71 6.3 Aortic Anomaly in Marfan Syndrome

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Contents

6.1 Introduction . . . . 71

6.2 Positive Diagnosis of Marfan Syndrome, and the Importance of Familial Screening . . . . 71

6.3 Aortic Anomaly in Marfan Syndrome . . . . 72

6.4 Exercise Limitation . . . . 72

6.5 Medical Therapy . . . . 73

6.6 Follow-Up . . . . 75

6.6.1 Technique of Measurement . . . . 75

6.6.2 Frequency for Follow-Up . . . . 76

6.6.3 Indications for Surgery . . . . 76

6.6.3.1 Aortic Regurgitation . . . . 76

6.6.3.2 Pregnancy . . . . 77

6.6.3.3 Neonatal Marfan Syndrome . . . . 77

6.7 Conclusion . . . . 77

6.1 Introduction

Traditionally, Marfan syndrome has always been associated with a high mortality rate, the result of aortic dissection and heart failure secondary to aortic dilatation: by the age of 40 years, 50% of men affected by Marfan syndrome were dead in a survey performed in 1972 [1]. But since the development of aortic surgery (Bentall intervention and more recently valve-sparing surgery), the life expectancy of Marfan syndrome patients has increased to more than 70 years [2], indicating that good medical and surgical management is effi- cient in these patients.

Marfan syndrome, a well-recognised disease with in- ternationally recognised criteria [3], has been linked to an anomaly in fibrilin 1 [4]. However, this anomaly probably only accounts for a few of the degenerative aneurysms and dissections of the ascending aorta [5]. An- other gene has also been linked to Marfan syndrome [6]. In addition, at least three other genetic localisations have been reported in familial forms of ascending aortic

aneurysms or dissections [7, 7a], but most ascending aortic aneurysms remain of unknown aetiology. How- ever, because the same mechanisms are probably in- volved in aortic dilatations of different aetiologies, the follow-up recommendations for Marfan syndrome are usually used for other aetiologies of aneurysmof the ascending aorta as well.

The mainstays of medical therapy are sports limitation, aiming at limiting stress on the aortic wall, and beta-blocking agents. Regular follow-up and aortic measurements are necessary to propose surgery before aortic dissection occurs. The aortic diameter is the single most important parameter for deciding surgery because the risk of dissection is greater as the aorta enlarges.

This measurement should be standardised.

6.2 Positive Diagnosis of

Marfan Syndrome, and the Importance of Familial Screening

Marfan syndrome is a polymorphic disease with large interfamilial and intrafamilial variability, complete pen- etrance and dominant autosomal transmission. Neo mutation may be responsible for 25% of the recognised cases. International criteria have been defined [3], with the aimof limiting overdiagnosis. To be diagnosed positive, a patient has to show major or minor features in at least three systems, including three major ªcriteriaº.

The criteria are less stringent for patients with a family history as this is one of the major criteria (Table 6.1).

However, because of the great variability of this disease and the progressive nature of the clinical features, in- conclusive diagnosis accounts for 10% of patients com- ing to our out-patient clinic.

Familial screening should be systematic because of the genetic nature of Marfan syndrome. This often pro- vides early recognition of affected individuals, allowing preventive measures and close follow-up before aortic complications. It is our experience that underdiagnosis could be improved by familial screening [8].

Medical Aspect

of the Aortic Diseases:

the Follow-Up and Its Warnings

Guillaume Jondeau, Gabriel Delorme, Olivier Milleron and Jessica Wilson

6

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The occurrence of familial forms of aneurysm in more than 10% of the non-Marfan population [9] justi- fies the systematic screening of direct family members of patients with ascending aortic aneurysms. Familial forms of bicuspid aortic valves have been reported [10,

10a], and bicuspid aortic valves have been associated with alteration of the wall of the ascending aorta which is similar to that observed in Marfan syndrome (cystic medial necrosis) [11]. This histological anomaly and not the haemodynamic consequences of bicuspid aortic valves is responsible for aortic dilation. Other familial ascending aortic aneurysms have been recognised unre- lated to bicuspid aortic valves or Marfan or Marfan-like disease [7, 12±14].

