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Cardiovascular Management of Marfan Syndrome: Implications for Nurse Practitioners
Cardiovascular Management of Marfan Syndrome: Implications for Nurse Practitioners Jonathan Yip, MN, NP, and Jo-Ann Sawatzky, PhD, RN ABSTRACT
Marfan syndrome (MFS) is a genetic disorder affecting 1 in 5,000 individuals. The diagnosis is made using a combination of genetic testing and the revised Ghent criteria. MFS is associated with the cardiovascular-related risks of aortic dilation and dissection. Therefore, the main goal of medical therapy is blood pressure control using beta-blockers and lifestyle modification. Prophylactic surgical intervention remains the single, definitive measure in preventing dissection or rupture. Nurse practitioners must be vigilant in caring for this population as these cardiovascular risks can be reduced by early identification and diagnosis and timely intervention. Keywords: aortic dilation, aortic dissection, cardiovascular complications, Marfan syndrome Ó 2014 Elsevier, Inc. All rights reserved.
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arfan syndrome (MFS) is a heritable disorder of connective tissue. It is a relatively common genetic disorder affecting 1 in 5,000 individuals without gender, racial, or ethnic predilection.1-3 MFS affects multiple systems of the body, with consequent cardiovascular-, skeletal-, ocular-, integument-, lung-, and dural-related symptoms.3-5 Based on earlier studies, the cause of MFS was thought to be primarily due to the mutation in the fibrillin-1 (FBN-1) gene on chromosome 15, resulting in abnormal fibrillin structure that causes the connective tissue disorder. More recent studies have shown that the dysfunctional transforming growth factor (TGF)-b cytokine plays a more critical role in extracellular matrix homeostasis or remodeling.6-8 The diagnosis of MFS is based on both genetic testing of FBN-1 and physical findings under the revised Ghent criteria. Although MFS manifests in varying degrees of severity, the most life-threatening Readers may receive 0.79 continuing education contact hours, including 0.17 contact hours of pharmacology credit, approved by the American Association of Nurse Practitioners, by reading this article and completing the online posttest and evaluation at https://cecenter.aanp.org/Program? area=JNP. 594
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consequences include aortic dilation and dissection, which can lead to aortic rupture and death. Hence, it is crucial for nurse practitioners (NPs) to have comprehensive knowledge of these complications, as it is not uncommon for NPs to encounter MFS patients in both acute and primary care practice. Currently, the opportunities for early diagnosis and the use of noninvasive serial aortic imaging, as well as advancements in the both medical and surgical management of MFS, have led to significant improvement in the life expectancy of all affected individuals.3,5 In this study we aim to provide NPs with a comprehensive overview of MFS and offer specific insights for the cardiovascular management of these individuals and their families. GENETIC OVERVIEW
MFS is the result of a faulty genetic make-up. Earlier studies concluded that MFS was primarily the result of a mutation in the FBN-1 gene on chromosome 15. FBN-1 encodes the extracellular matrix glycoprotein fibrillin, which is a major component of connective tissue microfibrils found throughout the body.1-3 More recent studies have indicated that the mutated FBN-1 gene also enhances the release of Volume 10, Issue 8, September 2014
TGF-b, which, in turn, plays a critical role in the cardiovascular pathophysiology of MFS.6,7 TGF-b is a cytokine that functions in the regulation of cell proliferation, differentiation, extracellular matrix formation, cell cycle, and apoptosis.6,7 It is the mutation in TGF-b receptor 2 gene that results in extracellular matrix homeostasis and/or cardiovascular remodeling, leading to a stiffer and less distensible aorta.3,6-8 MFS is an inheritable autosomal dominant disorder, which means that each offspring of an affected parent has a 50% chance of inheriting the altered FBN-1 gene.1 Although approximately 75% of all cases are found to be inherited, the remaining 25% occur due to spontaneous mutation.4 To date, > 1,000 different mutations involving the FBN-1 gene have been isolated, with most mutations being unique to a given family.1,2 However, family members with the same mutation causing MFS can exhibit a wide variation in clinical manifestations. No correlation has been found between the specific type of FBN-1 mutation and the clinical phenotype, which explains the extreme variations in clinical phenotypic presentations of MFS. Furthermore, the mutation in the FBN-1 gene can cause conditions other than Marfanlike disorders. None of the current genetic testing methods have the ability to identify all mutations of MFS.4,5 In 10% of patients with a definitive diagnosis of MFS, it is still not possible to find an FBN-1 gene mutation.5 As a result, genetic testing alone is insufficient to make the diagnosis. CLINICAL PRESENTATION
The clinical features of MFS can present in many different parts of the body. Although the most commonly affected regions are the skeletal, ocular, and cardiovascular systems, pulmonary, skin/integument, and dural symptoms have also been reported. An affected individual rarely has every feature. The classic clinical appearance of MFS is a tall, thin individual with disproportionally long arms, and usually a longer than normal lower half of the body. Other common external physical characteristics include pectus excavatum (funnel chest) or pectus carinatum (pigeon chest), double-jointed fingers, elongated thumb, long feet and toes with flat or highly arched www.npjournal.org
feet, scoliosis or kyphosis, severe myopia, crowded teeth, and striae atrophiae (stretch marks).2-4 In addition, common internal characteristics include lens dislocation (ectopia lentis) and a swelling sac around the spinal column (dura ectasia). Cardiovascular involvement results in complications, including the dilation and dissection of aorta, and mitral and/or aortic valve prolapse and/or regurgitation.2-4 Consequently, due to the highly variable presentation of affected individuals, it is essential for NPs to be familiar with the complex diagnostic process for MFS. CLINICAL DIAGNOSIS
The diagnosis of MFS was initially identified by Victor McKusick in 1955 as a classification of connective tissue disorder using his Heritable Connective Tissue Disorders monograph.9,10 Subsequently, a Berlin nosology was created in 1986 by an international panel of experts with the aim of facilitating accurate communication about the condition between health care providers.11 However, this Berlin nosology was later found to only focus on the physical characteristics associated with MFS, ignoring the genetic aspect of the disease. A newer version of the criteria, called the Ghent nosology, was established in 1996, after identification of the causal gene FBN-1.12 The Ghent nosology uses clinical findings of 6 organ systems along with family history and molecular findings to diagnose MFS.12 Recently, due to further advancements in medical research, Loeys et al13 published a revised Ghent nosology, with the intent to decrease the risk of premature or misdiagnosis of MFS. The new Ghent nosology is now the gold standard for the diagnosis of MFS. It puts more weight on the cardiovascular manifestations, with aortic root aneurysm and ectopia lentis being the cardinal clinical features. Thus, diagnosing MFS requires comprehensive patient and family history, including information about any family members who may have the disorder or had an unexplained early or sudden death. In the absence of any family history, the presence of these 2 manifestations is sufficient for the unequivocal diagnosis of MFS. In the absence of either of these 2 features, the presence of an FBN-1 mutation or a combination of systemic manifestations is required (Table 1). The Journal for Nurse Practitioners - JNP
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Table 1. Revised Ghent Criteria for Marfan Syndrome Diagnosis Systemic features
Scoring points
Wrist and thumb sign (ie, the thumb and fifth finger overlap when grasped around the wrist, and whole nail bed extends beyond the ulnar border when the hand is clenched
3
Wrist or thumb sign
1
Pectus carinatum (pigeon chest) deformity
2
Pectus excavatum (funnel chest) or chest asymmetry
1
Hindfoot deformity
2
Plain pes planus (ie, flat foot)
1
Pneumothorax
2
Lumbar sacral dural ectasia (enlargement of the neural canal)
2
