Sports and Marfan Syndrome
Awareness and Early Diagnosis Can Prevent Sudden Death
Mubadda A. Salim, MD; Bruce S. Alpert, MD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 29 - NO.5 - MAY 2001
In Brief: Marfan syndrome is an autosomal dominant disorder of the connective tissues. Its major manifestations are in the cardiovascular, musculoskeletal, and ocular systems. Recognizing the phenotypic presentation of tall stature, long limbs and fingers, chest deformity, myopia, midsystolic click, and systolic or diastolic murmur can lead to early diagnosis. Morbidity and mortality are primarily caused by cardiovascular involvement. The goal of medical therapy is to retard the aortic root dilation that leads to sudden death from dissection or rupture. Surgical interventions for mitral valve regurgitation and resection of aortic aneurysms are highly effective. In addition, individuals with Marfan syndrome should be restricted from participation in certain sports.
In 1986, the sudden death of former Olympic volleyball player Flo Hyman from a ruptured aortic aneurysm highlighted the need for better detection of Marfan syndrome (MFS) in athletes who may be at risk (1). MFS, a genetic disorder of the connective tissues, has an autosomal dominant inheritance caused by mutations in the gene for the fibrillin-1 protein (2). MFS represents one phenotypic end of the connective-tissue-disorder spectrum, but many of its features are shared with unaffected individuals (table 1). There is no universal molecular screening tool to identify different mutations or combinations of mutations. The prevalence of MFS in the general population is estimated at 2 to 3 per 10,000 (3).
Thorough history-taking and diagnostic testing are crucial. In a survey of 1,110 National Collegiate Athletic Association colleges, Pfister et al (4) demonstrated inadequate screening of athletes for MFS. A question regarding family history of MFS was present on only 59 (9%) of 625 forms analyzed, and a question regarding sudden death in the family before age 50 appeared on only 349 (56%). Physical examination items that pertain to MFS were present in only 14 (2%) of college forms.
However, screening for aortic root dilation—a major finding in MFS—may not be cost-effective in a large population of athletes. In a study from Japan, Kinoshita et al (5) found aortic root dilation in 5 (0.26%) of 1,929 athletes tested. The prevalence of aortic dilation was higher (0.96%) among athletes who participated in basketball and volleyball, presumably because of the advantage of height in these two sports. Features of MFS were present in 2 of these 5 athletes.
The major manifestations of MFS are musculoskeletal, ocular, and cardiovascular. The physical stigmata of MFS include tall stature, myopia, and abnormal cardiac auscultation. Typically, a midsystolic click (mitral valve prolapse) is heard in the apical region and may be followed by a late systolic murmur (mitral regurgitation). With significant aortic root dilation and aortic regurgitation, a diastolic murmur can be heard over the left sternal border associated with a wide pulse pressure and increased precordial activity. Cardiovascular manifestations are the major contributing factors for morbidity and mortality. In 1972, men who had MFS had only a 32% probability of survival to age 60. More striking was that 30% of male and 20% of female MFS patients did not live past age 30 (6). By 1995, improved awareness, diagnostic tools, and therapeutic interventions raised survival rates past age 30 to almost 100% for women and 85% for men (7).
The revised Gent diagnostic criteria (8) require major criteria in two organ systems with some involvement in a third organ system if the patient has no family history of MFS (table 2). In the presence of a family history of MFS, the index case needs one major criterion and the involvement of another organ system. Alternatively, the diagnosis can be made if a major criterion is present in one organ system, another organ system is involved, and a mutation known to cause MFS is detected.
Differential diagnosis. Several other connective tissue disorders are phenotypically related to MFS but do not meet the diagnostic criteria (3). These include the MASS phenotype (mitral valve prolapse, myopia, minimal or no aortic dilation, subtle skeletal changes, skin changes), familial tall stature, familial aortic aneurysm and dissection, familial ectopia lentis, contractural arachnodactyly, and Shprintzen-Goldberg syndrome (3). An experienced and knowledgeable physician may be able to make the initial diagnosis; however, referral to a medical specialist in cardiology or genetics who has expertise in the diagnosis and management of MFS is also necessary.
Musculoskeletal factors. Individuals who have MFS are typically taller than their unaffected siblings. Overgrowth of the tubular bones leads to greater height and the skeletal features of arachnodactyly and pectus excavatum. (3) Patients with MFS are often drawn to sports in which height provides an advantage, such as basketball or volleyball. Tall stature also may be a sign of several other disorders not related to MFS (9).
As a result of abnormal fibrillin, individuals who have MFS also have ligament laxity and an increased frequency of ligament injury, myalgias, and arthralgias (10). Severe pectus excavatum may reduce pulmonary function and may require surgical repair. The thumb sign is positive when the distal phalanx of the flexed thumb extends beyond the ulnar surface of the hand. The wrist sign is positive if the thumb and fifth digit overlap when wrapped around the contralateral wrist. Physicians who screen athletes for sports should be aware of MFS and should consider further evaluation in suspected cases. (See "Smooth Move for Marfan Screening," May 2000, page 37.)