6.3 Aortic Anomaly in Marfan Syndrome

Aortic dissection and dilatation are mainly observed on the proximal part of the ascending aorta in patients with Marfan syndrome: this portion of the aorta is sub- mitted to maximal haemodynamic stress, and is the richest in elastic fibres as well as in fibrillin 1. However, haemodynamic studies have clearly demonstrated that the entire aortic wall properties are altered [15, 16], even when the aortic diameter is within normal values [17]. Although less common, aortic dissection of the descending aorta also occurs in patients with Marfan syndrome [18]. It is interesting to note that although fibrilin is a ubiquitous molecule, wall properties of ar- teries others than the aorta are not altered in Marfan patients [15]. Therefore medical treatment and follow- up should be focused on the entire aorta.

It is generally assumed that patients with aortic dilatation who do not fulfil the Marfan criteria have abnormalities throughout the entire aortic wall. This has not been studied specifically, but is based on the facts that:

l Marfan syndrome, although clinically defined as a single entity, may be related to different genetic de- fects, and therefore includes different diseases (FBN1 mutation, TGFBR2 mutation or neither).

l Some overlap is seen in the clinical picture in patients with Marfan syndrome and nonsyndromic aortic dilation.

l Histology does not allow for recognition of Marfan syndrome, bicuspid aortic wall or dilation in relation with neither of these entities.

6.4 Exercise Limitation

Limitation of stress applied to the aortic wall may be achieved by limiting exercise and by beta-blocker therapy.

The avoidance of some exercise is based on the as- sumption that an increase in blood pressure is detrimental to patients because it favours aortic dilation, although no randomised data have been obtained. Actu- ally the reports of the detrimental effect of intense sports are limited to case reports [19±22]. Nevertheless, Table 6.1.Diagnostic criteria for Marfan syndrome [3]. The in-

volvement of three systems with two major criteria is required for the diagnosis of Marfan syndrome

Skeletal system

A major criterion is defined by the presence of at least four of the following:

l Pectus carinatum

l Pectus excavatumsevere enough to require surgery l Reduced upper to lower segment ratio or arm span to

height ratio greater than 1.05 l Positive wrist and thumb signs

l Reduced extension of the elbows (less than 1708) l Medial displacement of the medial malleolus associated

with pes planus

l Protrusio acetabuli of any degree (ascertained on radio- graphs, computed tomography, or MRI)

Involvement of the skeletal system is defined by the presence of two of the preceding features or the presence of one of the preceding features and two of the following: pectus excava- tumnot requiring surgery; joint hypermobility; high arched palate; facial features (at least two of the following: dolicho- cephaly; malar hypoplasia; enophtalmos, retrognathia; down- slanting palpebral fissures)

Ocular system

A major criterion is defined by ectopia lentis of any degree Involvement of the ocular system is defined by the presence of at least two of the following: flat cornea; increased axial length of the globe; hypoplastic ciliary muscle causing decreased miosis

Cardiovascular

A major criterion is defined by dilatation or dissection of the ascending aorta with or without aortic regurgitation and in- volving at least the sinuses of Valsalva

Involvement of the cardiovascular system requires the presence of at least one major criterion or one of the following:

mitral valve prolapse with or without mitral regurgitation;

dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis, under the age of 40 years; calcification of the mitral annulus under the age of 40 years; dilatation or dissection of the descending thoracic or abdominal aorta under the age of 40 years

Pulmonary system

Involvement is defined by either spontaneous pneumothorax or radiological evidence of apical blebs

Skin and teguments

Involvement is defined by either striae distensiae or a recur- rent or incisional hernia

DuraA major criterion is the presence of lumbosacral dural ectasia Family and genetic history

A major criterion is defined by one of the following: a first- degree relative who independently meets diagnostic criteria for Marfan syndrome; the presence of a mutation in the FBN1 gene that is likely to be pathogenic or the presence of a haplotype around the FBN1 gene locus inherited by descent and unequivocally associated with diagnosed Marfan syndrome in the family

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the pathophysiological background is strong enough to allow good convergence of views between recommendations [23, 24]. Recent recommendations have been published under the auspice of the American Heart Asso- ciation [25].

