Cardiovascular Care of Patients With Marfan Syndrome

Written By: Sam Savage

Published Date: March 31, 2005 Last Edited: March 31, 2005

Summary

Marfan syndrome is a genetic disorder with potentially fatal cardiovascular complications. These risks can be reduced by early diagnosis, appropriate review and timely intervention. Care of patients with Marfan syndrome should be multidisdplinary and multiprofessional. This article reviews the cardiovascular aspects of care and the nursing role.

Key words

* Cardiovascular disorders: prevention and screening

* Cardiovascular system and disorders

These key words are based on the subject headings from the British Nursing Index. This article has been subject to double- blind review.

MARFAN SYNDROME is a genetic, connective tissue disorder. It presents in various body systems: skeletal, ocular, cardiovascular, respiratory, muscular and integumentary (Pyeritz 2000). It was identified in Paris in the late 19th century by Professor Marfan, in a tall, young girl with disproportionately long limbs and arachnodactyly (long digits). These are classic physical signs of the syndrome. Further manifestations were discovered throughout the 20th century (Table 1 ) (De Paepe et al 1996). It is estimated that there are approximately 10,000 patients with Marfan syndrome in the UK, based on an occurrence of one in every 3,000-5,000 live births (van Karnebeek et al 2001). There are no apparent gender or racial differences for the syndrome.

It is caused by mutation in the fibrillin-1 (FBN-1) gene that encodes the glycoprotein fibrillin, on the long arm of chromosome 15. Fibrillin combines with other components to form microfibrils – a fundamental connective structure found throughout the body (Pyeritz 2000). Inheritance is autosomal dominant: there is a 50 per cent chance of an affected parent passing the mutation to his or her child (Pyeritz 2000). It is inherited in approximately 75 per cent of cases and occurs due to spontaneous mutation in the remaining 25 per cent (Pyeritz 2000). Family clusters are common so genetic screening and counselling are required. More than 150 different mutations of the FBN-1 gene have been isolated and it may be that each family has a unique genetic mutation for the syndrome (Pereira et al 1994). This could explain the considerable variability in the clinical presentations of Marfan syndrome. It also means that diagnosis cannot necessarily be made from genetic testing alone.

The wide spectrum of clinical phenotype – the observable characteristics of the genetic condition – and the lack of diagnostic blood tests make definite diagnosis problematic. Expert consensus has resulted in the Ghent diagnostic criteria (Table 1) (De Paepe et al 1996).

There is a subset of Marfan syndrome with severe manifestations which is recognisable at, or soon after, birth. These infants have a high mortality (Morse et al 1990). More typically, patients will be identified as potentially having Marfan syndrome during childhood or following family assessment after the diagnosis of a relative. As connective tissue changes can be confused with normal variation during adolescence, patients may need serial review before a definitive positive or negative diagnosis can be made (Lipscomb et al 1997). Uncertainty over diagnosis can create psychological stress – especially in adolescents. Clinicians need to be aware of this because it will affect concordance with review and treatment programmes. Diagnosis is further complicated by the presence of other related, or similar, conditions where microfibrils are also affected, such as congenital contractural arachnodactyly (CCA); familial mitral valve prolapse (MVP) syndrome; familial aortic dissection; familial ectopia lentis; familial tall stature; and Shprintzen-Goldberg syndrome. The latter is a rare FBN-1 mutation with similar presentation to Marfan syndrome but with more pronounced facial features and additional complications of craniostenosis and ocular proptosis (Pyeritz 2000).

If skeletal changes and body shape have not raised suspicion of Marfan syndrome, then the first clinical presentation is often lens dislocation or joint dislocation. A family history of aortic dissection or sudden unexplained death is important. These events should always raise the possibility of a Marfan syndrome diagnosis and initiate review. As this syndrome affects multiple body systems, review will involve a variety of specialists such as geneticist, cardiologist, ophthalmologist and orthopaedic surgeon (Child and Briggs 2002). Ideally, there should be a clinician experienced in Marfan syndrome coordinating overall care and specialist reviews. In the UK, in practice, services can be disjointed: shared responsibility through different healthcare levels (primary, secondary and tertiary) and clinicians may not always be accompanied by clear coordination. Genetic services and congenital cardiology are usually provided regionally at the tertiary level. There is a need to consider what methods of service delivery are required for this group of patients.