Protrusio acetabuli (ie, protruding socket into pelvis)
2
Reduced upper segment/lower segment AND increased arm/height AND no severe scoliosis
1
Scoliosis or thoracolumbar kyphosis
1
Facial features (3 of 5): Dolichocephaly (long narrow skull) Enophthalmos (backward displacement of the eye in the socket) Downslanting palpebral fissures Malar hypoplasia (underdeveloped midface) Retrognathia (receding jaw)
1
Skin striae (stretch marks)
1
Myopia > 3 diopters
1
Mitral valve prolapse (all types)
1
Note: Maximum score ¼ 20 points; 7 points ¼ systemic involvement. Adapted from Loeys et al.13
In the new Ghent criteria, the role of molecular testing of FBN-1 has become more important in the diagnostic assessment. Based on two studies, conducted in 2001 and 2004, Loeys and associates concluded that 97% of FBN-1 mutations could now be detected in MFS patients,14,15 thus providing substantive support for the new Ghent criteria. Although this new guideline may delay a definitive diagnosis of MFS, it will also decrease the risk of premature or misdiagnosis and facilitate worldwide 596
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discussion of risk and follow-up/management guidelines.13 Early diagnosis is critical because early medical and/or surgical management can prevent cardiovascular complications. Therefore, if the disease is suspected in an individual, it is important for the primary care provider, such as the NP, to utilize the established guidelines for clinical examination and diagnostic evaluation (Table 2).16 The guidelines include obtaining a detailed family history, performing an X-ray of the spine for scoliosis of > 20 or spondylolisthesis, and an X-ray of the pelvis for protrusio acetabulae. In addition, the guidelines also recommend magnetic resonance imaging or computed tomography scanning of lumbar and sacrum to rule out dural ectasia, as the prevalence of this is seen in 65% to 92% of the MFS population. A urine specimen should also be collected for metabolic screen or plasma amino acids to exclude homocystinuria for the first person in the family being evaluated for MFS. A referral for an ophthalmology examination is suggested to rule out ectopia lentis, myopia, and other abnormal eye conditions. Finally, a geneticist Table 2. Guidelines for Clinical Practice in Diagnosis of Marfan Syndrome 1. Detailed family history 2. Accurate height and weight to facilitate the calculation of body surface area in monitoring the diameter of aortic size standardized to age and body size 3. X-ray of spine for scoliosis of > 20 or spondylolisthesis 4. X-ray of pelvis for protrusio acetabulae 5. Lumbosacral magnetic resonance imaging (MRI) or computed tomography (CT) to rule-out dural ectasia 6. Urine specimen for metabolic screen or plasma amino acids to exclude homocystinuria for the first person in the family being evaluate for Marfan syndrome 7. Echocardiogram to assess the aortic root and heart dynamics 8. MRI or CT to assess the entire aorta 9. Holter monitoring for patients with presyncope or syncope to identify any dysrhythmias 10. Mandatory cardiology evaluation 11. Ophthalmology consult to rule-out ectopia lentis, myopia, and other abnormal eye conditions 12. Genetic consult to exclude other connective tissue disorder in individuals with predominant skeletal features Data from Ades16 (investigations listed may not be practical for all patients).
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consult is also necessary to exclude other connective tissue disorders in individuals with predominant skeletal features (Table 2). Specific to the cardiovascular system, a thorough cardiology evaluation is mandatory. This includes an echocardiogram to assess the aortic root and heart dynamics, magnetic resonance imaging or computed tomography to assess the entire aorta, and Holter monitoring for patients with symptoms of presyncope or syncope to identify any dysrhythmias. An accurate height and weight measurement should also be obtained to calculate body surface area, which is important for monitoring the diameter of aortic size standardized to age and body size (Table 2). Thus, the diagnostic process is quite complex. This process often requires a generalist, such as a family physician or an NP with broad experience with MFS patients, to coordinate a comprehensive multidisciplinary team comprising a cardiologist, cardiac surgeon, orthopedic surgeon, ophthalmologist, geneticist, and psychologist to confirm or exclude the diagnosis.17,18 Moreover, NPs providing care for this population need to be mindful that MFS may be misdiagnosed because the presenting symptoms can be similar to a wide range of disorders, including LoeyseDietz syndrome, familial thoracic aortic aneurysm, bicuspid aortic valve disease with associated aortopathy, familial ectopia lentis, MASS (mitral valve prolapse, aortic root diameter at upper limits of normal for body size, stretch marks of the skin, and skeletal conditions) phenotype, homocystinuria, and EhlerseDanlos syndrome.19 CARDIOVASCULAR COMPLICATIONS
Because cardiovascular complications are the most life threatening for the MFS patients, it is critically important for NPs to have a comprehensive understanding of how MFS can affect the cardiovascular system. Accordingly, the most significant medical complication of MFS is the dilation and dissection of the ascending aorta, which can lead to aortic rupture and premature death if untreated.1,2 This aortic condition is caused by abnormal FBN-1 and TGF-b levels, which lead to abnormal elastic properties in the aorta. As a result, the aortic wall becomes stiff, predisposing to dilation and dissection. In a study www.npjournal.org
done in the early 1970s, cardiovascular complications were the cause of death in > 90% of cases, with aortic rupture accounting for 80% of the deaths.20 Other possible cardiovascular manifestations of MFS include aortic regurgitation, mitral valve prolapse with or without mitral regurgitation (prevalence 60% to 80% of the MFS population), mitral annular calcification before the age of 40 years, pulmonary artery dilation in the absence of pulmonary valve stenosis before age 40, dilation and/or dissection of the descending or abdominal aorta before age 50 (seen in approximately 10% of MFS patients), tricuspid valve prolapse with or without tricuspid regurgitation, branch vessel dilation and dissection, and cardiac arrhythmias related to heart valve disease and with cardiomyopathy.2,17,21 Therefore, NPs need to be attentive in caring for a suspected MFS individual by performing careful physical assessments and early diagnostic tests, and by making appropriate referrals. An early diagnosis of MFS is crucial because both medical and prophylactic surgery interventions can slow the aortic dilation and prevent aortic dissection and rupture. MANAGEMENT OF CARDIOVASCULAR MANIFESTATIONS
Advances in medical and prophylactic surgical interventions have resulted in significant improvement in the life expectancy of MFS population. Based on a research study conducted on 257 MFS patients in the early 1970s by Murdoch et al20 at The Johns Hopkins University Hospital in Baltimore, the average life expectancy of untreated, affected patients was found to be about 32 years. With the opportunities for early diagnosis through the use of noninvasive serial aortic imaging, timely medical management with lifestyle modifications, beta-blocker therapy, and prophylactic surgery interventions, life expectancy for MFS patients has improved dramatically. In a 2008 study, Judge and Dietz22 reported a mean survival age of 72 years. However, cardiovascular problems continue to affect an estimated 9 of 10 individuals diagnosed with MFS.23,24 Therefore, it is important for NPs to have a clear understanding of the potential cardiovascular complications and the ways to assess for and manage these issues to avoid the dire consequences of this disease. The Journal for Nurse Practitioners - JNP
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Imaging Studies