ªBurstº exertion (or sprinting), characterised by rapid acceleration and deceleration over short distances, should be avoided. Exercise of this type is encountered in a variety of sports, such as basketball (particularly full-court play), soccer, and tennis. Therefore, prefer- ence is given to recreational sporting activities such as informal jogging without a training regimen, biking on level terrain, or lap swimming, in which energy expend- iture is largely stable and consistent, even over relatively long distances or periods of time.

Intense static (isometric) exertion, such as lifting free weights, may prove to be adverse by increasing wall stress and weakening the aortic media in patients with Marfan syndrome, particularly if aortic dilatation is al- ready present.

Recreational sports are categorised with regard to high, moderate, and low levels of exercise and are graded on a relative scale (from0 to 5) for eligibility with 0±1 indicating generally not advised or strongly discouraged, 4±5 indicating probably permitted, and 2±3 indicating in- termediate and to be assessed clinically on an individual basis.

This classification is proposed for patients with no or only mild aortic dilation. Sports are classified as:

0: Body building, weightlifting, scuba diving 1: Ice hockey, rock climbing, windsurfing, surfing 2: Basketball, racquetball/squash, running (sprinting),

skiing (downhill), skiing (cross-country), soccer, baseball/softball, motorcycling, sailing

3: Tennis (singles), touch (flag) football, biking, jogging, swimming (lap), hiking, horseback riding 4: Tennis (doubles), treadmill/stationary bicycle 5: Modest hiking, bowling, golf, Skating, snorkelling,

brisk walking

Therefore, exercise limitation in patients with Marfan syndrome should be individualised, and the final deci- sion is taken by the patients. They need to understand the deleterious effect of isometric exercise, competition, and the better tolerance of the endurance type of exercise, with limited intensity.

6.5 Medical Therapy

Medical therapy has been developed based on the as- sumption that aortic dilation and dissection are fa- voured by the repeated aortic stretch secondary to blood ejection by the left ventricle. Therefore, it was initially aimed at decreasing dp/dt and the rebound wave. The use of beta-blockers in this setting was rein-

forced by the observed benefit on turkeys prone to aortic dissection [26]. However, invasive haemodynamic measurements performed in patients scheduled for aortic surgery (and hence significant dilatation of the initial aorta) failed to demonstrate any significant decrease in dp/dt with acute injection of beta-blockers and actu- ally showed an increase in the rebound wave, responsible, in conjunction with bradycardia, for an increase in pulse pressure [27]. It is therefore unclear if acute beta- blockade decreases the stress applied to the initial aorta during each systole. Beta-blockade may also prove beneficial through bradycardia; however, the importance of this mechanism has not been ascertained and is rarely quoted even if it is likely to be the main mechanism by which beta-blockers improve the prognosis of the patients. More recently, a beneficial effect of beta-blocking agents on aortic compliance of patients was proposed [28]. The proposed mechanism would be to acutely decrease blood pressure and, in the long term, limitation of aortic alteration and dilatation.

The benefits of beta-blockade in Marfan patients were evaluated during an open label, placebo control, parallel group study performed in 70 Marfan patients older that 12 years (Fig. 6.1) [29]. Propranolol was used at a dose aimed at limiting the peak exercise heart rate below 100 beats/min. The mean follow-up was 10 years.

