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Medical management of young patients with the Marfan syndrome
Progress in
Pediatric Cardiology Progress in Pediatric Cardiology 5 (1996) 167-174
Medical management of young patients with the Marfan syndrome Mubadda A. Salim* , Bruce S. Alpert The Depamnent
of Pediatrics,
Division
of Cardiology,
The University of Tennessee, TN 38105, USA
777 Washington
Avenue,
Suite 215, Memphis,
Abstract The Marfan syndrome can be associatedwith high morbidity and reduced survival, primarily from cardiovascular complications.Thesemanifestationsinclude abnormalitiesof the mitral valve and progressivedilation of the proximal aorta. In recent yearsmedicaland surgicaladvanceshave dramatically improved the outlook for patientswith the Marfan syndrome. Acute medicaltreatment of the Marfan syndromeusually involves managingcomplicationssuchasheart failure from severe mitral and/or aortic valve regurgitation. The long term treatment involves the use of &adrenergic blockade to retard progressivedilation of the aortic root and to prevent dissection.The efficacy of this therapy hasbeen documentedin several prospectivetrials. Echocardiographyor magneticresonanceimagingis usedto evaluate the sizeof the aortic root, allowingfor frequent non-invasive follow-up. These techniques can also be used to gauge the effectiveness of pblockade, detect cardiovascularcomplications,and help to determinethe optimal timing for surgicalinterventions. Compositegraft repair of the aortic valve and ascendingaorta is a life-savingprocedure in patients with the Marfan syndromewith severedilation of the aortic root. P-adrenergicblockade should be continued after surgery to protect againstarterial dilation and dissection elsewhere. Keywords:
Marfan syndrome;Padrenergic blockade;Atenolol; Aorta; Pediatrics
1. Introduction
In patients with the Marfan syndrome premature death is largely due to cardiovascular complications. A quarter of a century ago, life expectancy was markedly reduced by about one-third in both male and female patients [l]. At that time a 40-year-old man with the syndrome had only a 32% probability of living another 20 years. In cases where the cause of death could be identified, cardiovascular problems were responsible in over 90% of patients. Most of the deaths were from aortic complications and occurred between the second and fifth decades. Survival was somewhat better in women than in men. By 1993 the overall survival had improved consider*Corresponding author, Tel.: + 1 901 5723380;fax: + 1 901 5725107.
ably for both sexes. More than 80% of men with the Marfan syndrome were likely to survive to 60 years of age [21. Nonetheless, cardiovascular complications continued to be the chief cause of death and morbidity remained high, with at least one-quarter of patients requiring cardiovascular surgery. As documented elsewhere in this review, [3,4] advances in surgical technique and postoperative care have contributed to a marked improvement in survival after elective repair of the dilated aortic root and the mitral valve. It has also become obvious, however, that mildly affected patients were often not included in earlier surveys, and that reports of a lengthened life-expectancy may be exaggerated. It cannot be denied, however, that patients with the Marfan syndrome have benefitted significantly from the early diagnosis and aggressive medical management demonstrated during the past several decades. This review focuses on this early diagnostic and medical management.