According to Canadas et al5 and Milewicz et al,25 serial echocardiographic surveillance is indicated for all MFS patients, because the prognosis is primarily determined by progressive aortic dilation resulting in dissection or rupture. Thus, it is important for NPs to ensure that these patients are referred to a cardiologist. The frequency of imaging studies should be tailored to each individual, as recommended by the cardiologist. The initial evaluation should include an echocardiogram with a 6- to 12-month followup to determine the rate of aortic enlargement.5,25 Thereafter, annual imaging studies are recommended. More frequent studies are indicated when the rate of change in aortic size is > 0.5 cm (0.2 inch) per year or the absolute aortic size increases to > 4.5 cm (1.77 inches), or with significant aortic valvular regurgitation.25,26 (The aortic diameter is typically measured at the sinuses of Valsalva in relation to age and body surface area.26,27) More frequent computed tomography or magnetic resonance imaging of the entire aorta is recommended if the descending thoracic aorta, arch, or abdominal aorta are enlarged or if the aorta has dissected. Similarly, after aortic root surgery, a minimum of annual imaging of the thoracic aorta is recommended. More frequent imaging may also be required if evidence of the rate of dilation of the descending aorta or arch is rapid or if the aorta is > 4.5 cm (1.77 inches), unless it is documented to be stable at that size.25,27 Medical Management
In addition to serial imaging, aggressive medical management is extremely important for all MFS patients with mild to moderate aortic root enlargement, regardless of their symptoms. According to Kodolitsch et al2 and Hiratzka et al,28 the main goal of medical therapy is to slow aortic growth and to prevent further aortic injury, with the hope of delaying the need for prophylactic surgical intervention. This goal is accomplished with blood pressure control and lifestyle modification (Table 3). Specific to blood pressure management, recently published guidelines by the American College of Cardiology (ACC), American Heart Association 598
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Table 3. Guidelines for Medical Management of Marfan Syndrome Systolic blood pressure goal < 120 mm Hg, if known aortic dissection < 110 mm Hg Heart rate target < 70 beats/minute (resting) or < 100 beats/min (after submaximal exerciseerunning up and down 2 flights of stairs) Medication agents: first line, beta-blockers; second line, calcium antagonist For additional blood pressure control, consider combining other antihypertensive agents, such as calcium antagonists, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers Lifestyle modificationseavoid high-intensity, competitive, and collision contact sports; avoid isometric/static exercise; tailor all exercise programs to individual patient’s status Data from Kodolitsch et al,2 Keane et al,4 Moberg et al,19 Milewicz et al,25 and Hiratzka et al.28
(AHA), and American Association for Thoracic Surgery (AATS)28 recommend aggressive blood pressure control with beta-blockers, such as atenolol or propranolol. These particular drugs tend to be the primary choices for many practitioners due to their longer half-lives, relative cardioselectivity with fewer central nervous system and other side effects, and the ability to optimize patients’ compliance with less frequent dosing. Classic clinical trials of beta-blockers for aortic protection have demonstrated that a decrease in myocardial contractility and pulse pressure helps to lower the rate of aortic dilation and cardiovascular events.18 Based on evidence from a recent clinical trial, Hiratzka et al28 found that beta-blockers also improve the elastic properties of the aorta, particularly in patients with an aortic root diameter of < 40 mm (1.73 inches). Therefore, unless contraindicated, NPs should be encouraged to use beta-blockers to reduce the rate of aortic dilation in all MFS patients.25,28 The goal of beta-blocker therapy is to achieve a resting heat rate of < 70 beats/min, and a heart rate of < 100 beats/min after submaximal exercise (eg, running up and down two flights of stairs). In addition, the systolic blood pressure goal is < 120 mm Hg, or < 110 mm Hg in patients with diagnosed aortic dissection.2,25,28 The recommended second-line therapy for patients who do not Volume 10, Issue 8, September 2014
tolerate the use of beta-blockers is the calcium antagonist verapamil.4 However, because of the number of major side effects of beta-blockers, such as increasing airway resistance and hypoglycemia, as well as exacerbating peripheral vascular disease and claudication, clinical trials continue to explore alternative options for these patients. For example, in recent clinical trials using mouse models of MFS, Moberg et al,19 Yetman et al,23 and Habashi et al24 found that both an angiotensinconverting enzyme inhibitor, enalapril, and an angiotensin receptor blocker, losartan, provided greater benefits in improving aortic distensibility and reducing aortic stiffness and root diameter. To date, there have been no published large-scale human trials with clear clinical indications to substantiate the effectiveness of these drugs as the first-line therapy.19,29 Therefore, although they remain the standard of care for all patients with MFS, if a beta-blocker is contraindicated or poorly tolerated, or additional blood pressure control is required for the MFS patient, NPs should consider a combination of other antihypertensive agents, such as calcium antagonists, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers.4,19 Specific to lifestyle modification, the intention is to reduce any additional direct physical stress to the aortic wall. Thus, NPs should advise all MFS patients to avoid high-intensity, competitive, and collision contact sports, as these activities may precipitate aortic dissection or rupture.2,23 Isometric/static exercise, such as weight-lifting, steep inclines, gymnastics, push-ups, and pull-ups, should also be avoided. Isokinetic/dynamic exercise, such as stationary biking, can increase heart rate and cardiac output but also decrease peripheral resistance.2,23 Therefore, patients can participate in these exercises at a decreased level of intensity. Recreational exercises that are of low and moderate intensity, such as bowling, golfing, skating (but not ice hockey), snorkeling (but not scuba diving), brisk walking, modest hiking, and doubles tennis, are likely permitted. The bottom line is that, as primary care providers for these MFS patients, NPs should tailor all exercise programs based on the patient’s unique cardiovascular status. www.npjournal.org
Even with optimal medical management of the MFS patients, the aortic root diameter may eventually reach the threshold size, indicating the need for more aggressive treatment. To this end, surgical interventions are required to reduce morbidity and mortality in this population. Surgical Management
Prophylactic surgical intervention remains the single, definitive measure in preventing dissection or rupture of the aorta in MFS patients.2,6 According to Ades,16 prophylactic aortic root replacement in MFS patients is recommended due to the lower operative mortality rate of 1% to 2%, whereas, for acute ascending aortic dissection, the operative mortality rate is up to 20%. Furthermore, statistically, MFS patients who have aortic dissection have considerably reduced longterm survival rates of between 50% and 70% at 10 years.16 Most MFS patients present with type A aortic root/ascending aorta dilation and dissection, whereas type B descending thoracic and abdominal is less common.25 In a recent retrospective study by Schoenhoff et al18 involving 86 MFS patients, with 91% presenting with type A, 8% with type B, and 1% with aortic root aneurysm and dilative cardiomyopathy, underwent heart transplantation as a primary procedure. The most recent guidelines recommend prophylactic surgery when the following criteria are met: The aortic root diameter exceeds 5 cm (1.97 inches) in adults. The aortic root size exceeds 4.5 cm (1.77 inches) with a family history of aortic dissection. There is a rapid aortic growth rate of > 5% per year or > 2 mm (0.08 inch) per year in adults. The presence of aortic insufficiency is significantly impairing life functioning. The change in descending aortic size suddenly exceeds 0.5 cm (0.2 inch) in 1 year. The descending aorta exceeds 5.0 to 6.0 cm (1.97 to 2.36 inches) or twice the diameter of contiguous normal aorta. For pregnancyeelective surgery before contraception for aortic root dilation 4.5 cm (1.77 inches).16,17,25 The advancement of medical knowledge has given a rise to more prophylactic surgical options for MFS The Journal for Nurse Practitioners - JNP