Ocular components. Ectopia lentis, associated with MFS in 50% to 80% of patients (11), involves superior dislocation of the lens (either medial or lateral) from stretching of the ocular zonules rather than from disruption (3). Because it occurs in relatively few other conditions, ectopia lentis is an important characteristic of MFS. Collision in sports may further injure the lens. Patients who have MFS also have an elongated globe that stretches the retina making it more likely to detach, especially in a collision. Using a cushioned eye guard to prevent injury to the globe is recommended for most sports. Patients should avoid sports that may result in blows to the head such as boxing or high diving.
Other findings. Other signs of MFS may prove problematic for the athlete. Spontaneous pneumothorax or pulmonary apical blebs on a chest radiograph (7) should alert the treating physician to the possibility of MFS in an individual not previously diagnosed.
Involvement of the cardiovascular system accounts for the increased risk of death in patients with MFS. Two features, musculoskeletal phenotype and significant abnormalities of the mitral valve, typically occur when MFS manifests in infancy (12,13). Mitral valve prolapse and regurgitation may lead to severe congestive heart failure. Some patients may require mitral valve replacement and, depending on the type of valve used (tissue or mechanical), will have special needs and restrictions from activities.
For patients of any age, aortic root dilation is the major concern for the treating physician. Mutation of the fibrillin gene results in abnormal structural integrity of the ascending aorta (14,15). The aortic root dilation starts at the sinuses of Valsalva and extends distally (16). A study by Roman et al (16) found that patients did not develop aortic root complications during a mean follow-up of 49 months if the initial evaluation did not reveal involvement of the sinuses of Valsalva. Patients with an initially larger aortic root had a significantly higher risk of complications. In another study (17), patients who had a family history of significant complications resulting from MFS had increased aortic root dilation and decreased survival compared with those with a more benign family history.
Risk factors for aortic dilation are important in determining the interventions needed to prevent aortic dissection and rupture. Aortic sinus dilation that extends into the ascending aorta has been shown to increase the risk of progressive aortic dilation. The resulting aortic regurgitation may lead to further dilation as the stroke volume increases (16).
MFS is a progressive disorder, and involvement of an organ system may not be evident at an early age but may develop later. As such, lack of aortic root dilation in an individual who fits the criteria for MFS does not necessarily mean that no dilation will occur. This presents a dilemma regarding the need for follow-up. Some experts recommend aortic root screening every 3 to 5 years. Monitoring the skeletal and other abnormalities should be performed by a qualified specialist who is familiar with MFS.
Beta-blockers. Aortic distensibility in children (18) and adults (19,20) who have MFS has been reported to be decreased compared with the unaffected population. In contrast, our research showed similar aortic root distensibility of both unaffected children and those with MFS (21). In children, beta-blockers did not change the aortic root distensibility (21); however, in adults beta-blockers increased distensibility and decreased aortic stiffness (22). Patients who had an aortic root diameter greater than 40 mm did not demonstrate this post-beta-blockade improvement and showed progression of aortic valve regurgitation (22).
The goal of therapy is to retard or even prevent aortic root dilation. The abnormal aortic elastic properties in patients who have MFS has led to attempts to reduce stress on the aortic wall. The abnormal structure of the aortic wall is believed to increase hemodynamic burden during systole. Beta-blockers have both negative ino- tropic and chronotropic effects on the left ventricle (23).
Data in turkeys showed that the use of beta-blockers could prevent spontaneous rupture of the aortic root (24); however, the initial human experience with propranolol hydrochloride was not rewarding. In 1977, Ose and McKusick (25) reported that 5 of 25 patients suffered fatal complications of aortic aneurysm during follow-up of 14 months to 5 years. Echocardiography was not uniformly available at that time, and there was no other reliable noninvasive method of measuring aortic root diameter. Some of the patients may have had significant dilation before starting therapy.
In a prospective, open-label, randomized evaluation of the effects of propranolol, Shores et al (26) demonstrated significant reduction in the rate of dilation of the aortic root in the treatment group. The control group included 38 patients (mean age, 14.5) who were followed for 9.3 years; the treatment group included 32 patients (mean age, 15.4) who were followed for 10.7 years. All patients were between 12 and 50 years old at the start of the study. The analysis was performed according to the intention-to-treat principle. Propranolol was used in all patients, and the dosage was based on resting heart rate, a postexercise heart rate less than 100/min, or echocardiographic evidence of a 30% increase in the systolic time interval (the ratio of left ventricular preejection to ejection times).
The aortic ratio (ratio of measured aortic diameter and the expected diameter based on the patient's body surface area and age) was plotted against follow-up time. A steeper slope indicated faster dilation of the aortic root. The slope of the curve of the aortic ratio plotted against time was significantly steeper for the control group than for the treatment group (P< 0.001). Moreover, 5 patients in the treatment group (2 did not take the prescribed propranolol) and 9 in the control group reached a therapeutic endpoint (death, congestive heart failure, aortic regurgitation, aortic dissection, or cardiovascular surgery). The 2 deaths in the control group were sudden and occurred in patients who had a history of arrhythmia (1 with Wolff-Parkinson-White syndrome); neither had aortic dissection.