The mean slope of the regression line of the aortic-root dimensions, which reflects the rate of dilatation, was 3 times lower in the treatment group than in the control group, and end points (death, dissection, aortic dilatation over 60 mm or aortic regurgitation) tended to be lower in the treatment group (five including two not taking their pills vs nine controls). The effect of beta- blockade was observed irrespective of the importance of initial dilatation. Although the design of this phar- macological therapeutic study does not fulfil the criteria of modern studies, it was felt by the medical commu- nity to be sufficient to demonstrate the benefit of beta- blockers in adults, which are therefore recommended irrespective of the aortic diameter.

In children, no randomised study has ever been performed and discussion regularly recurs. Two retrospective analyses have suggested a benefit in children: one reporting a decrease in the rate of the aortic dilatation (absolute diameter and diameter normalised for age and body size) in female patients less than 17 years old or in male patients less than 19 years old when compared with children not receiving treatment [30]. The second study compared patients presenting under the age of 21 with contraindication to beta-blockade with patients who presented at a similar age and were given beta-blockade either at Johns Hopkins University or at the University of Tennessee [31]. The protective effect of beta-blockade was also evidenced in this study and appeared to be more pronounced when initiated earlier.

It is therefore generally recommended that all Marfan patients in whomdiagnosis is certain, adult as well as

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children, should be treated with beta-blockade when tolerated although the consensus is less strict in young- er patients without aortic dilatation.

The question arises as to what should be proposed to patients who do not tolerate the beta-blockers? Alter- native therapy is proposed on the basis of the presup- posed pathophysiological beneficial haemodynamic effect of beta-blockade: bradycardic calciumantagonists are usually used with the aimto decrease heart rate and to slow the left ventricular ejection. No study, however, has demonstrated their clinical benefit.

It has recently been reported that smooth muscle cells, cultured fromaortic tissue of patients with Mar- fan syndrome, showed a shorter survival than smooth muscle cells obtained from normal aorta in the case of serumdeprivation [32, 33]. This observation has been reproduced and it was shown that the use of angiotensin converting enzyme inhibition prolonged survival of these deprived cells to normal values [34]. This appeared to be the result of decreased stimulation of angiotensin II (ATII) type 2 receptors because sartans were devoid of this preventive effect, whereas ATII type 2 receptor blocker reproduced the beneficial effect of the angiotensin converting enzyme inhibition. Although ob-

tained in a pure in vitro study, these results may sug- gest alternative or more likely additive therapy for patients with Marfan syndrome.

Recent studies in mouse models of Marfan syndrome has led to new understanding of the pathophysiology of this disease. Increased TGF-b signaling has been shown in Fbn1-hypomorphic mice in lung [34a] and in mitral valve tissue of knock-in mice harboring a missense mutation [34b]. These phenotypes were rescued by a TGF- b neutralizing antibody [34a,b]. Fibrillin-1 shares homology with latent TGF-b binding proteins (LTBPs), which bind to the small latent complex of TGF-b and sequestrate it to the extracellular matrix [34c]. Thus fibrillin-1 abnormalities may lead to altered sequestration of the latent formof TGF-b in the extracellular matrix and therefore increased TGF-b activity [34d]. This finding, in addition of the mutations in TGF beta-receptors 2 and 1 leading to aortic aneurysmalone or integrated into a Loyes Dietz syndrome, or a classical Marfan syndrome, challenges the classical thinking of fibrillinopa- thy leading to elastin misarrangement and therefore weakness of aortic wall. They indicate that TGF-b signaling abnormalities underlie the pathogenesis of Mar- fan syndrome, especially for some diseased organs.

Finally, very recently, blocking angiotensin 2 type 1 receptors with losartan (antagonizing TGF-b pathway in some animal models) has been shown to limit the aortic dilation in the mouse model, when given very early on [34e]. Whether this finding will lead to modifica- tions in management of Marfan syndrome and further aortic aneurysmin the man is the subject of clinical studies to be performed in the near future.