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patients. For example, in the presence of severe aortic valve regurgitation, the Bentall composite valve graft is the classic standard procedure of choice. This procedure includes aortic root and valve replacement with either a biologic valve, which is preferred for patients who intend to become pregnant or with a relative contraindication for long-term anticoagulation, or a mechanical valve. In the absence of aortic valve regurgitation, a valve-sparing aortic root replacement may be considered.17,28 However, in a recent systematic review and meta-analysis of > 1,385 patients, Benedetto et al30 concluded that valve-sparing aortic root replacement is emerging as the surgical choice because there are no differences in outcomes between the two procedures. The valvesparing aortic root replacement procedure also has the advantage of avoiding possible complications related to lifelong anticoagulation, which in turn makes this an attractive option for many younger MFS patients.30 Finally, according to Bristol,31 a newly emerging surgical option is the exostent surgical procedure, which involves an external aortic root support using medically approved Dacron plastic cloth as a jacket for wrapping the contour of patient’s aorta, including the sinuses of Valsalva and the origins of the coronary arteries. The advantage of this option is that there is no need for cardiopulmonary bypass and it is reversible. As of 2009, there have been 20 successful procedures done on MFS patients.31 In summary, the cardiac surgeon may present one of several surgical options to the MFS patient. However, the NPs must be familiar with each of these options to facilitate the provision of optimal preoperative education and postoperative followup care. Postoperative Cardiovascular Care
NPs play a central role in managing postoperative MFS patients through education on the need to continue long-term medical treatment and sustaining lifelong surveillance. NPs may also act as primary care coordinators to ensure optimal follow-up care during the transition from an acute care setting back into a primary care setting. Long-term anticoagulation therapy, such as the classic treatment with warfarin, is indicated for patients with 600
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mechanical valve replacement or in the presence of atrial fibrillation.17 Thus, NPs working in an acute or primary care setting must ensure that they are up to date on anticoagulation management protocols and managing the titration appropriately. In addition, NPs must also be aware of the potential complications that may occur after prophylactic surgery, such as the development of coronary ostial aneurysms. These aneurysms develop at the site of reimplantation, as a result of the weakened wall of the coronary ostium. Although these aneurysms generally do not progress to requiring intervention, occasionally pseudoaneurysms develop at the site of coronary anastomosis and do require surgical repair.4,28 After the prophylactic repair of the ascending aorta, the arch and descending aorta sites are still at risk for subsequent onset of dilation and dissection. In fact, a significant number of patients require surgical repairs at other sites throughout the aorta, especially those who have a dissection at the time of the initial aortic surgery. Based on a study conducted in 2006 on the long-term survival and complications after aortic aneurysm repair, Engelfriet et al32 found that 189 of the 268 patients in their study (70%) required subsequent multiple operations. Therefore, to reduce this risk, it is imperative for NPs who are providing care for these patients to ensure that beta-blocker or alternative medical therapy is resumed and sustained postoperatively.28,33 The 2010 ACC, AHA, and AATS guidelines28 recommend serial imaging of the entire aorta at 1, 3, 6, and 12 months after aortic repair, and annually thereafter if the patient’s condition is stable. Magnetic resonance imaging is preferred because it minimizes radiation exposure over time. NPs play a key role in providing patients with the rationale for long-term surveillance and thus enhancing compliance with the medical regimens. Finally, it is important for NPs to educate postoperative MFS patients regarding the need for antibiotic prophylaxis if they intend to undergo any dental or surgical procedures due to the increased risk for bacterial endocarditis in this population.4,16 Overall, due to the ongoing risk of cardiovascular complications in MFS patients before and after surgery, it is crucial for NPs who care for these Volume 10, Issue 8, September 2014
patients to ensure the ongoing monitoring of aorta size before and after surgery. In addition, NPs must be vigilant regarding the continuation of medical therapy so that the patients can live long and healthy lives. Pregnancy in MFS
Primary care NPs may encounter young, female MFS patients seeking advice regarding pregnancy. Therefore, it is critical for NPs to be aware that all pregnancies are considered high risk for MFSafflicted women. This is due to the increased risk of cardiovascular complications in the affected mothers and a 50% risk of transmission of MFS to the fetus.34 Also, the risk of dissection is significantly higher in these women, especially during the third trimester and in the immediate postpartum period.21 Therefore, beta-blockers should be continued during and after delivery. Labetalol or metoprolol is generally recommended for pregnant MFS patients because atenolol may impair fetal growth.28 According to Ades16 and Goland et al,35 women with a maximal aortic diameter of < 4 cm (1.57 inches) are at low risk (1%) for a rapid change in aortic size or aortic tear during pregnancy or immediately after delivery. The risk of dissection is up to 10% when > 4 cm (1.57 inches). The risk increases proportionally with aortic size. Current guidelines suggest elective surgical repair of aortic aneurysms before conception for women with aortic root dilation 4.5 cm (1.77 inches).36 Therefore, when NPs encounter an MFS patient who is considering pregnancy, they should coordinate a multidisciplinary evaluation to include experts, such as a geneticist, cardiologist, or surgeon, and an obstetrician. CONCLUSIONS
MFS is a hereditable connective tissue disorder affecting multiple body systems. However, the cardiovascular complications of aortic dilation and dissection are the most life threatening as they can lead to aortic rupture and death. The opportunities for early diagnosis and the use of noninvasive serial aortic imaging and advancements in both the medical and surgical management of MFS have led to a significant improvement in life expectancy of all www.npjournal.org
affected individuals. Ongoing research is being conducted in an attempt to achieve an even higher level of success in managing this disorder. It is not uncommon for NPs to encounter MFS patients in acute and primary care practice. Because delays or misdiagnoses of cardiovascular complications can be fatal, it is crucial for the NPs to have comprehensive knowledge of these complications. The information in this article provides NPs with the necessary insights into MFS, particularly with regard to cardiovascular management. This knowledge and insight will facilitate the provision of optimal care for MFS patients and their families.
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23. Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propanolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005;95:1125-1127. 24. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in mouse model of Marfan syndrome. Science. 2006;312:117-121. 25. Milewicz DM, Dietz HC, Miller CD. Treatment of aortic disease in patients with Marfan syndrome. Circulation. 2005;111:e150-e157. 26. Kodolitsch YV, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007;93:755-760. 27. Macura KJ, Szarf G, Fishman EK, Bluemke DA. Role of computed tomography and magnetic resonance imaging in assessment of acute aortic syndromes. Semin Ultrasound CT MR. 2003;24:232-254. 28. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/ SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010;121:e266-e369. 29. Motro M, Fisman EZ, Tenenbaum A. Cardiovascular management of Marfan syndrome. Isr Med Assoc J. 2008;10:182-185. 30. Benedetto U, Melina G, Takkenberg J, et al. Surgical management of aortic root disease in Marfan syndrome: a systemic review and meta-analysis. Heart. 2011;97:955-958. 31. Allen C, Pepper J. External aortic support for people with Marfan syndrome. BMJ. 2010;340:c1692. http://dx.doi.org/10.1136/bmj.c1692. 32. Engelfriet PM, Boersma E, Tijssen JGP, Bouma MB, Mulder BJM. Beyond the root: dilation of the distal aorta in Marfan’s syndrome. Heart. 2006;92:1238-1243. 33. Erbel R, Alfonso F, Boileau C, et al. Diagnosis and management of aortic dissection. Eur Heart J. 2001;22:1642-1681. 34. Houston L, Tuuli M, Macones G. Marfan syndrome and aortic dissection in pregnancy. Obstet Gynecol. 2011;117:956-960. 35. Goland S, Barakat M, Khatri N, Elkayam U. Pregnancy in Marfan syndrome: maternal and fetal risk and recommendations for patient assessment and management. Cardiol Rev. 2009;17:253-262.
