death of Marfan patients is mainly determined by aortic dissection. The risk of type A dissection clearly increases with larger aortic root diameter at the level of the sinuses of Valsalva, which is found in up to 80 % of the Marfan patients. However, aortic dissection may occasionally occur in patients with no or only mild aortic dilation [3]. Not only the aortic root but also other parts of the aorta may be dilated [4]. Additional predictors for aortic dissection are aortic elasticity and aortic tortuosity [5–8]. Decreased aortic elasticity determined by noninvasive measurement of local distensibility and flow wave velocity with magnetic resonance imaging (MRI) has been an individual predictor. In addition, increased elongation of the aorta, leading to a curved and tortuous aorta, has been found to correlate with increasing aortic diameter and independently predicts aortic dissections in Marfan patients as well [9].
The definition of aortic dilation in the diagnostic criteria for adults relies on a Z-score above 2, which may be calculated with different Z-score equations [10]. Different methods are used for aortic dilation in different publications. Currently, the Z-score normalized for height is recommended [11].
A dilated aorta is often asymptomatic. The presence of significant aortic, tricuspid, or mitral regurgitation may lead to symptoms of ventricular volume overload. Some patients with Marfan syndrome have a slightly impaired left and right ventricular ejection fraction without significant valvular regurgitation, which may be due to a fibrillin defect in the myocardium [12], especially patients with a non-missense fibrillin-1 mutation had left ventricular dilation [13]. However, the left ventricular dimensions and systolic function were found to be normal in most Marfan patients, and none fulfilled the criteria for dilated cardiomyopathy [14].
The combination of increased height and a structural abnormality of the blood vessels may cause impaired orthostatic tolerance, leading to fatigue and orthostatic hypotension [15]. To counteract orthostatic drops in blood pressure, patients can be educated in physical maneuvers, such as leg crossing and muscle tensing.
14.1.3 Late Outcome
Life expectancy of Marfan patients has improved substantially up to a median survival of 60–70 years, due to the advances in medical and surgical therapy [16]. In about 15 % of the patients, the first aortic event occurs in the distal aorta [17, 18]. However, the aortic root is mostly the first site to be affected. The 18-year survival rate after aortic root replacement has been reported to be 76 % [19]. After aortic root replacement, patients deserve intensive surveillance because of an increased risk of developing aneurysms and dissections distal to the site of the graft [3, 17, 20, 21]. The increased risk of postsurgical complications may be a more advanced disease in patients undergoing aortic surgery, hemodynamic factors and altered wall mechanics due to the impact of intervention at the level of the root, or tissue damage because of clamping of the aorta during the operation.
In a small series of 40 patients with Marfan syndrome, MRI showed coronary ostial aneurysms in 27 (43 %) patients after 3 months to 19 years after elective aortic root surgery [22]. Coronary ostial aneurysms are usually not progressive and may be developed due to perioperative stretch of the weakened wall of the coronary ostium. However, follow-up studies are needed to confirm that these aneurysms are not clinically relevant.
14.2 Genetics
Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15q21 encoding fibrillin-1, a large glycoprotein in the extracellular matrix [1]. FBN1 mutations induce abnormal or deficient fibrillin-1 protein synthesis, which affects the structural integrity of the extracellular matrix and weakens the supporting tissues. Fibrillin-1 normally binds to a large latent complex, which comprises the inactive form of transforming growth factor-β (TGF-β) [23]. FBN1 mutations or the damaged extracellular matrix seems to lead to an increased plasma TGF-β level [24], which is associated with aortic root dilation in a mouse model of Marfan syndrome [25], as well as with aortic dilation rate in Marfan patients [26].
In approximately 90 % of the Marfan patients, an FBN1 mutation is identified, and almost all of the currently 3000 registered FBN1 mutations are unique to an affected individual or family. Genotype-phenotype correlations have been complicated by this large number of unique mutations and clinical heterogeneity among family members. One interesting classification is based on the effect of the FBN1 mutation on the fibrillin-1 protein, referred to as dominant negative or haploinsufficient mutations [27]. Dominant negative mutations, such as cysteine substitutions, lead to a disturbed protein folding and generally a higher prevalence of ectopia lentis. On the other hand, haploinsufficient mutations, such as premature termination codon mutations, lead to a lower production of normal fibrillin-1 protein and generally more often to skeletal features and cardiovascular involvement, such as aortic dissection [28, 29].
14.3 Treatment
14.3.1 Surgical Treatment
The threshold diameter for aortic surgery is 50 mm for any level of the aorta, or 45 mm for the aortic root in combination with either a family history of dissection, progressive dilation of more than 2 mm/year by repetitive measurement using the same imaging technique, severe aortic or mitral valve regurgitation, or if pregnancy is desired. Lower thresholds for intervention may be considered according to the lower body surface area (BSA) in patients of small stature or according to patient’s preference [30]. On average, women have a smaller aorta (by 5 mm), which is only partly explained by a smaller BSA [31]. An indexed aortic diameter (adjusted for BSA) could be useful for operative decision-making [32]; surgery then would be indicated at an aortic diameter of 4.5 cm in patients with a BSA of 1.65 m2, 5.0 cm at a BSA of 1.8 m2, and 5.5 cm at a BSA of 2 m2.
