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Anatomical and functional evaluation of the cardiovascular system in Marfan syndrome

Nollen, G.J.

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Citation for published version (APA):Nollen, G. J. (2004). Anatomical and functional evaluation of the cardiovascular system in Marfan syndrome.

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Download date: 24 Nov 2020

CHAPTER R

Summary y

Adaptedd from: What is new in thee Marfan syndrome?

GijsJ.. Nollen1, Barbara J.M. Mulder1

Fromm the Department of Cardiology1 of the Academic Medical Center, Amsterdam,, The Netherlands

Internationall Journal of Cardiology, In press

116 6

Introduction n Thee Marfan syndrome is an autosomal dominant disorder of connective tissue, caused by

mutationss in the FBN1 gene on chromosome 15q21 encoding a large glycoprotein called

f ibr i l l in-1,, a main component of extracellular microfibrils found in a wide range of tissues1.

Thee Marfan syndrome is characterised by highly variable cl inical manifestations in

primari lyy skeletal, ocular and cardiovascular organ systems2. Prevalence has been

estimatedd at 2-3 per 10.000 and about 25-30% of cases represent new mutations3-4.

Prognosiss is mainly determined by progressive dilatation of the aorta, potentially leading

too aortic dissection and death at young age5. Prophylactic surgery and treatment wi th b-

adrenergicc blocking agents have improved life expectancy substantially, from 47 years in

19722 to 61 years in 19956'7'8-9. Early identification of patients with Marfan syndrome is

thereforee of considerable importance.

Genetics s Marfann syndrome is the result of mutation in the FBN1 gene^Figure 1). More than 500

mutationss have been identified and almost all are unique to an affected individual or

family10.. FBN1 consists of 65 exons, with almost every domain of fibril l in-1 being encoded

byy an individual exon. The locations of the mutation are spread throughout the FBN1

gene.. The majority of mutations are missense mutations (about two-thirds of all FBN1

mutations)) that alter a single amino acid out of the 2.871 amino acids that constitute the

protein11.. Most of these missense mutations occur in EGF-like domains and are predicted

too disrupt calcium binding and/or the secundary structure of the domain1 2 . About 2 0 % of

alll reported mutations cause a frameshift with a downstream premature termination codon

andd approximately 12 % of all mutations found to date are splice site mutations11.

Genotype-phenotypee correlations in the Marfan syndrome have been complicated by the

largee number of unique mutations reported, as well as by cl inical heterogeneity among

individualss with the same mutat ion1 3 1 4 . At present it is still not possible to find a mutation

17 7

4-* *

Q_ _

100 15 20 25 30 35 40 45 50 55 60 65

EGF-like,, calcium-binding

D D Hybridd jjj Proline rich | EGF-like, not calcium-binding

Figuree 1 Schematic representation of the domain organization of fibrillin-1

1 1 C O O H H

inn approximately 20% of the patients with a definite diagnosis of Marfan syndrome15.

Moreover,, mutations in the FBN1 gene have also been found in patients with other

fibrillinpathies.. Some associations have emerged, however. Skipping of exons 24-32

correlatess with the most severe, neonatal forms of Marfan syndromel61718. Mutations

thatt change a cysteine residueor a residue that is crucial for calcium binding in one of the

cbEGF-likee domains usually cause classic Marfan syndrome19,20. A significant subset of

mutationss located in exons 59-65 (the last seven exons of FBN1) seem to be associated

withh mild phenotypes21.

Inn Chapter 8, we investigated whether type or location of the FBN1 was associated with

aorticc stiffness assessed by magnetic resonance (MR) imaging. Thirty novel FBN1 mutations

weree detected. There was no association between FBN1 genotype and aortic stiffness.

Thiss is similar to other known poor genotype-phenotype associations in patients with

Marfann syndrome. The study provides further evidence that type or location of the FBN1

mutationn do not influence phenotypic severity; other modifiers of phenotypic expression

mustt be implicated, which is subject for further studies.

Hutchinsonn et al. suggested that differences in normal FBN1 expression could contribute

too the clinical variability seen in families with Marfan syndrome, and should be considered

ass a potential modifier of phenotype22.