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36. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al. ESC guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:3147-3197.
Jonathan Yip, MN, NP, BN, BSc, is a nurse practitioner at the Saint Boniface General Hospital in Winnipeg, MB, Canada, and he can be reached at [email protected]. Jo-Ann V. Sawatzky, PhD, RN, is an associate professor, associate dean of graduate programs, and faculty development coordinator in the Faculty of Nursing at the University of Manitoba in Winnipeg. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest. 1555-4155/14/$ see front matter © 2014 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2014.06.008
Readers may receive 0.79 CE contact hours, including 0.17 contact hours of pharmacology credit, offered by AANP, by completing the online posttest and evaluation at https://cecenter.aanp.org/Program?area=JNP.
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Marfan syndrome (MFS) is a genetic disorder affecting 1 in 5,000 individuals. The diagnosis is made using a combination of genetic testing and the revised Ghent criteria. MFS is associated with the cardiovascular-related risks of aortic dilation and dissection. Therefore, the main goal of medical therapy is blood pressure control using beta-blockers and lifestyle modification. Prophylactic surgical intervention remains the single, definitive measure in preventing dissection or rupture. Nurse practitioners must be vigilant in caring for this population as these cardiovascular risks can be reduced by early identification and diagnosis and timely intervention. Keywords: aortic dilation, aortic dissection, cardiovascular complications, Marfan syndrome Ó 2014 Elsevier, Inc. All rights reserved.
M
arfan syndrome (MFS) is a heritable disorder of connective tissue. It is a relatively common genetic disorder affecting 1 in 5,000 individuals without gender, racial, or ethnic predilection.1-3 MFS affects multiple systems of the body, with consequent cardiovascular-, skeletal-, ocular-, integument-, lung-, and dural-related symptoms.3-5 Based on earlier studies, the cause of MFS was thought to be primarily due to the mutation in the fibrillin-1 (FBN-1) gene on chromosome 15, resulting in abnormal fibrillin structure that causes the connective tissue disorder. More recent studies have shown that the dysfunctional transforming growth factor (TGF)-b cytokine plays a more critical role in extracellular matrix homeostasis or remodeling.6-8 The diagnosis of MFS is based on both genetic testing of FBN-1 and physical findings under the revised Ghent criteria. Although MFS manifests in varying degrees of severity, the most life-threatening Readers may receive 0.79 continuing education contact hours, including 0.17 contact hours of pharmacology credit, approved by the American Association of Nurse Practitioners, by reading this article and completing the online posttest and evaluation at https://cecenter.aanp.org/Program? area=JNP. 594
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consequences include aortic dilation and dissection, which can lead to aortic rupture and death. Hence, it is crucial for nurse practitioners (NPs) to have comprehensive knowledge of these complications, as it is not uncommon for NPs to encounter MFS patients in both acute and primary care practice. Currently, the opportunities for early diagnosis and the use of noninvasive serial aortic imaging, as well as advancements in the both medical and surgical management of MFS, have led to significant improvement in the life expectancy of all affected individuals.3,5 In this study we aim to provide NPs with a comprehensive overview of MFS and offer specific insights for the cardiovascular management of these individuals and their families. GENETIC OVERVIEW
MFS is the result of a faulty genetic make-up. Earlier studies concluded that MFS was primarily the result of a mutation in the FBN-1 gene on chromosome 15. FBN-1 encodes the extracellular matrix glycoprotein fibrillin, which is a major component of connective tissue microfibrils found throughout the body.1-3 More recent studies have indicated that the mutated FBN-1 gene also enhances the release of Volume 10, Issue 8, September 2014
TGF-b, which, in turn, plays a critical role in the cardiovascular pathophysiology of MFS.6,7 TGF-b is a cytokine that functions in the regulation of cell proliferation, differentiation, extracellular matrix formation, cell cycle, and apoptosis.6,7 It is the mutation in TGF-b receptor 2 gene that results in extracellular matrix homeostasis and/or cardiovascular remodeling, leading to a stiffer and less distensible aorta.3,6-8 MFS is an inheritable autosomal dominant disorder, which means that each offspring of an affected parent has a 50% chance of inheriting the altered FBN-1 gene.1 Although approximately 75% of all cases are found to be inherited, the remaining 25% occur due to spontaneous mutation.4 To date, > 1,000 different mutations involving the FBN-1 gene have been isolated, with most mutations being unique to a given family.1,2 However, family members with the same mutation causing MFS can exhibit a wide variation in clinical manifestations. No correlation has been found between the specific type of FBN-1 mutation and the clinical phenotype, which explains the extreme variations in clinical phenotypic presentations of MFS. Furthermore, the mutation in the FBN-1 gene can cause conditions other than Marfanlike disorders. None of the current genetic testing methods have the ability to identify all mutations of MFS.4,5 In 10% of patients with a definitive diagnosis of MFS, it is still not possible to find an FBN-1 gene mutation.5 As a result, genetic testing alone is insufficient to make the diagnosis. CLINICAL PRESENTATION
The clinical features of MFS can present in many different parts of the body. Although the most commonly affected regions are the skeletal, ocular, and cardiovascular systems, pulmonary, skin/integument, and dural symptoms have also been reported. An affected individual rarely has every feature. The classic clinical appearance of MFS is a tall, thin individual with disproportionally long arms, and usually a longer than normal lower half of the body. Other common external physical characteristics include pectus excavatum (funnel chest) or pectus carinatum (pigeon chest), double-jointed fingers, elongated thumb, long feet and toes with flat or highly arched www.npjournal.org
feet, scoliosis or kyphosis, severe myopia, crowded teeth, and striae atrophiae (stretch marks).2-4 In addition, common internal characteristics include lens dislocation (ectopia lentis) and a swelling sac around the spinal column (dura ectasia). Cardiovascular involvement results in complications, including the dilation and dissection of aorta, and mitral and/or aortic valve prolapse and/or regurgitation.2-4 Consequently, due to the highly variable presentation of affected individuals, it is essential for NPs to be familiar with the complex diagnostic process for MFS. CLINICAL DIAGNOSIS
The diagnosis of MFS was initially identified by Victor McKusick in 1955 as a classification of connective tissue disorder using his Heritable Connective Tissue Disorders monograph.9,10 Subsequently, a Berlin nosology was created in 1986 by an international panel of experts with the aim of facilitating accurate communication about the condition between health care providers.11 However, this Berlin nosology was later found to only focus on the physical characteristics associated with MFS, ignoring the genetic aspect of the disease. A newer version of the criteria, called the Ghent nosology, was established in 1996, after identification of the causal gene FBN-1.12 The Ghent nosology uses clinical findings of 6 organ systems along with family history and molecular findings to diagnose MFS.12 Recently, due to further advancements in medical research, Loeys et al13 published a revised Ghent nosology, with the intent to decrease the risk of premature or misdiagnosis of MFS. The new Ghent nosology is now the gold standard for the diagnosis of MFS. It puts more weight on the cardiovascular manifestations, with aortic root aneurysm and ectopia lentis being the cardinal clinical features. Thus, diagnosing MFS requires comprehensive patient and family history, including information about any family members who may have the disorder or had an unexplained early or sudden death. In the absence of any family history, the presence of these 2 manifestations is sufficient for the unequivocal diagnosis of MFS. In the absence of either of these 2 features, the presence of an FBN-1 mutation or a combination of systemic manifestations is required (Table 1). The Journal for Nurse Practitioners - JNP