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2. The Marfan
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syndrome in infancy
The cardiovascular manifestations of the Mar-fan syndrome can present at any age from infancy to late adulthood [S-131. When its manifestations are detected in infancy the child is usually severely affected or diagnostic evaluation is requested because of concern by a parent or relative with the Marfan syndrome. In many cases the most severely affected infants have no identifiable relative with the syndrome, and their abnormalities represent new mutations in fibrillin-1 [14]. In infants the cardiovascular manifestations of the Marfan syndrome include prolapse and regurgitation of the mitral and tricuspid valves and dilation of the aortic root, especially at the level of the sinuses of Valsalva. The prevalence rates of these abnormalities can be as high as 80% in infants diagnosed with the syndrome [7,10]. These lesions, especially those producing mitral valve regurgitation, can be fatal at a very young age [lo]. For example, of 22 patients with the infantile Marfan syndrome reported by Morse et al. [lo] three (13.6%) died during the first year of life from aortic dissection, cardiopulmonary failure, and after mitral valve replacement. Sisk et al. [7] reported on the longitudinal follow-up of 15 children who were diagnosed with the Marfan syndrome before 4 years of age. At follow-up all of them had dilation of the aortic root. Mitral valve function was diminished at later follow-up examinations in nine patients, four of whom, all with a negative family history, required mitral valve replacement between 11 months and 12 years of age. 2.1. Cardiac arrhythmia
Cardiac arrhythmia can be a manifestation of the Marfan syndrome. Paroxysmal atria1 tachycardia was observed in one child who was thought to have ‘no significant heart disease’ and atria1 fibrillation and multiform ventricular extra systoles were observed in three others with mitral valve regurgitation [6]. These arrhythmias were probably related to the functional abnormalities of the mitral valve with dilation of the left atrium rather than to specific structural cardiovascular abnormalities of the Mar-fan syndrome. The Wolff-Parkinson-White syndrome has also been reported in children with the syndrome [12]. 2.2. Congenital heart disease
The significance of an association between the Marfan syndrome and congenital heart disease remains controversial [6,12]. In El Habbal’s report of 186 Mar-fan patients younger than 20 years of age, the incidence of bicuspid aortic valve, atria1 septal defect,
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and tetralogy of Fallot was 9.7%, 2.7%, and l.l%, respectively [12]. These rates are significantly higher than those reported for these defects in the general population (2%, 0.06%, and 0.03%, respectively). El Habbal also reported that bicuspid aortic valve was associated with an increased incidence of severe cardiovascular sequelae in Marfan patients, and he hypothesized that flow through the two cusps produced turbulence in the ascending aorta which contributed to elevated aortic wall stress and an increase in the rate of aortic dilation. Other authors have not confirmed an increased incidence of congenital heart defects in patients with the syndrome [15]. 2.3. Survival in childhood
In children with the Mar-fan syndrome the survival rate is lower than that in normal children. Reported mortality rates range from 1.6% 191 to 44% [16]. Most of the deaths occurred in infants during the first year of life, and were caused by heart failure from mitral and/or aortic valve insufficiency. Postoperative death after valve surgery was also an important cause. 3. Medical
therapy
3.1. Padrenergic
blockade
In 1977 Ose and McKusick were the first to report a trial of /3-adrenergic blockade to try to prevent aortic dissection in patients with the Marfan syndrome [17]. Twenty-five patients were treated with propranolol for 14 months to 5 years. Five died during follow-up, all from dissecting aortic aneurysm or its complications. The dose of propranolol ranged from 120-160 mg/day in adults and from 40-80 mg/day in children. The results of treatment were inconclusive, probably because the method of analysis was not able to measure a significant progression of aortic root dilation, and also because some of the patients had marked aortic dilation when treatment was started. A more recent study of Marfan patients with a dilated aorta has measured an increase in vascular impedance with acute @blockade treatment begun after nitroprusside therapy [ 181. 3.2. Eqerimental
work