Untill recently, three models of the pathophysiology of Marfan syndrome have been

proposed.. Initially, a dominant negative model of pathophysiology was hypothesized, in

whichh the mutant fibrillin monomer disrupts assembly of normal fibrillin-1 into microfibrils

orr is itself misincorporated into the microfibril23. The level of mutant protein modulates

thee severity of the disease. Two other models are disturbence of tissue homeostasis of

elasticc fibers, and increased susceptibility of fibrillin to proteolysis24,25.

Recentlyy in a study by Neptune et al. a fourth model of pathophysiology has been

proposed26.. It was shown that mice deficient in fibrillin-1 had marked dysregulation of

transformingg growth factor-P (TGF-0) activation and signaling, resulting in apoptosis in

thee developing lung. Perinatal antagonism of TGF-p attenuated apoptosis and rescued

alveolarr septation in vivo.

Thiss pathogenetic mechanism might also underlie other manifestations of Marfan

syndrome,, including myxomatous changes of valve leaflets and bone overgrowth. If this

modell could be confirmed in humans, some pathologies might become amenable to

perinatall treatment.

Tablee 1 . Diagnostic Criteria for Marfan's Syndrome

Familyy history

Genetics s Cardiovascular r

Ocular r

Skeletal l

Pulmonary y

Skin n

Centrall nervous system

Independentt diagnosis in parent child,, sibling Mutationn FBN1 Aorticc root dilation Dissectionn of ascending aorta

Ectopicc lens

(44 needed):

Pectuss excavatum needing surgery Pectuss carinatum Pess planus Wristt and thumb sign Scoliosiss > 20 or Spondylolisthesis s Armm span-height ratio > 1.05 PfDtrusk)) acetabulae (xray, MRI) Diminishedd extension elbows (< 170 °)

Lumbosacrall dural ectasia (CT or MRI)

None e

None e Mitrall valvar prolapse Calcificationn of the mitral

vatve(<< 40 yrs.) Dilationn pulmonary trunk Dtlation/dissectionn of

descendingg aorta (22 needed):

Flatt cornea Myopia a Elongatedd globe

(2-33 major, or 1 major and 2 minorr signs):

Moderatee pectus excavatum Highh narrowly arched palate Typicall face Jointt hypermobility

Spontaneouss pneumothorax Apicall bulla Unexplainedd stretch marks (striae) Recurrentt or incisional herniae

Becausee of the intragenic heterogeneity molecular genetic screening is hampered to a

considerablee extent, and diagnosis is still based mainly on cl inical major and minor

features,, as defined by a multidisciplinary counci l of experts in the f ield, known as the

Ghentt nosology13 (Table 1).

Inn the Ghent nosology, dural ectasia was added to the major criteria for Marfan syndrome.

Inn a recent study, quantitative criteria for dural ectasia were established using MR imaging27.

Durall sac - vertebral body ratio was calculated at all lumbosacral levels from L1 through

S1.. A dural sac - vertebral body ratio at L3 > 0.47 or at SI > 0.57 could identify Marfan

syndromee wi th 9 5 % sensitivity and 9 8 % specificity. No other major criterion reaches the

sensitivityy and specificity of dural ectasia for Marfan syndrome.

I I9 9

Q. . to to

JC C U U

Cardiovascularr manifestations Thee most common cardiovascular manifestations of Marfan syndrome include mitral

valvee prolapse and regurgitation, but aortic di latation, especially of the aortic root, is the

mostt common cause of morbidity and mortality. Dilatation of the sinus of Valsalva is

foundd in 60-80% of adults with Marfan syndrome. Elastic fibers, composed of elastin

depositedd in microfibrils, are relatively more prevalent in the ascending aorta than in any

otherr region of the arterial tree28. This biochemical feature, coupled with the repetitive

stresss of left ventricular ejection, probably accounts for aortic dilatation usually occurring

primarilyy in the aortic root29-30. The rate of dilatation is heterogeneous and

unpredictable3132.. Beta-blockers have been shown to reduce the rate of aortic dilatation

andd to improve survival in patients with Marfan syndrome during a follow-up of more

thann 10 years7. Echocardiography in the parasternal long-axis view is mostly used for

measurementt of the aortic root. MR imaging is particularly useful for imaging of the

entiree aorta, for patients with dysformed chest wall and asymmetrically aortic roots33.