Cardiovascular complications

Patients with Marfan syndrome have serious cardiovascular complications. The most common are aorta dilation, dissection and rupture; aortic valve regurgitation; and MVP and regurgitation (Child and Briggs 2002). There are also reports of tricuspid regurgitation, pulmonary artery dilation, pulmonary valve stenosis, cardiomyopathy and arrhythmias (Adams and Trent 1998). Estimates of the frequency of cardiac complications vary from 50 per cent to 80- 90 per cent of patients with the syndrome (Child and Briggs 2002, Holcomb 2000). The wide variation in estimates reflects the lack of large studies.

Table 1. Ghent diagnostic criteria

Cardiovascular complications represent the most significant threat to life (Dean 2002). In 1972 the median life expectancy for patients with Marfan syndrome was 45 years (Murdoch et al 1972). This had risen to 70 years in a review of 417 patients in 1995. This was attributed to earlier intervention, better diagnosis and the inclusion of patients with milder variants in the study (Silverman et al 1995).

Aorta and aortic valve Aortic aneurysm as a complication of Marfan syndrome was first described by Taussig in 1943 (Gott et al 1999). The extracellular matrix of the arterial wall, mainly in the media layer, is progressively weakened in the syndrome (Child and Briggs 2002). The arterial wall becomes stiffer and less distensible. These changes are systemic to other elastic arteries, resulting in intracranial aneurysms for example, but only dilation in the aorta, and occasionally the pulmonary artery, are clinically significant (Pyeritz 2000).

Dilation is usually located in the ascending aorta, which is under the greatest haemodynamic stress, but can occur in the arch and descending aorta. When dilation is in the area of the sinus of Valsalva there is often aortic valve compromise. Aortic valve regurgitation is rarely seen when the aortic dimension is less than 40mm and is almost always present when the diameter is greater than 60mm (Pyeritz 2000). Aortic dilation is common in patients with Marian syndrome: in a study of 52 children, 43 had aortic dilation (van Karnebeek et al 2001). The same study found 13 of the 52 had aortic valve regurgitation. Aortic dilation is associated with an increased risk of sudden dissection and rupture – emergencies that carry a significant mortality (Silverman et al 1995, Wijetunge 2002). The risk to life is greatest with retrograde dissections because these may compromise the coronary arteries and the pericardium. Patients should be advised of the classic symptoms of aortic dissection – sudden onset severe pain, often located either retrosternally or between the shoulder blades, occasionally in the abdominal midline, ‘tearing’ or ‘sharp’ in nature; pallor; loss of peripheral pulses; paraesthesia; and paralysis – and the need to seek immediate medical assistance.

Aortic dilation is progressive but the natural history of dilation shows a marked variability between patients. It may be that some patients are especially vulnerable genetically or that some additional environmental factors are implicated. While dilation increases the risk of dissection and rupture, they are not inevitable consequences of dilation. Treatment of aortic dilation and aortic valve regurgitation is both medical and surgical. Medical therapy is to reduce haemodynamic strain, usually with beta blockers, and surgical treatment is aortic root replacement and aortic valve replacement. Beta blockers Beta blockers have been used since the 1960s to reduce arterial wall tension in patients with acute aortic aneurysms and dissections. The prophylactic use of beta blockers in patients with Marfan syndrome to slow progressive aortic dilation was first proposed in the 1970s (Halpern et al 1971). Beta blockers might slow progression of aortic regurgitation (Ose and McKusick 1977).