A combined study (27) from the University of Tennessee (UT) and Johns Hopkins Hospital (JHH), showed that the rate of aortic root dilation was significantly lower in the treatment group compared with the control group. The JHH patients were treated as described above. The UT patients received an increasing dose of atenolol until symptoms of intolerance to the medication developed, a dose of 2 mg/kg/day was achieved, or the maximal exercise heart rate decreased 30 to 40/min or to less than 80% of the pretreatment value. The UT patients took a larger dose of beta-blocker and demonstrated a lower rate of dilation of aortic root diameter (0.7 ± 1.8 mm/yr) compared with the JHH group (1.1 ± 1.1 mm/yr). Both treatment groups had significantly slower rates of dilation than the control group (2.1 ± 1.6 mm/yr). The mean age of the patients in this study was 11.4 years.
Based on these studies, we recommend beta-blocker therapy to all MFS patients if aortic root diameter exceeds 95% for age. Bronchospasm, Raynaud's phenomenon, and severe diabetes are contraindications to beta-blocker use (3). We initiate therapy with atenolol (1 mg/kg/day) and increase it as tolerated based on the heart rate response. In adults or adolescents, the target resting heart rate is less than 60/min or less than 100/min postexercise. Follow-up every 6 months should include assessment of aortic root diameter by an imaging modality (echocardiogram, computed tomography, or magnetic resonance imaging). Dose adjustment of beta-blockers is based on the patient's symptoms and heart rate (28).
Surgical intervention. In an aortic root replacement with a valved composite graft, called a Bentall procedure, a tubular graft replaces the ascending aorta and is attached to a prosthetic valve in the aortic position (29). This procedure is typically reserved for patients who have a significantly dilated aorta, usually greater than 55 mm. In a multicenter study of aortic root replacement in 675 patients, Gott et al (30) reported a 30-day mortality rate of 1.5% for elective repair, 2.6% for urgent repair (within 7 days of surgical consult), and 11.7% for emergency surgery (within 24 hours of surgical consult). Some cases of aortic dissection occurred even with aortic root diameters of less than 50 mm. The authors also recommended close follow-up of aortic root diameter and elective surgery if it reaches 55 to 60 mm. A portion of the MFS patients underwent valve-sparing surgery in which the aneurysm, but not the aortic valve, was removed. Because the entire structure of the aorta is abnormal, rupture of other segments may occur after repair of the ascending aortic aneurysm. Twenty-two (3.4%) of 653 patients discharged after ascending aortic aneurysm repair suffered a late fatal dissection and/or rupture of the residual aorta (30).
Which Sports for Which Patients?
Sports are a combination of dynamic and static exercise (table 3). Dynamic exercise, such as distance running, involves a relatively small intramuscular force developing in the context of large changes in muscle length and joint movement. During dynamic exercise, progressive increases in oxygen consumption, cardiac output, systolic blood pressure, heart rate, and stroke volume lower peripheral vascular resistance and produce moderate or little decrease in diastolic blood pressure. Static exercise, such as weight lifting, produces an increase in the muscle contractile force generated without a significant change in either the muscle length or joint movement (31). Static exercise modestly increases oxygen consumption, heart rate, and cardiac output. Peripheral vascular resistance increases significantly and persists during static exercise, often with an increase in both the systolic and diastolic blood pressure but no change in stroke volume (31).
Exercise increases the pressure gradient in patients with prosthetic aortic or mitral valves (32). The 26th Bethesda conference (33,34) recommended activity levels for athletes with prosthetic and bioprosthetic valves based on their anticoagulation status and left ventricular function. Patients who have a mitral valve replacement (prosthetic or bioprosthetic), are not taking anticoagulants, and have normal or near-normal left ventricular function can participate in low-to-moderate static and low-to-moderate dynamic activities (see table 3). Patients are also advised to avoid moderately static activities that carry a risk of bodily collision such as auto racing, high diving, motorcycling, or equestrian events. Patients who have an artificial aortic valve, are not taking anticoagulants, and have normal function of both the valve and left ventricle can participate in low-static and low-dynamic activities. Higher levels of activities may be permitted based on the athlete's abilities and hemodynamics. All patients using anticoagulants should avoid sports that have a risk of collision (table 4).
Marfan syndrome is a relatively common connective-tissue disorder that carries a significant risk of sudden death. Improved diagnostic awareness can substantially improve survival rates. After diagnosis is confirmed, active patients should:
The authors wish to thank Jewell C. Ward, MD, PhD, for a thoughtful review of this manuscript before it was submitted for publication.
Dr Salim and Dr Alpert are pediatric cardiologists in the Department of Pediatrics, Division of Cardiology, at the University of Tennessee Memphis. Address correspondence to Mubadda A. Salim, MD, 777 Washington Ave, Suite 215, Memphis, TN 38105; e-mail to [email protected].