AA relatively unknown cardiovascular manifestation of Marfan syndrome is dilatation of

thee main pulmonary artery (Chapter 2). Normal values for the pulmonary artery root

havee been established recently34. Of 50 patients with Marfan syndrome, MR imaging

showedd in 37 (74%) patients an enlarged pulmonary artery root above the upper limit of

normal,, 34.8 mm. Dilatation of the pulmonary artery was more prominent in the root

thann in the distal main pulmonary artery, similar to the dilatation process in the aortic

roott in patients with Marfan syndrome. There was a good correlation between pulmonary

andd aortic root diameter, indicating that pulmonary root dilatation seems to increase

withh progressive involvement of the cardiovascular system. Until now, pulmonary artery

aneurysmm and dissection are rare, but they may become of more clinical relevance in the

nearr future because of increased longevity in patients with Marfan syndrome.

Inn Chapter 3, we reported about measurement of dimensions of the pulmonary artery

usingg a simple spin echo (SE) MR imaging-technique (Axial SE-MRI). We compared these

dataa with contrast enhanced MR-angiography (CE-MRA) and found approximately equal

valuess with both techniques. We concluded that SE-MRI is a simple and reliable method to

measuree pulmonary artery dimensions in patients with Marfan syndrome, which could

veryy well be used for follow-up. Besides, a slight asymmetry in the pulmonary artery root

waswas detected.

Althoughh not included in the diagnostic criteria for Marfan syndrome, it has been

speculatedd that a fibrillin defect in the myocardium may predispose patients with Marfan

syndromee to LV dilatation and reduced LV function4'3536. Recently, in a study of 36

patientss with Marfan syndrome without significant valvular regurgitation, LV dimensions

weree found within the normal range37. No abnormal change in LV dimension was observed

duringg an average follow-up period of 10.8 years. Mean ejection fraction was %

(rangee 50% to 69%) and there was no change in ejection fraction over time. The authors

concludedd that LV dilatation and dysfunction do not occur in most patients with Marfan

syndromee in the absence of important valvular regurgitation.

Aorticc stiffness

Thee risk of aortic dissection rises appreciably with increasing aortic size, but it may occur

att any point in the course of the disease3839. As an additional potential predictor for

aorticc dissection noninvasive aortic stiffness has been investigated in patients with Marfan

syndrome40'41'42. .

sionall MR imaging of the entire aorta. Levels for measurementss are indicated with solid lines, slocityy between these levels was calculated.

en n

ai ai Q. . 03 3

- C C

U U I2I I

E E E E

Groeninkk et al. demonstrated decreased aortic elasticity (increased aortic stiffness)

determinedd by measurement of local distensibility and flow wave velocity with MR imaging

inn non-operated patients with Marfan syndrome41 (Figure 2).

Afterr aortic root replacement, both patients presenting with dissection at the time of the

operationn and electively operated patients with Marfan syndrome deserve intensive

attentionn because aneurysms and dissection of the aorta may develop distal to the site of

thee graft7-43.

Inn a population of 117 patients with Marfan syndrome no significant differences in aortic

elasticityy could be demonstrated between 39 patients with and 78 without aortic root

replacementt (Chapter 5)44. This agrees with the observation of Finkbohner et al. that the

incidencee of surgery for aneurysm or dissection in the thoracoabdominal aorta is similar

(16%)) in electively operated and non-operated patients with Marfan during a follow-up

periodd of 25 years42. Patients after elective aortic root replacement are probably not at

Figuree 2 Three-dimen n distensibility y Floww wave v

higherr risk for aortic complications in the residual aorta than non-operated patients44.

Inn Chapter 6, we investigated the heterogeneous response to (3-blockade in patients with

Marfann syndrome by means of a non-invasive assessed aortic pressure-area curve. This

neww noninvasive method to derive aortic pressure-area curves showed that most patients

withh Marfan syndrome had a similar pressure-area curve to control subjects with similar

bloodd pressures. Five patients on P-blockade showed a transition point in the pressure-

areaa curve, which could play a crucial role in the heterogeneous response to B-blocking

therapyy in Marfan patients. We concluded that patients with a transition at low blood

pressuress may not benefit from B-blocking agents.