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Table 1. Revised Ghent Criteria for Marfan Syndrome Diagnosis Systemic features
Scoring points
Wrist and thumb sign (ie, the thumb and fifth finger overlap when grasped around the wrist, and whole nail bed extends beyond the ulnar border when the hand is clenched
3
Wrist or thumb sign
1
Pectus carinatum (pigeon chest) deformity
2
Pectus excavatum (funnel chest) or chest asymmetry
1
Hindfoot deformity
2
Plain pes planus (ie, flat foot)
1
Pneumothorax
2
Lumbar sacral dural ectasia (enlargement of the neural canal)
2
Protrusio acetabuli (ie, protruding socket into pelvis)
2
Reduced upper segment/lower segment AND increased arm/height AND no severe scoliosis
1
Scoliosis or thoracolumbar kyphosis
1
Facial features (3 of 5): Dolichocephaly (long narrow skull) Enophthalmos (backward displacement of the eye in the socket) Downslanting palpebral fissures Malar hypoplasia (underdeveloped midface) Retrognathia (receding jaw)
1
Skin striae (stretch marks)
1
Myopia > 3 diopters
1
Mitral valve prolapse (all types)
1
Note: Maximum score ¼ 20 points; 7 points ¼ systemic involvement. Adapted from Loeys et al.13
In the new Ghent criteria, the role of molecular testing of FBN-1 has become more important in the diagnostic assessment. Based on two studies, conducted in 2001 and 2004, Loeys and associates concluded that 97% of FBN-1 mutations could now be detected in MFS patients,14,15 thus providing substantive support for the new Ghent criteria. Although this new guideline may delay a definitive diagnosis of MFS, it will also decrease the risk of premature or misdiagnosis and facilitate worldwide 596
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discussion of risk and follow-up/management guidelines.13 Early diagnosis is critical because early medical and/or surgical management can prevent cardiovascular complications. Therefore, if the disease is suspected in an individual, it is important for the primary care provider, such as the NP, to utilize the established guidelines for clinical examination and diagnostic evaluation (Table 2).16 The guidelines include obtaining a detailed family history, performing an X-ray of the spine for scoliosis of > 20 or spondylolisthesis, and an X-ray of the pelvis for protrusio acetabulae. In addition, the guidelines also recommend magnetic resonance imaging or computed tomography scanning of lumbar and sacrum to rule out dural ectasia, as the prevalence of this is seen in 65% to 92% of the MFS population. A urine specimen should also be collected for metabolic screen or plasma amino acids to exclude homocystinuria for the first person in the family being evaluated for MFS. A referral for an ophthalmology examination is suggested to rule out ectopia lentis, myopia, and other abnormal eye conditions. Finally, a geneticist Table 2. Guidelines for Clinical Practice in Diagnosis of Marfan Syndrome 1. Detailed family history 2. Accurate height and weight to facilitate the calculation of body surface area in monitoring the diameter of aortic size standardized to age and body size 3. X-ray of spine for scoliosis of > 20 or spondylolisthesis 4. X-ray of pelvis for protrusio acetabulae 5. Lumbosacral magnetic resonance imaging (MRI) or computed tomography (CT) to rule-out dural ectasia 6. Urine specimen for metabolic screen or plasma amino acids to exclude homocystinuria for the first person in the family being evaluate for Marfan syndrome 7. Echocardiogram to assess the aortic root and heart dynamics 8. MRI or CT to assess the entire aorta 9. Holter monitoring for patients with presyncope or syncope to identify any dysrhythmias 10. Mandatory cardiology evaluation 11. Ophthalmology consult to rule-out ectopia lentis, myopia, and other abnormal eye conditions 12. Genetic consult to exclude other connective tissue disorder in individuals with predominant skeletal features Data from Ades16 (investigations listed may not be practical for all patients).
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consult is also necessary to exclude other connective tissue disorders in individuals with predominant skeletal features (Table 2). Specific to the cardiovascular system, a thorough cardiology evaluation is mandatory. This includes an echocardiogram to assess the aortic root and heart dynamics, magnetic resonance imaging or computed tomography to assess the entire aorta, and Holter monitoring for patients with symptoms of presyncope or syncope to identify any dysrhythmias. An accurate height and weight measurement should also be obtained to calculate body surface area, which is important for monitoring the diameter of aortic size standardized to age and body size (Table 2). Thus, the diagnostic process is quite complex. This process often requires a generalist, such as a family physician or an NP with broad experience with MFS patients, to coordinate a comprehensive multidisciplinary team comprising a cardiologist, cardiac surgeon, orthopedic surgeon, ophthalmologist, geneticist, and psychologist to confirm or exclude the diagnosis.17,18 Moreover, NPs providing care for this population need to be mindful that MFS may be misdiagnosed because the presenting symptoms can be similar to a wide range of disorders, including LoeyseDietz syndrome, familial thoracic aortic aneurysm, bicuspid aortic valve disease with associated aortopathy, familial ectopia lentis, MASS (mitral valve prolapse, aortic root diameter at upper limits of normal for body size, stretch marks of the skin, and skeletal conditions) phenotype, homocystinuria, and EhlerseDanlos syndrome.19 CARDIOVASCULAR COMPLICATIONS
Because cardiovascular complications are the most life threatening for the MFS patients, it is critically important for NPs to have a comprehensive understanding of how MFS can affect the cardiovascular system. Accordingly, the most significant medical complication of MFS is the dilation and dissection of the ascending aorta, which can lead to aortic rupture and premature death if untreated.1,2 This aortic condition is caused by abnormal FBN-1 and TGF-b levels, which lead to abnormal elastic properties in the aorta. As a result, the aortic wall becomes stiff, predisposing to dilation and dissection. In a study www.npjournal.org
done in the early 1970s, cardiovascular complications were the cause of death in > 90% of cases, with aortic rupture accounting for 80% of the deaths.20 Other possible cardiovascular manifestations of MFS include aortic regurgitation, mitral valve prolapse with or without mitral regurgitation (prevalence 60% to 80% of the MFS population), mitral annular calcification before the age of 40 years, pulmonary artery dilation in the absence of pulmonary valve stenosis before age 40, dilation and/or dissection of the descending or abdominal aorta before age 50 (seen in approximately 10% of MFS patients), tricuspid valve prolapse with or without tricuspid regurgitation, branch vessel dilation and dissection, and cardiac arrhythmias related to heart valve disease and with cardiomyopathy.2,17,21 Therefore, NPs need to be attentive in caring for a suspected MFS individual by performing careful physical assessments and early diagnostic tests, and by making appropriate referrals. An early diagnosis of MFS is crucial because both medical and prophylactic surgery interventions can slow the aortic dilation and prevent aortic dissection and rupture. MANAGEMENT OF CARDIOVASCULAR MANIFESTATIONS
Advances in medical and prophylactic surgical interventions have resulted in significant improvement in the life expectancy of MFS population. Based on a research study conducted on 257 MFS patients in the early 1970s by Murdoch et al20 at The Johns Hopkins University Hospital in Baltimore, the average life expectancy of untreated, affected patients was found to be about 32 years. With the opportunities for early diagnosis through the use of noninvasive serial aortic imaging, timely medical management with lifestyle modifications, beta-blocker therapy, and prophylactic surgery interventions, life expectancy for MFS patients has improved dramatically. In a 2008 study, Judge and Dietz22 reported a mean survival age of 72 years. However, cardiovascular problems continue to affect an estimated 9 of 10 individuals diagnosed with MFS.23,24 Therefore, it is important for NPs to have a clear understanding of the potential cardiovascular complications and the ways to assess for and manage these issues to avoid the dire consequences of this disease. The Journal for Nurse Practitioners - JNP