Over the past 30 years, the composite replacement of the aortic valve and ascending aorta (“Bentall procedure”) has been a low-risk and very durable operation for aortic root aneurysm in Marfan patients. In a series of 675 Marfan patients undergoing aortic root surgery, the operative mortality rate was 1.5 % for elective operations and 11.7 % for emergency operations [33]. However, in patients with initially normal aortic valves, valve-sparing operations with root replacement by a Dacron prosthesis and reimplantation of the coronary arteries into the prosthesis (the David procedure) have now become the preferred choice of surgery. Either type of aortic root replacement appears to be safe, reproducible, and associated with excellent 5–10-year results. Freedom from reoperation of the aortic valve after the David procedure was 94.8 %, with a slow progressive deterioration of aortic valve function after long-term follow-up [19]. A homograft or bioprosthetic valve may also be considered to avoid anticoagulant therapy.
Information concerning the outcomes of endovascular stenting in Marfan patients is scarce. In Marfan patients with aortic dissection, the use of endovascular stenting should only be considered in life-threatening emergencies as a bridge to definite therapy, since these aortas demand close clinical and imaging surveillance to detect progressive dilation, resulting in high endoleak rates, a 12 % mortality rate, and a 14–18 % need of a new surgical procedure [34–36].
Personalized external aortic root support (PEARS) is a novel surgical approach, stabilizing the aortic root and decreasing the risk of aortic dissection in patients with Marfan syndrome. Although prospective follow-up data is currently lacking, in the first 30 selected patients operated with PEARS, the perioperative burden was less without any aortic or valvular event after 1.4–8.8 years of follow-up [37].
14.3.2 Medical Treatment
In patients with Marfan syndrome, and especially in patients with aortic dissection, rigorous antihypertensive medical treatment is important, aiming at a systolic blood pressure less than 120 mm Hg. The most commonly prescribed drugs are β-adrenergic blockers, which reduce the aortic dilation rate in patients with Marfan syndrome, due to its effects in reducing the blood pressure and the force on the left ventricular ejection [38, 39]. Losartan, an angiotensin II receptor 1 blocker, might be an alternative or complementary therapy to β-blockers, since losartan reduces arterial pressure and potentially interferes with the pathophysiology of Marfan syndrome by TGF-β antagonism. After evidence for effectiveness of losartan in a mouse model of Marfan syndrome [40], a small pilot study in children and adults demonstrated a beneficial effect of losartan combined with β-blockers (n = 15) on aortic dilation rate compared with β-blockers alone (n = 13) after 35 months of echocardiographic follow-up [41]. Subsequently, eight randomized clinical trials were initiated to test losartan effectiveness; so far, four studies have been published [42]. The COMPARE trial demonstrated a beneficial effect of losartan on top of β-blockers on aortic root dilation rate in a larger cohort (n = 145) as measured by MRI and additionally demonstrated the beneficial effect of losartan on the distal part of the aorta after aortic root surgery [43]. The Marfan Sartan trial evaluated the benefit of adding losartan to a high dose of β-blockers. Remarkably, in this cohort of 292 children and adults, aortic dilation rate was similar for the losartan- and placebo-treated group after 3.5 years of echocardiographic follow-up [44]. The Pediatric Heart Network study demonstrated that both losartan and atenolol were equally effective in reducing aortic dilatation rate in a large, blinded trial including 608 children during 3 years by echocardiography [45]. The last published trial so far demonstrated in 140 Marfan patients aged 5–60 years that losartan was not inferior in respect to atenolol and tended to be more favorable in the losartan monotherapy group when corrected for BSA or Z-score measured by MRI over 3 years of follow-up [46]. The discrepancies in outcome between the studies may be explained by the different study designs [42]. Until the results of the ongoing three trials and meta-analysis are known, we can conclude that losartan does not seem to be more effective in reducing the aortic dilation rate than a high dosage of β-blockers, but that losartan can safely be administered as an alternative or as an additive to β-blocker therapy, especially in patients with intolerance or side effects of β-blockers [42].
14.4 Outpatient Assessment
14.4.1 Follow-Up
Optimal long-term outcome demands lifelong follow-up with imaging of the aortic root by means of echocardiography and the entire aorta by means of MRI at regular intervals. This is particularly true if a dissection has occurred and its stability is being monitored. Patients with mitral valve prolapse and moderate or severe mitral regurgitation should also be followed with yearly echocardiography. Antihypertensive medical treatment, aiming at a systolic blood pressure less than 120 mm Hg, is important in all patients with Marfan syndrome. After aortic dissection, systolic blood pressure should not exceed 110 mm Hg. Lifelong and regular follow-up of these patients requires involvement of trained specialists with ample expertise in a tertiary referral center.
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