The clinical evidence base for the use of beta blockers in patients with Marfan syndrome is not extensive. There has been one randomised controlled trial of a beta blocker in patients with the syndrome (Shores et al 1994). This compared aortic dilation, as well as clinical endpoints such as aortic dissection and mortality, in 70 patients with Marfan syndrome over a ten-year study: 32 were given propranolol 212mg +/- 68mg; and a control group of 38 had no medicines. The results of the trial showed that high doses of propranolol slowed aortic dilation. There was a \less strong link with the clinical endpoints. During the study ten of the 32 patients taking propranolol experienced side effects – lethargy, depression, insomnia, dream disturbance, heart blocks and mild bronchospasm – although no patient had to stop treatment because of side effects. Further studies have examined the effectiveness of beta blockers in reducing haemodynamic stresses (Reed and Alpert 1992, Yin et al 1989) and in slowing aortic dilation in patients with Marfan syndrome (Rossi-Foulkes et al 1999, Salim et al 1994).

Several questions remain about the prophylactic use of beta blockers for patients with Marfan syndrome:

* Is there a class effect for all beta blockers or are some beta blockers more effective than others?

* Is there an optimum dose?

* Do all patients need prophylactic beta blockers or is there a high-risk sub-group of patients?

* When should beta blockers be started?

* Should they be continued for life?

A complication is that the response of patients with Marfan syndrome to beta blockers is heterogeneous (Haouzi et al 1997, Legget et al 1996, Nollen et al 2004). The incidence of side effects with beta blockers means the benefits of their use need to be considered for individual patients with an appreciation of the risks. One centre recommends using beta blockers if the aortic root is greater than 95 per cent predicted size for that patient’s body size (Salim and Alpert 2001). Another recommendation is that all patients should be considered for beta blockers (Pyeritz 2000). There is also research examining the use of magnetic resonance imaging (MRI) mapping of aortic distensibility as a potential means of identifying patients with Marfan syndrome who have a normal sized but vulnerable aorta and may benefit from early treatment (Groenink et al 2001).

For patients who are unable to take beta blockers, other anti- hypertensives, such as angiotensin-converting enzyme (ACE) inhibitors, have been suggested as an alternative but there are no trials of such drugs in Marfan syndrome (Child and Briggs 2002).

Aorta and aortic valve surgery Surgical treatment of aortic dilation and aortic valve regurgitation is usually by combined aorta graft and prosthetic valve replacement (Gott et al 1999). Benthall and DeBono first described the composite graft valve procedure in 1968 (Treasure 2000). Less commonly, if the sinus of Valsalva is not widely dilated and the valve cusps not stretched, a valve-saving operation is also possible (Pyeritz 2000). While mortality is high in emergency aortic repair, it is low in elective procedures and case studies of patients undergoing this procedure show good long- term outcomes, although absolute numbers remain relatively small. The timing of when to perform surgery has been widely considered in the literature. Expert consensus is that surgery is best undertaken when the indications listed in Box 1 are present (Groenink et al 1999). Late aortic dissections have occurred in patients who have already had aortic repair so there is a need for regular ongoing cardiac review (Treasure and Briggs 2002).

Mitral valve prolapse (MVP) Patients with Marfan syndrome often have MVP, potentially leading to mitral regurgitation, arrhythmias, heart failure and pulmonary hypertension (Pyeritz 2000). In a study of children with Marfan syndrome, MVP occurred in 46 of 52 cases and 25 had mitral regurgitation (van Karnebeek et al 2001). In a study of nine patients with Marfan syndrome and mitral regurgitation all had a dilated annulus, five had a prolapsed mitral valve leaflet and two had ruptured chordae tendineae (Bozbuga et al 2003). Calcification of the mitral valve annulus is also frequently present.

If patients with MVP are asymptomatic and mitral regurgitation is mild or moderate no surgery is indicated. For patients with mitral valve compromise the surgical options are repair or replacement. A review of 160 patients with Marfan syndrome and surgical intervention showed 29 required mitral valve repair and seven mitral valve replacements (Gillinov et al 1994). Repair has been controversial because the underlying connective tissue disorder makes the repair theoretically vulnerable in terms of durability. Repair does have the advantage of preserving the papillary muscles, and therefore left ventricular shape and function, as well as avoiding chronic anti-coagulation. Outcomes are good: in a study of nine patients with Marfan syndrome, mitral regurgitation and left ventricular dilation, surgical procedures on the mitral valve were performed successfully without any complications (Bozbuga et al 2003). However, it should be noted that the cases in the literature are small in absolute numbers so the evidence base is not extensive. For patients with mitral valve disorders and heart failure, medical treatment would be as recommended for all cases of heart failure.