An experimental model of the aortic pathology found in the Marfan syndrome was created in broadbreasted turkeys who developed aortic rupture when they were fed amniopropionitrile [19]. When the turkeys were fed amniopropionitrile supplemented with L- or D-L-propranolol, aortic rupture did not develop. Practolol, a cardioselective P-blocker, produced a similar effect with rupture in only 13.1% of
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birds. The use of the o-isomer of propranolol had no significant effect on the incidence of aortic rupture (62.4%) as compared to control animals (54.2%). The efficacy of the therapy correlated with the reduction in the maximum rate of pressure rise (dP/dt) in the carotid artery. Moreover, histologic examination of the aorta in turkeys who did not receive L- or D-L-propranolol revealed extensive degeneration of elastic fibers and disappearance of the internal elastic membranes, whereas these changes were very mild in turkeys fed L- or DL-propranolol [19]. In an in-vitro study of dogs, Prokop et al. [201 showed that only pulsatile flow in the aorta contributed to the dissecting forces in the presence of an intimal tear, whereas nonpulsatile flow produced no aneurysms, even at aortic pressures as high as 400 mmHg. The extent of dissection for each pulsation was related to the maximum rate of pressure rise in the aorta (dP/dt,,,). These animal studies and other investigations have led to several therapeutic trials of p-adrenergic blockade in patients with the Marfan syndrome. The abnormal mechanical properties of the ascending aorta relate to the structural defects of the aortic wall. Abnormalities in fibrillin synthesis and deposition in the extracellar matrix appear to explain the wide array of ocular, skeletal and cardiac abnormalities found in the Marfan syndrome [14,21-231. In patients with the syndrome the ascending aorta and the abdominal aorta have been shown to have decreased distensibility and increased stiffness as compared to these sites in normal individuals, [24-261 and these abnormalities did not change after therapy with atenolol [27]. The pulsatile burden of left ventricular ejection and the reduced elasticity of the aorta produce shear forces that diminish the integrity of the aortic wall and lead to dilation. The reduction in left ventricular contractile force after p-adrenergic blockade may be important in slowing the rate of dilation of the ascending aorta and its consequent complications [271. Factors that predict an increased risk of aortic dissection and death include an aortic root diameter of 60 mm or more and a family history of death from a dissecting aortic aneurysm in a close relative under 40 years of age 1281. The configuration of the aortic root at the initial evaluation is another predictor of aortic dilation and of its complications - subsequent severe dilation, need for aortic surgery, and severe aortic valve regurgitation [24]. In patients with dilation localized to the sinuses of Valsalva, significantly less progression of aortic root dilation has been seen, as compared to those with generalized dilation extending beyond the sinuses of Valsalva to the supraaortic ridge and proximal ascending aorta [29]. padrenergic blockade has not been shown to protect indefinitely from aortic dilation and dissection [28,29].
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im-
3.3. Clinical efficacy of /3-adrenergic blockade
The earliest, albeit preliminary, report of the benefit of propranolol in the preventive treatment of patients with the Marfan syndrome was in 1983 [30]. Thereafter, additional sporadic reports of a decrease in the progression of aortic dilation appeared, usually as abstracts or as a part of a larger series of patients, most of whom did not receive therapy [9,31-341. Two prospective studies have evaluated the efficacy of P-adrenergic blockade in patients with the Marfan syndrome. Shores et al. [351 reported the results of a randomized, open-label study of patients between 12 and 50 years of age [35]. There were 32 patients in the treatment group and 38 patients in the control group. Patients were followed every 6-12 months to detect and evaluate aortic valve regurgitation with echocardiographic evaluations including measurements of the aortic root diameter. The initial dose of propranolol used was 10 mg four times a day. Thereafter the dose was increased until the heart rate after moderate exercise was below 100 beats/min or the left ventricular systolic time interval (PEP/ET) was increased by 30%. At the start of the study the control and treatment groups were comparable in blood pressure, resting heart rate, systolic time intervals, and aortic diameter. Because of a wide range of ages, the ratio