After surgery, the same precautions should prevail as only part of the abnormal aorta has been removed.

Therefore beta-blockade and exercise limitation remain necessary.

Blood pressure control is absolutely critical in the Marfan population, and the prevalence of hypertension is increasing as life expectancy improves. It is of upmost importance in patients who have only part of their dissected aorta removed in surgery.

In these patients aortic dilatation often occurs inexorably and is usually maximal in the higher part of the descending thoracic aorta, often requiring surgery some years later. In our experience, 50% of the patients presenting dissection of the descending aorta, usually as an extension of a dissection of the ascending aorta, had been operated on or had died within 5 years. Beta- blockade and decreasing blood pressure are two of the few medical tools available to delay this high-risk surgery. We aimfor a systolic blood pressure lower than 130 mmHg in this population, or lower if tolerated, and beta-blockade is mandatory.

Fig. 6.1. Benefit of beta-blockade in patients receiving beta- blocker therapy [29]

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6.6 Follow-Up

The principal aimof follow-up is to propose surgery before aortic dissection has occurred. The aortic diameter is the principal predictor of aortic rupture or dissection [35]. In a large retrospective study gathering thoracic aortic aneurysms from different aetiologies, the risk for rupture or dissection was 6.9% per year, and death, rupture, or dissection was 15.6% per year for a size greater than 6.0 cm. The odds ratio for rupture increases 27-fold compared with lower values [36]. Similarly, patients operated on at the John Hopkins University had a greater risk of being operated on because of aortic dissection when the aortic diameter was greater [37]. Operative and post- operative mortality is higher when surgery is performed in an emergency setting. Lastly, the presence of dissection of the descending aorta is indicative of poor prognosis: in our experience, new surgery or death was encountered in 50% of the patients after 5 years. Therefore, measurement of the ascending aortic diameter is of critical importance for us to be able to propose timely surgery for replacement of the aortic root.

6.6.1 Technique of Measurement

Aortic root diameter can be measured using echocardiography, a computed tomography (CT) scan, or MRI.

Transthoracic echocardiography remains the preferred

investigation because of easy accessibility and good vi- sualisation of the aortic root in most patients. However, in some patients, mainly as a result of chest deforma- tion, it may be difficult to obtain a reliable aortic diameter using transthoracic echocardiography, in which case alternative techniques should be used (CT or MRI).

Whichever investigation is performed, great care must be taken to measure the diameter of the aorta in a plane which is perpendicular to the major axis of the vessel, during telediastole (Fig. 6.2): horizontal images, for example, such as those obtained from a CT scan before reconstruction, may show a distorted aortic root, obliquely imaged, which results in an overestimation of the aortic diameter. In any case, if doubt exists about the exact measurement of the aorta, the use of another technique to validate the figure obtained is recommended, at least for the first measurement. The same holds true when a brisk increase in diameter is observed during follow-up: confirmation of the evolution of the diameter should be obtained before surgery is considered.

However, the aortic dilatation may not be strictly symmetrical and the antero-posterior measurement made by echocardiography may then be a underestimation of the maximal aortic diameter at the level of the sinuses of Valsalva [38]. It appears therefore reasonable to systematically visualise the aortic root in the short- axis view to avoid gross underestimation of the maximal diameter in the case of frankly asymmetrical dilatation. The importance of a slight discrepancy is more difficult to evaluate as the validated prognostic marker is the antero-posterior diameter.

The aim for measuring the aortic diameter is two- fold: first, to make the diagnosis of aortic dilatation, a major sign for the diagnosis of Marfan syndrome, and, second, to propose timely surgery.

The importance of normal values to recognise dilatation of the ascending aorta is obvious. Normal values have been published for adults and children, and are dependent on age and body surface area [39]. In adults the normal values from Roman et al. [39] are largely recognised as the standard. Specific nomograms for tall men (more than 189 cm) and women (more than 175 cm) have been proposed [40].