Other cardiac complications It has been suggested that not all cases of sudden death in patients with Marfan syndrome may be due to aortic dissection. Arrhythmias and cardiomyopathy have both been considered as additional causative factors.

Patients with Marfan syndrome may have supra-ventricular and ventricular dysrhythmia and the incidence rises with MVP (Pyeritz 2000). Arrhythmias were considered in a longitudinal study of 70 patients with Marfan syndrome who were followed up for 24 years (Yetman et al 2003). All had cardiovascular involvement identified at diagnosis and all were started on beta blockers. Although none died of aortic dissection, 4 per cent (n=3) died of an arrhythmia. The authors linked these deaths to the patients having enlarged left ventricles, MVP and repolarisation abnormalities (Yetman et al 2003).

It seems that some patients with Marfan syndrome may have an unusual pattern of trans-mitral valve diastolic blood flow with reduced ventricular compliance and myocardial contraction. Diastolic dysfunction, in a study of 28 patients with Marfan syndrome, differed from 28 controls (patients without Marfan syndrome) and was independent of valve disease (Porciani et al 2002). Cardiomyopathy, without valve involvement, may be due to defects in the cardiac muscle (Pyeritz 2000).

Cardiovascular assessement and review

Patients being assessed for Marfan syndrome should all have an initial cardiovascular consultation with a clinician experienced in the syndrome. Clinical assessment is aimed at assisting the diagnosis by establishing major and minor cardiovascular criteria of the Ghent diagnostic criteria (De Paepe et al 1996). Investigations will establish baselines of cardiac structure and function to guide follow-up reviews.

History taking should include a thorough family history. It is important to differentiate hereditary from spontaneous mutations and to map the family tree so that assessment of other family members can take place. A history of a family member with aortic dissection or an unexplained sudden death is both a potential major diagnostic criteria and a risk factor for future complications. It must be remembered that most isolated family histories of aortic aneurysms, scoliosis, tall stature and myopia are not caused by Marfan syndrome (Pyeritz 2000). Symptoms and functional capacity need to be established: dyspnoea and fatigue could suggest heart failure from mitral regurgitation, for example.

A careful cardiovascular examination should be performed. Cardiac apex beat should be palpated for downward and left lateral displacement that may suggest left ventricular hypertrophy or a sternal heave that may suggest right ventricular hypertrophy. Cardiac auscultation may reveal MVP as a midsystolic click and mitral regurgitation as a pansystolic murmur heard best at the apex. Aortic regurgitation may be heard best as an early diastolic murmur nearer the base. Changes in the aorta can be suggested if there are differences in blood pressure between the upper limbs or radio- femoral pulse delays, although absence of these signs does not rule out aortic dilation or coarctation. Blood pressure needs accurate measurement because hypertension will initiate active treatment.

Box 1. Indications for aortic surgery

Investigations should include a minimum of 12-lead electrocardiogram (ECG) and transthoradc echocardiogram. On ECG evidence of arrhythmias, hypertension or hypertrophy may be present – although there are no ECG patterns or changes specific to Marfan syndrome (Pyeritz 2000). The presence of skeletal abnormalities – such as pectus excavatum – might affect the cardiac axis and the voltage recorded by the electrodes. A transthoracic echocardiogram should be performed to assess chamber sizes, valve structure and function, flow across valves and the aortic size at several points, including measurement across the sinus of Valsalva. Echocardiogram measurements need to be applied against a nomogram of body surface area to take into account different heights and weights, especially in children – these are available online (www.marfan.org). As there are technological limits to the accuracy of transthoracic echocardiogram and skeletal abnormalities can make transthoracic echocardiogram difficult, there may be a role for other scanning modalities – tranoesphageal echocardiogram, computerised tomography and MRI – and scanning further down the aorta in some cases (Leech 2002).