of the actual aortic root diameter to the diameter predicted by age, height, and weight was used for statistical comparisons. The rate of dilation, as indicated by plotting the slope of this ratio against the length of follow-up, was significantly lower in the treatment group. The rate of change was not related to the aortic diameter at the beginning of study in either the treatment or the control groups. There were several clinical end points: voluntary withdrawal, death, aortic dissection, aortic regurgitation audible by auscultation, cardiovascular surgery, congestive heart failure, or an intractable adverse reaction to propranolol. A clinical end point was reached by five patients in the treatment group, two of whom did not comply with therapy. Acute aortic dissection occurred in two, aortic valve regurgitation developed in two, and one child developed an aortic root diameter greater than 60 mm. In the control group two patients died suddenly, four developed acute aortic dissection, two had aortic valve regurgitation, and one patient had progressive aortic root dilation to greater than 60 mm. Control and treatment groups were followed for a mean of 9.3 years and 10.7 years, respectively. Although the two groups were not significantly different for survival without reaching a clinical end
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point at the end of follow-up, the survival rate without reaching a clinical end point was significantly different at intermediate follow-up periods between 3.5 and 6 years and 7-9 years. Neither of the two deaths in the control group was caused by aortic dissection [35]. The absence of sudden death in the treated patients was thought to be due, at least in part, to the antiarrhythmic effects of propranolol. The two patients with sudden death had a history of paroxysmal supraventricular tachycardia, and one of them had the Wolff-Parkinson-White syndrome. Mitral valve prolapse, a common abnormality in the Marfan syndrome, has been associated with supraventricular tachycardia and with an atrioventricular bypass tract
DA. In another study, we examined both the general effect of /3-adrenergic blockade on the rate of aortic root dilation and the specific effect of the dose-response relationship [37]. This study included patients from the Johns Hopkins Hospital (JHH) and the LeBonheur Children’s Medical Center at the University of Tennessee (UT). Charts were reviewed of all patients diagnosed with the Marfan syndrome who were initially evaluated at the JHH between 1978 and 1990, were treated with P-blockade, and who were re-evaluated at least once between 1991 and 1992. Patients who had their first visit after 21 years of age were excluded. None of the selected patients participated in the randomized, prospective trial of propranolo1 presented above [351. The patients in the UT group were evaluated prospectively between 1986 and 1992. Each received /3-adrenergic blockade and biannual follow-up evaluations. A control group was not formed because of ethical considerations. During these time periods, all patients with the diagnosis of the Marfan syndrome were considered for chronic P-adrenergic blockade therapy. Several criteria were used to withhold P-blockade therapy: a history of bronchospasm which required treatment on two or more occasions in 1 year; diabetes mellitus under treatment; signs of severe ventricular dysfunction; a resting bradycardia below 50 beats/min; and patients or parents who refused the treatment. The JHH treatment protocol used a starting dose of the p-blocker of 0.5-1.0 mg/kg/day. The dose was increased in increments of 20-40 mg of propranolo1 or 12.5-25 mg of atenolol until adequate blockade was demonstrated by exercise testing. Patients older than 5 years were asked to run up and down two flights of stairs and the heart rate was measured at the end of this stressor. A heart rate greater than 110 beats/min immediately after exercising indicated a need for an increase in the dose of the p-blocker. During the initial period of treatment, follow-up every 4-6 weeks was required to determine the optimal dose.