The normal values are more difficult to determine in children: it is our experience and that of others [41]

that in some children an aorta initially considered as dilated according to the normal values proposed by Ro- man et al. is subsequently found to be within normal limits during follow-up. Other nomograms have been proposed with wider normal ranges [41]; the ratio of the sinus of Valsalva over the annulus has been found to be independent of age, height, and weight by some authors [42], and a ratio above 1.45 has been proposed as a diagnostic cutoff in children [43]. According to these authors, the principal limitation of this ratio is related to the dilatation of the aortic annulus, responsible Fig. 6.2.Measurement of aortic diameter [39]

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for aortic insufficiency. Normal values have been proposed by others for the aortic annulus [44]. Normalisa- tion by the square root of the body surface area has also been proposed, with a mean normal value of 21 mm/m²[45].

6.6.2 Frequency for Follow-Up

Currently the recommended follow-up for aortic root measurement is once a year, when the aortic dilation is moderate. However, when the diameter comes to values close to surgical threshold, a 6-month interval follow-up is usually proposed. Similarly, when the aortic diameter appears to increase, the confirmation of the measurement using another technique is necessary and repeated measurements at 2-month intervals may be performed to confirmthe evolution of the diameter and the indication for surgery or the stabilisation of the diameter at a new value, allowing for medical management.

6.6.3 Indications for Surgery

The indications for surgery are based on the apprecia- tion of the risk of aortic dissection. Factors associated with increased risk are:

l First of all, the aortic diameter at the level of the sinuses of Valsalva (maximal diameter) [35] (cf. su- pra). The risk increases dramatically after 60 mm, although aortic dissection may occur when the aorta is of normal size [37]. Indications for surgery have been proposed in the past when the aortic diameter was 60 mm. With the progress in surgery, the limit of 55 mm has been proposed [46], and nowadays most teams would propose surgery when the aortic diameter is reaching 50 mm, as is stated in the recently published recommendations from the Europe- an Society of Cardiology [47], particularly if other risk factors are present. A proposition for standard- isation of the aortic diameter by height has been made by Svensson and Khitin [48], who proposed that surgery should be considered when the ratio of the aortic area divided by the height is greater than 10 [r² (centimetres) ´ p/height (metres)]. However, the relation between aortic dilatation and the risk of aortic rupture is probably mediated both through the law of Laplace, which is independent of body size, and through the fragility of the aortic wall, which will be more important when the diameter of the aorta is greater than baseline values. This last phenomenon is better evaluated by the normalised aortic diameter, either by a ratio compared with the normal theoretical value, or by height or body surface area, depending on the authors. Therefore, the

importance of normalising the aortic diameter for the purpose of timing surgery is not clear-cut.

l The fact that aortic dilatation is diffuse and goes beyond the sinuses of Valsalva on the ascending aorta has been associated with an increased risk for aortic dissection [35].

l A family history of aortic dissection [49], which is considered as an indication for earlier surgery, especially if the aortic diameter before dissection is known and is only mildly enlarged.

l Rapid dilation of the aorta.

l The absence of beta-blocker therapy.

l Probably aortic regurgitation. Beyond increasing the risk for aortic dissection through an increase in stroke volume, aortic regurgitation, in the long run, alters aortic leaflets, making valve-sparing intervention more difficult.

l Pregnancy (cf. infra) is a specific situation.

It is our current practice to propose surgery when the aortic diameter is above 50 mm, and we do not index this value for body size. Our experience is that with this threshold, aortic valve sparing operation is almost always possible and the risk for aortic dissection is minimal. However, aortic dissection may rarely occur after minimal dilatation of the aorta.

After surgery the patient remains at risk, as only part of the entirely abnormal aorta has been removed.