For patients with a clear diagnosis of Marfan syndrome but no cardiovascular compromise, an annual cardiovascular review of echocardiogram and clinical assessment is recommended (Child and Briggs 2002, Dean 2002). If patients have cardiovascular compromise – in terms of symptoms, valve dysfunction or an aorta greater than 40mm – it is recommended that review is not less than every six months (Child and Briggs 2002). Women who are pregnant and have Marfan syndrome should be frequently reviewed jointly with an obstetrician.

Nursing role

On diagnosis and on review, patients and their families need information about th\eir condition and assistance with the psychosocial adaptations needed to cope with the disease. Specific advice should be given about sports, dental procedures, family and work-related issues and what to do in an emergency. Acute aortic dissection is rare but patients and their families should be advised that sudden thoracic pain, especially a tearing pain in the back, associated with dizziness or loss of consciousness, requires urgent transfer to hospital by ambulance. The appropriateness of beta blockers in individual cases should be discussed and the indications for surgical referral explained. These are all areas where nursing skills can be valuably employed. Patients are likely to be reviewed most frequently by the cardiac team, and much specific advice is given to avoid cardiac complications, so it would seem logical for the cardiac team to act as key clinicians alongside the primary care team. Current UK service provision does not include many cardiac specialist nurses in adult congenital and genetic heart disease clinics. Little has been published by nurses on the syndrome in the UK and there is a need for research to consider what nursing interventions would be most effective in this patient group. Nursing staff need to raise their awareness of Marfan syndrome to help identify patients and reduce under-diagnosis, to provide psychological support to patients and their families and to be vigilant for complications when they nurse patients with Marfan syndrome.

Psychosocial issues People with Marfan syndrome often have distinctive physiognomy and may be sensitive about their appearance. Many report being bullied and teased at school (van Tongerloo and De Paepe 1998). They have to adapt psychologically to having a chronic and progressive disorder, which may or may not make them feel unwell but is potentially fatal. In a study of 17 patients aged under 35, the condition had an impact on physical activities, schooling and job opportunities, although most patients felt they were coping well (van Tongerloo and De Paepe 1998). This was confirmed by a large study of 174 patients with Marfan syndrome in the United States who reported psychological issues but an overall adequate quality of life (Peters et al 2002).

The disorder has implications for patients’ reproductive choices and relationships and these should be sensitively discussed alongside genetic counselling (Ryan-Krause 2002). Feelings of guilt about passing on the condition to children, or of being a family member who has been found not to have the condition, have been reported (Ryan-Krause 2002). There is some research that has suggested a link between attention deficit hyperactivity disorder (ADHD) and Marfan syndrome (Hofman et al 1988, Lannoo et al 1996).

Sports advice One of the common referral scenarios is of young athletes who have had medical examinations that raised the possibility of Marfan syndrome due to skeletal signs (Ryan-Krause 2002). The tall stature and long limbs often present in the disorder are especially useful for sports such as basketball, volleyball and some athletics. A special gift for these sports also means special risks: ocular, skeletal and cardiovascular. An elongated globe stretches the retina and cilia muscles and makes lens dislocation likely. Ligament laxity makes joint dislocations likely. Static high- demand sports, like weight lifting, place extra strain on the aortic wall and this increases the risk of dissection. Up to 10 per cent of aortic dissections in patients with Marfan syndrome follow physical exertion (Child and Briggs 2002). Patients who have had valve surgery are at increased risk of bleeding and bruising from contact sports due to the use of anti-coagulants. Patients with Marfan syndrome should be advised to avoid contact sports, static high- demand sports and wear eye protection for racket sports (Salim and Alpert 2001).

Dental advice Patients with valvular heart disease are at increased risk of endocarditis. They should take prophylactic antibiotics peri-operatively and to cover invasive dental work (Bonow et al 1998). Because patients with Marfan syndrome may have valve abnormalities and are also more likely than average to require dental work – if they have high arched palates and teeth crowding – they should be advised on the need for prophylactic antibiotics before dental work likely to result in bleeding (Ryan-Krause 2002).