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On the first visit, patients following the UT protocol had a complete history and physical examination, a maximal exercise test, and comprehensive two-dimensional echocardiography. After follow-up visits at 6 week intervals, patients were reevaluated every 6 months. For patients over 6 years of age a maximal exercise test on a cycle ergometer was performed before starting therapy and at 12 month intervals thereafter. The initial dose of atenolol was 1 mg/kg/day divided into two doses. It was increased until the maximal exercise heart rate had decreased by 30-40 bpm or to about 80% of the pretreatment maximal heart rate. The goal was to increase the dose of atenolol to approximately 2 mg/kg/day. Atenolol dose was increased progressively until the patient reached this goal dose, had the targeted reduction in exercise heart rate, or developed clinically unacceptable drug side-effects. In the JHH control group, 13 patients who could or would not take the p-blockers were followed prospectively. Cross-sectional echocardiographic images were used to find the region of the aortic root with the greatest diameter and this dimension was measured from an M-mode tracing using the leading edge method. Computerized tomography or magnetic resonance imaging were used when thoracic deformity precluded accurate echocradiographic measurements. The results of this study are summarized in Table 1. There were 20 patients in the UT group, 80 patients in the JHH treatment group, and 13 patients in the JHH control group. All of the patients were younger than 21 years of age at entry into the study, and the follow-up duration was similar among the three groups. The rate of change in aortic dilation in the control group was 2.1 f 1.6 mm/year. This was not different from the results reported by Pyeritz in 1983 [30]. However, in the two treatment groups the rates of change of aortic dilation were significantly lower (UT 0.7 f 1.8 mm/year, JHH 1.1 L- 1.1 mm/year) than in those in the control group. The dose of P-adrenergic blockade used in the UT patients (1.9 f 0.6 mg/kg) was significantly larger than the dose used in the JHH patients (1.3 + 0.9 mg/kg; P < 0.008). Although the rate of aortic dilation was not significantly different between the two treatment groups, the UT group tended to have a lower mean rate of dilation. Patients in the JHH treatment group tended to be younger at the start of therapy, but they had aortic root diameters that were similar to those in the UT group. At the start of therapy, the aortic root dimension indexed to body surface area was significantly lower in the UT group than in both the JHH treatment and control groups. A faster rate of aortic root dilation was apparent during the childhood years, as shown in Fig. 1. The maximal rate of dilation was between 5 and 15 years
M.A.
Table 1 Demographic and echocardiographic
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findings [7] a
a vs. b
JHH
P
b
b vs. c P
(n = 80)
Male (%) Age at therapy start (year) Age at last follow up (year) Duration of follow up (year) Initial height (cm) Final height (cm) Initial weight (kg) Final weight (kg) Initial body surface area cm*) Final body surface area cm*) Initial aortic root diameter (mm) Final aortic root diameter (mm) Aortic root growth rate (mm/year) Initial aortic root indexed (mm/m*) Final aortic root indexed (mm/m*) Aortic root rate of growth (mm/year/
74
56 (70) 10.4 + 3.4 15.8 + 6.5 5.5 k 2.7 151 * 31 174 * 22 41.2 f 20.4 58.6 f 19.9 1.34 f 0.48 1.72 f 0.40 31.1 f 7.0 37.0 f 8.6 1.1 * 1.1 25.2 f 7.2 22.2 + 5.1 -0.7 + 1.0
NS
< 0.005 NS NS < 0.0009 NS < 0.0002 < 0.02 < 0.005 < 0.05 NS NS NS < 0.003 < 0.02 < 0.025
13 (651 14.1 + 3.4 18.5 * 4.8 4.2 + 2.1 177 + 18 181 + 16 61.3 f 19.6 71.3 f 26.1 1.70 * 0.53 1.92 + 0.37 34.0 f 5.4 35.5 + 7.4 0.7 + 1.8 19.7 f 4.1 19.0 f 4.6 0.0 f 1.5
NS
< 0.009 NS NS < 0.01 NS < 0.02 NS < 0.02 < 0.05 NS < 0.05 < 0.03 < 0.003 < 0.002 NS
a vs. c
C
Control (n = 13)
P
7 (54) 10.2 &- 4.6 15.7 f 4.3 5.7 + 1.8 146 * 37 149 f 69 37.8 + 20.9 61 .Of 24.4 1.27 + 0.41 1.66 f 0.33 31.3 f 7.4 42.4 + 11.1 2.1 f 1.6 26.5 + 7.9 26.0 * 6.8 0.0 f 1.2
NS NS NS NS NS < 0.04 NS NS NS NS NS
< 0.05 < 0.006 NS < 0.02 < 0.05
m*) Beta-blocker dose (mg/kg/day)
1.3 f 0.9
< 0.008
of age. This is in contrast to the rate of aortic growth in normal subjects [12]. This accelerated rate of dilation in childhood deserves special attention because aortic dilation in early life may make subsequent P-blockade ineffective in preventing complications. Patients who required aortic root surgery during follow-up had greater aortic root diameters at the time of initial evaluation. The indexed aortic root size
1.9 f 0.6
0
for the JHH treatment group decreased by 0.7 mm/year/m’ during the follow-up period. This reduction was not observed in either the UT treatment group or the control group. This finding raises the intriguing hypothesis that if P-adrenergic blockade is used early enough in patients with the Marfan syndrome, it can actually improve the tensile strength of the aortic wall, allowing it to withstand the hemody-
Fig. 1. The relationship between aortic root diameter (mean f SD.) and age in patients with the Marfan syndrome receiving Padrenergic blockade therapy [7].