Thee prognostic significance of aortic stiffness was investigated in a prospective follow-up

studyy of 78 non-operated patients with Marfan syndrome (Chapter 7). During a 6-year

follow-up,, 4 (5%) of 78 patients developed an aortic dissection (1 type A, 2 type B, and

11 infra-renal dissection). Twenty (26%) of the 78 patients had progressive aortic root

dilatationn (mean aortic diameter increase > 1 mm/year). There were 5 (6%) patients with

progressivee descending thoracic aortic dilatation and 6 (7%) with progressive abdominal

aorticc dilatation. Multivariate analysis revealed that local distensibility was an independent

predictorr of progressive thoracic descending aortic dilatation. For progressive aortic root

andd abdominal aortic dilatation local initial diameter appeared to be the major predictor.

Thiss means, that for optimal risk assessment and monitoring of patients with Marfan

syndrome,, both aortic stiffness and diameter should be assessed.

Aorticc surgery Untill recently, composite replacement of the aortic valve and ascending aorta was the

standardd operation for aortic root aneurysm in patients with Marfan syndrome. Over the

pastt 30 years, composite valve graft has become a low risk operation and a very durable

onee for these patients. In a recent report by Gott and associates on the results of aortic

roott replacement in 675 patients with Marfan syndrome, the operative mortality was

1.5%% for elective operations and 11.7 % for emergency operations45. Five and 10-year

survivall after aortic root replacement was 84% and 75%, respectively45.

Aorticc root replacement in patients with Marfan syndrome has been associated with a

considerablee higher risk of redissection and recurrent aneurysm than in patients with

anotherr etiology of aortic disease46. Presence of dissection, either acute or chronic, at the

timee of first operation is a significant predictor of subsequent repeat aortic operation42.

Otherr risk factors for reoperation are hypertension and smoking42.

Forr those patients wishing to avoid anticoagulation therapy two types of valve-sparing

Figuree 3 MRR imaging angiography of a patients with coronary ostial aneurysmss in both reimplanted coronary arteries.

operationss have been introduced in the early 1990s: reimplantation of the aortic root

(David'ss procedure), and remodelling of the aortic root (Yacoub's procedure)4748. Either

typee of valve-sparing aortic root replacement appears to be safe, reproducible, and

associatedd with reasonable 5- to 10-years results for selected patients, at least in institutions

withh cardiac surgeons who have considerable personal experience with this procedure49.

Survivall was excellent in a recent report from the Toronto group, although 25% of the

patientss had severe aortic regurgitation 10 years after valve-sparing aortic root

replacement50.. The long-term results of valve-sparing aortic root replacement, and the

overalll incidence of all valve-related and aorta-related complications in large numbers

off patients with Marfan syndrome are still unknown.

AA relatively unknown postoperative complication, both after aortic valve-sparing operations

andd after composite aortic valve replacement is coronary ostial aneurysm51 (Chapter 4)

(Figuree 3). In a series of 40 patients with Marfan syndrome who underwent MR imaging

33 months to 19 years after elective aortic root surgery 27 (43%) patients had coronary

ostiall aneurysms. Coronary ostial aneurysms were more frequently seen in patients < 35

yearss of age at operation versus those > 35 years of age. Time after operation, did not

influencee the prevalence of coronary ostial aneurysms. Therefore, it seems likely that

coronaryy ostial aneurysms are not progressive and develop due to perioperative stretch of

thee weakened wall of the coronary ostium. Follow-up studies, however, are needed to

confirmm this.

Overr the past 30 years improvement of diagnostic modalities and aggressive medical

andd surgical therapy, have resulted in considerable improvement of life expectancy of

patientss with Marfan syndrome.

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51.. Meijboom LJ, Nollen GJ, Merchant N, Webbb GD, Groenink M, David TE, de Mol BA,, Tijssen JG, Romkes H, Mulder BJ. Frequencyy of coronary ostial aneurysms afterr aortic root surgery in patients with the Marfann syndrome. Am J Cardiol 2002;89:1135-1138. .