Therefore, exercise limitation and beta-blocker therapy remain necessary. The diameter of the remaining native aorta should be checked using a CT scanner or MRI every few years. When dissection of the descending aorta is present, generally as an extension of a dissection of the ascending aorta, the aortic diameter should be checked every year, as dilatation usually inexorably occurs. As stated earlier, after 5 years, only 50% of the Marfan patients presenting a dissection of the descending aorta remained free of complication or surgery. The higher part of the descending aorta is usually where there is predominant dilatation and so should be checked. We usually propose surgery when the maximal diameter is above 60 mm.

6.6.3.1 Aortic Regurgitation

Aortic regurgitation may be related to different mechanisms. The first mechanism, aortic dilatation, particularly of the sino-tubular junction, leads to an increase in aortic orifice area and central, axial, aortic regurgitation. In this case the aortic regurgitation is roughly pro- portional to aortic dilatation. This is rare when the aortic diameter is lower than 40 mm, and is the rule when the aortic diameter is greater than 60 mm. The second mechanism which can be responsible for aortic regurgitation irrespective of the aortic diameter is the prolapse of an aortic leaflet leading to an eccentric regurgitant jet. Endocarditis should be prevented as soon as regur-

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gitation is present, of either the aortic or the mitral valve.

Whatever the mechanism, the aortic regurgitation alters the aortic valve leaflets, so that long-termregurgi- tation renders valve-sparing operation difficult. The other classic complication of aortic regurgitation, i.e.

heart failure, which was of major importance in the past [1], is now very seldomseen in adults. Indications for surgery are now almost always related to aortic dilation and not to heart failure or important aortic regurgitation. Important aortic regurgitation is sometimes encountered after valve-sparing surgery, and may neces- sitate replacement surgery.

6.6.3.2 Pregnancy

Pregnancy is associated with an increased risk of aortic dissection: combining the figures of the different series reported, a risk of around 4% can be calculated in women for each pregnancy. In these series, most of the women were unaware of the diagnosis, and were not receiving beta-blockers. The recommendation is to advise the risk of pregnancy as acceptable when the ascending aorta is less than 40 mm in diameter, and to advise against pregnancy when it is above 40±45 mm. Beta- blockers should be taken throughout pregnancy and after delivery, and close echocardiographic follow-up should be performed with examination after 3 and 6 months of pregnancy, and every month thereafter including once a month after delivery. Most of the reported dissections occurred during the third trimester and so delivery is generally induced to limit its dura- tion. Caesarean section is recommended when the aortic diameter is more than 40 mm or is increasing rapid- ly. Every effort should be made to maintain constant blood pressure at delivery.

It has been proposed that pregnancy after preventive aortic surgery, particularly after valve-sparing operation, is low risk. However, part of the abnormal aorta remains in place, and one of our patients presented dissection of the descending aorta during pregnancy after preventive aortic valve sparing surgery.

6.6.3.3 Neonatal Marfan Syndrome

The neonatal formof Marfan disease is beyond the scope of this review. Aortic dilation is often present, but the cardiovascular manifestation is congestive heart failure secondary to mitral and aortic regurgitation. The prognosis is dismal, with death occurring within months, and the prevalence of neonatal mutation is much higher in this form of the disease than in the adult population.

6.7 Conclusion

Marfan syndrome is a genetic disease, the best recognised aetiology of ascending aortic aneurysm. Because of its genetic nature, familial screening is crucial to di- agnose the disease before complications have occurred.

Regular follow-up with echocardiography should allow timely surgery for aortic root replacement, ideally using a valve-sparing procedure. Beta-blockage and avoidance of violent sports are the mainstay of medical therapy and may delay surgery or even avoid it in some patients. Medical therapy and close follow-up should be maintained after surgery in all patients. Blood pressure control and close follow-up is of upmost importance in patients with persistent dissection of the descending thoracic aorta.

Patients with aortic aneurysmor dissection who do not fulfil the Marfan criteria and who have unknown aetiology, should also have systematic familial screening because of the familial pattern of inheritance in some cases.

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