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namic forces. Recall the animal data presented earlier that demonstrated an intact aortic elastic laminae in turkeys fed propranolol and disruption in those who did not receive it [19]. 4. Recommendations
for management
4.1. Infants
All infants with clinical signs or a family history of the Marfan syndrome should have a complete evaluation by a pediatric cardiologist and a geneticist [38,39]. The evaluation should include a systematic appraisal of the several non-cardiovascular systems that can be involved. The cardiac evaluation should include a detailed general physical evaluation and a cardiovascular examination to detect signs of heart failure from mitral valve disease. A comprehensive echocardiographic study should be performed as a baseline study to evaluate the competence of all valves and the diameter and shape of the aortic root. Criticism of the use of body surface area as an index for aortic root dimensions in children has led to an alternative suggestion that the diameter of the annulus of the aortic valve be used as an internal control for each patient [40]. The validity of this method in young Marfan patients deserves study. In the presence of signs and symptoms of heart failure or severe mitral regurgitation, the patient should be treated with anti-congestive measures, including digoxin, diuretics, and afterload reduction drugs [lo]. The timing of mitral valve surgery, thoroughly discussed elsewhere in this review, is important because a large portion of the deaths in infants with the Marfan syndrome is caused by mitral valve deformity and dysfunction. p-adrenergic blockade is indicated in infants who have a large and deformed aortic root without signs of heart failure or other drug contraindications. At the University of Tennessee, we begin treatment when the largest diameter of the aortic root is above the 95th percentile predicted for age. Other centers start therapy at the time the diagnosis is established, regardless of the diameter of the aorta. While this approach may be useful in preventing early stages of aortic root dilation, it can lead to the treatment of patients with only mild aortic involvement which may never cause morbidity or mortality. Atenolol is the current drug of choice because of its &-selective effect on the heart and its reduced pulmonary and central nervous system side effects. We advocate two doses a day to reduce the potential for lethargy when a single large daily dose is used. Propranolol is given four times a day, and it more readily crosses the blood-brain barrier. The initial
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dose of atenolol is 0.5-l mg/kg/day, divided into two doses. In young infants, monitoring should include assessment of the resting heart rate response and identification of side effects such as lethargy, poor feeding, and hypoglycemia. The first follow-up evaluation should be 4-6 weeks after starting therapy. Thereafter bi-annual follow-up is adequate. At each visit a complete physical examination should be made to search for signs of progressive mitral valve disease or heart failure; the diameter of the aortic root should be re-measured by echocardiography. Because systematic exercise testing is not feasible in infants and young children, criteria for adequate P-blockade are not available for these patients with the Marfan syndrome. However, adequate blockade can be inferred by noting a reduction in the resting heart rate below 100 beats/min or by a 20% reduction from the pretreatment rate. The families of children with the Marfan syndrome should also be evaluated for the condition because of its dominant inheritance transmission. This is especially important in the first-degree relatives of the index case [39]. Genetic counseling for the parents of an affected child should include a clear explanation of the 50% risk of the syndrome occurring in other offspring [39]. 4.2. Children atzd adolescents