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Imaging Studies
According to Canadas et al5 and Milewicz et al,25 serial echocardiographic surveillance is indicated for all MFS patients, because the prognosis is primarily determined by progressive aortic dilation resulting in dissection or rupture. Thus, it is important for NPs to ensure that these patients are referred to a cardiologist. The frequency of imaging studies should be tailored to each individual, as recommended by the cardiologist. The initial evaluation should include an echocardiogram with a 6- to 12-month followup to determine the rate of aortic enlargement.5,25 Thereafter, annual imaging studies are recommended. More frequent studies are indicated when the rate of change in aortic size is > 0.5 cm (0.2 inch) per year or the absolute aortic size increases to > 4.5 cm (1.77 inches), or with significant aortic valvular regurgitation.25,26 (The aortic diameter is typically measured at the sinuses of Valsalva in relation to age and body surface area.26,27) More frequent computed tomography or magnetic resonance imaging of the entire aorta is recommended if the descending thoracic aorta, arch, or abdominal aorta are enlarged or if the aorta has dissected. Similarly, after aortic root surgery, a minimum of annual imaging of the thoracic aorta is recommended. More frequent imaging may also be required if evidence of the rate of dilation of the descending aorta or arch is rapid or if the aorta is > 4.5 cm (1.77 inches), unless it is documented to be stable at that size.25,27 Medical Management
In addition to serial imaging, aggressive medical management is extremely important for all MFS patients with mild to moderate aortic root enlargement, regardless of their symptoms. According to Kodolitsch et al2 and Hiratzka et al,28 the main goal of medical therapy is to slow aortic growth and to prevent further aortic injury, with the hope of delaying the need for prophylactic surgical intervention. This goal is accomplished with blood pressure control and lifestyle modification (Table 3). Specific to blood pressure management, recently published guidelines by the American College of Cardiology (ACC), American Heart Association 598
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Table 3. Guidelines for Medical Management of Marfan Syndrome Systolic blood pressure goal < 120 mm Hg, if known aortic dissection < 110 mm Hg Heart rate target < 70 beats/minute (resting) or < 100 beats/min (after submaximal exerciseerunning up and down 2 flights of stairs) Medication agents: first line, beta-blockers; second line, calcium antagonist For additional blood pressure control, consider combining other antihypertensive agents, such as calcium antagonists, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers Lifestyle modificationseavoid high-intensity, competitive, and collision contact sports; avoid isometric/static exercise; tailor all exercise programs to individual patient’s status Data from Kodolitsch et al,2 Keane et al,4 Moberg et al,19 Milewicz et al,25 and Hiratzka et al.28
(AHA), and American Association for Thoracic Surgery (AATS)28 recommend aggressive blood pressure control with beta-blockers, such as atenolol or propranolol. These particular drugs tend to be the primary choices for many practitioners due to their longer half-lives, relative cardioselectivity with fewer central nervous system and other side effects, and the ability to optimize patients’ compliance with less frequent dosing. Classic clinical trials of beta-blockers for aortic protection have demonstrated that a decrease in myocardial contractility and pulse pressure helps to lower the rate of aortic dilation and cardiovascular events.18 Based on evidence from a recent clinical trial, Hiratzka et al28 found that beta-blockers also improve the elastic properties of the aorta, particularly in patients with an aortic root diameter of < 40 mm (1.73 inches). Therefore, unless contraindicated, NPs should be encouraged to use beta-blockers to reduce the rate of aortic dilation in all MFS patients.25,28 The goal of beta-blocker therapy is to achieve a resting heat rate of < 70 beats/min, and a heart rate of < 100 beats/min after submaximal exercise (eg, running up and down two flights of stairs). In addition, the systolic blood pressure goal is < 120 mm Hg, or < 110 mm Hg in patients with diagnosed aortic dissection.2,25,28 The recommended second-line therapy for patients who do not Volume 10, Issue 8, September 2014
tolerate the use of beta-blockers is the calcium antagonist verapamil.4 However, because of the number of major side effects of beta-blockers, such as increasing airway resistance and hypoglycemia, as well as exacerbating peripheral vascular disease and claudication, clinical trials continue to explore alternative options for these patients. For example, in recent clinical trials using mouse models of MFS, Moberg et al,19 Yetman et al,23 and Habashi et al24 found that both an angiotensinconverting enzyme inhibitor, enalapril, and an angiotensin receptor blocker, losartan, provided greater benefits in improving aortic distensibility and reducing aortic stiffness and root diameter. To date, there have been no published large-scale human trials with clear clinical indications to substantiate the effectiveness of these drugs as the first-line therapy.19,29 Therefore, although they remain the standard of care for all patients with MFS, if a beta-blocker is contraindicated or poorly tolerated, or additional blood pressure control is required for the MFS patient, NPs should consider a combination of other antihypertensive agents, such as calcium antagonists, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers.4,19 Specific to lifestyle modification, the intention is to reduce any additional direct physical stress to the aortic wall. Thus, NPs should advise all MFS patients to avoid high-intensity, competitive, and collision contact sports, as these activities may precipitate aortic dissection or rupture.2,23 Isometric/static exercise, such as weight-lifting, steep inclines, gymnastics, push-ups, and pull-ups, should also be avoided. Isokinetic/dynamic exercise, such as stationary biking, can increase heart rate and cardiac output but also decrease peripheral resistance.2,23 Therefore, patients can participate in these exercises at a decreased level of intensity. Recreational exercises that are of low and moderate intensity, such as bowling, golfing, skating (but not ice hockey), snorkeling (but not scuba diving), brisk walking, modest hiking, and doubles tennis, are likely permitted. The bottom line is that, as primary care providers for these MFS patients, NPs should tailor all exercise programs based on the patient’s unique cardiovascular status. www.npjournal.org
Even with optimal medical management of the MFS patients, the aortic root diameter may eventually reach the threshold size, indicating the need for more aggressive treatment. To this end, surgical interventions are required to reduce morbidity and mortality in this population. Surgical Management
Prophylactic surgical intervention remains the single, definitive measure in preventing dissection or rupture of the aorta in MFS patients.2,6 According to Ades,16 prophylactic aortic root replacement in MFS patients is recommended due to the lower operative mortality rate of 1% to 2%, whereas, for acute ascending aortic dissection, the operative mortality rate is up to 20%. Furthermore, statistically, MFS patients who have aortic dissection have considerably reduced longterm survival rates of between 50% and 70% at 10 years.16 Most MFS patients present with type A aortic root/ascending aorta dilation and dissection, whereas type B descending thoracic and abdominal is less common.25 In a recent retrospective study by Schoenhoff et al18 involving 86 MFS patients, with 91% presenting with type A, 8% with type B, and 1% with aortic root aneurysm and dilative cardiomyopathy, underwent heart transplantation as a primary procedure. The most recent guidelines recommend prophylactic surgery when the following criteria are met: The aortic root diameter exceeds 5 cm (1.97 inches) in adults. The aortic root size exceeds 4.5 cm (1.77 inches) with a family history of aortic dissection. There is a rapid aortic growth rate of > 5% per year or > 2 mm (0.08 inch) per year in adults. The presence of aortic insufficiency is significantly impairing life functioning. The change in descending aortic size suddenly exceeds 0.5 cm (0.2 inch) in 1 year. The descending aorta exceeds 5.0 to 6.0 cm (1.97 to 2.36 inches) or twice the diameter of contiguous normal aorta. For pregnancyeelective surgery before contraception for aortic root dilation 4.5 cm (1.77 inches).16,17,25 The advancement of medical knowledge has given a rise to more prophylactic surgical options for MFS The Journal for Nurse Practitioners - JNP