Pregnancy advice and management Patients with Marfan syndrome face two important issues related to having children. First, because the condition has autosomal dominant inheritance, there is a 50 per cent chance of the gene being transferred from parent to child (Elkayam et al 1995). It is also possible that the child may have a more severe or complex presentation than the affected parent. The second issue is that pregnancy can increase the risk of aortic dissection in women with Marfan syndrome (Rahman et al 2003). Four aortic dissections were reported in a study of 91 pregnancies in women with Marfan syndrome (Lipscomb et al 1997) and another series of 24 pregnancies reported two aortic dissections (Rahman et al 2003). All women have a risk of aortic dissection in the third trimester and a month post-partum but the risks appear higher in women with Marfan syndrome.

A review of the literature found more than 30 cases of cardiovascular complications during pregnancy (Elkayam et al 1995). It is thought this risk is highest in women with pre-existing cardiovascular complications before pregnancy. A study of 45 pregnancies in 21 women with Marfan syndrome found two aortic dissections – which occurred in women already identified as having cardiovascular compromise before pregnancy – and found no evidence of increased risk of longer-term problems (Rossiter et al 1995). The increased dissection risk may be due to hyperdynamic strain, hormonal changes and structural changes in the arterial wall during pregnancy.

While pregnancy is usually complication-free for women with Marfan syndrome, it cannot be guaranteed and it is recommended that special measures are taken: pre-pregnancy counselling about genetic inheritance and pregnancy risks to mother and fetus; scanning of the aorta to include thoracic and abdominal aorta; repeat echocardiograms each trimester and review jointly by cardiologist and obstetrician. Any evidence of aortic dilation means Caesarean section – if the fetus is viable – or termination of pregnancy. Cardiac surgery can be performed as required after delivery or termination. Various beta blockers have been used in pregnancy (propranolol, atenolol and metoprolol) but there is no clear recommendation for routine use (Pyeritz 2000).

Work-related issues

Patients are advised to avoid work that involves repetitive heavy lifting to minimise excessive aortic wall strain. As fatigue is a commonly reported symptom in Marfan syndrome this may affect career decisions. In the UK fitness to drive is regulated by the Driver and Vehicle Licensing Agency (DVLA). Patients with Marfan syndrome need to notify the DVLA if they have a Group 2 licence (public service vehicles and heavy goods vehicles) and must be able to demonstrate annual cardiac reviews – the presence of an aortic root greater than 55mm will disbar the driver until satisfactory treatment. In other circumstances, such as being symptomatic, patients may need medical advice on their suitability to continue driving and the rules are available at the DVLA website (www.dvla.gov.uk). Patients should also be advised on the necessity of informing insurers of their diagnosis as failure to disclose may invalidate policies.

Conclusion

Marfan syndrome is a complex disorder with potentially fatal complications. The most serious complications are cardiovascular. The improvement in prognosis over the past 30 years suggests regular cardiac review, advice and timely intervention are important and beneficial (Silverman et al 1995). The nature of the cardiovascular review means that there are roles naturally suited to the skills of doctors, nurses and cardiac physiologists. As the cardiovascular complications are the most serious and need annual review, it is likely the cardiac team will be the most active clinicians once the diagnosis has been made. The involvement of other specialties such as genetics, orthopaedics, ophthalmology and psychology is likely to be more episodic, depending on particular needs. Links with patient groups and associations can provide a means of involving patients in the service in a more integrated manner.

There are a limited number of doctors with an interest in Marfan syndrome and patients with genetic heart disease have traditionally been cared for alongside patients with congenital heart disease in tertiary cardiac centres. This may not be the only model of care in the future. It has the advantage of specialism and availability of scanning and other resources but has the disadvantage of often significant journeys for the patient and oversubscribed clinics.

Awareness of Marfan syndrome is important for all healthcare staff because it is thought to be under-recognised and diagnosed. To assist in planning services and to consider the effectiveness of interventions further research is necessary to consider service needs from a patient perspective and to consider how the nursing role can be best deployed

Nicholson C (2005) Cardiovascular care of patients with Marfan syndrome. Nursing Standard. 19, 27, 38-44. Date of acceptance: December 8 2004.

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