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patients. For example, in the presence of severe aortic valve regurgitation, the Bentall composite valve graft is the classic standard procedure of choice. This procedure includes aortic root and valve replacement with either a biologic valve, which is preferred for patients who intend to become pregnant or with a relative contraindication for long-term anticoagulation, or a mechanical valve. In the absence of aortic valve regurgitation, a valve-sparing aortic root replacement may be considered.17,28 However, in a recent systematic review and meta-analysis of > 1,385 patients, Benedetto et al30 concluded that valve-sparing aortic root replacement is emerging as the surgical choice because there are no differences in outcomes between the two procedures. The valvesparing aortic root replacement procedure also has the advantage of avoiding possible complications related to lifelong anticoagulation, which in turn makes this an attractive option for many younger MFS patients.30 Finally, according to Bristol,31 a newly emerging surgical option is the exostent surgical procedure, which involves an external aortic root support using medically approved Dacron plastic cloth as a jacket for wrapping the contour of patient’s aorta, including the sinuses of Valsalva and the origins of the coronary arteries. The advantage of this option is that there is no need for cardiopulmonary bypass and it is reversible. As of 2009, there have been 20 successful procedures done on MFS patients.31 In summary, the cardiac surgeon may present one of several surgical options to the MFS patient. However, the NPs must be familiar with each of these options to facilitate the provision of optimal preoperative education and postoperative followup care. Postoperative Cardiovascular Care
NPs play a central role in managing postoperative MFS patients through education on the need to continue long-term medical treatment and sustaining lifelong surveillance. NPs may also act as primary care coordinators to ensure optimal follow-up care during the transition from an acute care setting back into a primary care setting. Long-term anticoagulation therapy, such as the classic treatment with warfarin, is indicated for patients with 600
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mechanical valve replacement or in the presence of atrial fibrillation.17 Thus, NPs working in an acute or primary care setting must ensure that they are up to date on anticoagulation management protocols and managing the titration appropriately. In addition, NPs must also be aware of the potential complications that may occur after prophylactic surgery, such as the development of coronary ostial aneurysms. These aneurysms develop at the site of reimplantation, as a result of the weakened wall of the coronary ostium. Although these aneurysms generally do not progress to requiring intervention, occasionally pseudoaneurysms develop at the site of coronary anastomosis and do require surgical repair.4,28 After the prophylactic repair of the ascending aorta, the arch and descending aorta sites are still at risk for subsequent onset of dilation and dissection. In fact, a significant number of patients require surgical repairs at other sites throughout the aorta, especially those who have a dissection at the time of the initial aortic surgery. Based on a study conducted in 2006 on the long-term survival and complications after aortic aneurysm repair, Engelfriet et al32 found that 189 of the 268 patients in their study (70%) required subsequent multiple operations. Therefore, to reduce this risk, it is imperative for NPs who are providing care for these patients to ensure that beta-blocker or alternative medical therapy is resumed and sustained postoperatively.28,33 The 2010 ACC, AHA, and AATS guidelines28 recommend serial imaging of the entire aorta at 1, 3, 6, and 12 months after aortic repair, and annually thereafter if the patient’s condition is stable. Magnetic resonance imaging is preferred because it minimizes radiation exposure over time. NPs play a key role in providing patients with the rationale for long-term surveillance and thus enhancing compliance with the medical regimens. Finally, it is important for NPs to educate postoperative MFS patients regarding the need for antibiotic prophylaxis if they intend to undergo any dental or surgical procedures due to the increased risk for bacterial endocarditis in this population.4,16 Overall, due to the ongoing risk of cardiovascular complications in MFS patients before and after surgery, it is crucial for NPs who care for these Volume 10, Issue 8, September 2014
patients to ensure the ongoing monitoring of aorta size before and after surgery. In addition, NPs must be vigilant regarding the continuation of medical therapy so that the patients can live long and healthy lives. Pregnancy in MFS
Primary care NPs may encounter young, female MFS patients seeking advice regarding pregnancy. Therefore, it is critical for NPs to be aware that all pregnancies are considered high risk for MFSafflicted women. This is due to the increased risk of cardiovascular complications in the affected mothers and a 50% risk of transmission of MFS to the fetus.34 Also, the risk of dissection is significantly higher in these women, especially during the third trimester and in the immediate postpartum period.21 Therefore, beta-blockers should be continued during and after delivery. Labetalol or metoprolol is generally recommended for pregnant MFS patients because atenolol may impair fetal growth.28 According to Ades16 and Goland et al,35 women with a maximal aortic diameter of < 4 cm (1.57 inches) are at low risk (1%) for a rapid change in aortic size or aortic tear during pregnancy or immediately after delivery. The risk of dissection is up to 10% when > 4 cm (1.57 inches). The risk increases proportionally with aortic size. Current guidelines suggest elective surgical repair of aortic aneurysms before conception for women with aortic root dilation 4.5 cm (1.77 inches).36 Therefore, when NPs encounter an MFS patient who is considering pregnancy, they should coordinate a multidisciplinary evaluation to include experts, such as a geneticist, cardiologist, or surgeon, and an obstetrician. CONCLUSIONS
MFS is a hereditable connective tissue disorder affecting multiple body systems. However, the cardiovascular complications of aortic dilation and dissection are the most life threatening as they can lead to aortic rupture and death. The opportunities for early diagnosis and the use of noninvasive serial aortic imaging and advancements in both the medical and surgical management of MFS have led to a significant improvement in life expectancy of all www.npjournal.org
affected individuals. Ongoing research is being conducted in an attempt to achieve an even higher level of success in managing this disorder. It is not uncommon for NPs to encounter MFS patients in acute and primary care practice. Because delays or misdiagnoses of cardiovascular complications can be fatal, it is crucial for the NPs to have comprehensive knowledge of these complications. The information in this article provides NPs with the necessary insights into MFS, particularly with regard to cardiovascular management. This knowledge and insight will facilitate the provision of optimal care for MFS patients and their families.
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Jonathan Yip, MN, NP, BN, BSc, is a nurse practitioner at the Saint Boniface General Hospital in Winnipeg, MB, Canada, and he can be reached at [email protected]. Jo-Ann V. Sawatzky, PhD, RN, is an associate professor, associate dean of graduate programs, and faculty development coordinator in the Faculty of Nursing at the University of Manitoba in Winnipeg. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest. 1555-4155/14/$ see front matter © 2014 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2014.06.008
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Volume 10, Issue 8, September 2014