The evaluation of the Marfan syndrome in children and adolescents is the same as in infants. p-blockade therapy is started either at the time of diagnosis or when the aortic root diameter is above the 95th percentile as predicted by body surface area in normal children. The initial dose of atenolol, 1 mg/kg/ day, is increased at subsequent visits in increments of 0.25-0.5 mg/kg/day until a final dose of 2 mg/kg/ day is reached or drug side-effects interfere with daily activity. At each follow-up visit a cardiovascular evaluation should include echocardiographic measurement of the aortic root diameter and shape. Adequate P-blockade is determined by the heart rate response to exercise testing. Testing can be performed either by running briskly up- and-down two flights of steps or by a more structured maximal test with a cycle ergometer or treadmill. The goal heart rate should be below 100 beats/min after running the stairs or a maximal exercise heart rate which is 20% or 30-40 beats/min less than the pre-treatment maximal rate. In most patients the dose of atenolol can be gradually increased to a goal level of 2 mg/kg/day without unacceptable side effects. At this dosage the major side effects include tiredness and easy fatigue. Side effects of propranolol reported by Shores et al. [35] included: lethargy, depression, insomnia, dream disturbance, mild bronchospasm, and accentuated ef-
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fects from alcohol. The dose of P-blocker had to be reduced in only one patient in this study who developed third degree atrioventricular heart block. Most patients tolerate the side effects, and bothersome symptoms frequently disappear during follow-up [30]. Some teenagers report falling asleep in school after the morning dose. In this case, a reduction in dosage can help to alleviate these symptoms and encourage compliance. In adolescents, careful and prompt attention to side effects and concerns can help to improve and maintain compliance. Moderate physical exercise is allowed in patients with the Marfan syndrome, but participation in most competitive sports is discouraged. Aerobic, non-contact forms of exercise are ideal for these children, because they allow for longer periods of activity without large changes in heart rate, arterial blood pressure, and coronary driving pressure. 4.3. Surgery
In the Marfan syndrome aortic valve regurgitation occurs as the aortic root dilates. P-adrenergic blockade retards the rate of aortic root dilation but it does not provide complete or indefinite protection. When the root diameter at the sinuses of Valsalva is twice the mean predicted diameter, follow-up evaluations should be increased to every 3 months. The practice of waiting to replace the dilated aorta until its diameter is 60 mm does not protect all patients from dissection [23]. In patients who developed aortic dissection, Fyeritz noted that the aortic root diameter measured 1 day to 1 year before dissection was < 60 mm in 15 (38%) of 40 patients [28]. Close follow-up should include frequent measurements of the aortic diameter by echocardiography or magnetic resonance imaging, [42] as discussed elsewhere in this review issue. In 100 consecutive JHH patients with the Marfan syndrome who underwent composite graft repair of the aortic valve and ascending aorta, the hospital mortality rate was only 1% [43]. The late mortality after surgery for aortic dilation and dissection is also encouragingly low [3,43]. 4.4. Post-operatiuecare
When patients are adequately anticoagulated, significant complications related to the prosthetic valve have not been reported. In the JHH experience the incidence of infective endocarditis was 6% [43] and it was 5.2% in patients reported from Houston’s Methodist Hospital [441. This risk of endocarditis with prosthetic valves has raised the issue of using homograft conduits for the repair. At this time, however, there are not sufficient data in patients with the Marfan syndrome for adequate evaluation.
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/3-adrenergic blockade should be maintained after surgery because the same changes in the aortic wall that led to the initial aneurysm and dissection can produce subsequent aneurysms in other parts of the arterial system [44]. In a review of 192 patients who underwent surgery for the Marfan syndrome complications, Finkbohner et al. [44] reported that the initial surgery was done in the ascending aorta in 83.8% of patients. The others had initial surgery at other aortic sites. On follow-up, 70% of all patients had subsequent aneurysms or dissection at other arterial sites. Other regions of the aorta were involved in 95% of the patients, and one or more of the major aortic branches was affected in 5% of patients. A second surgical procedure was performed in 101(53%) of the 192 patients. The need for subsequent surgery was significantly related to the presence of acute or chronic dissection at the time of initial surgery, the development of hypertension between the first and second surgery, and a history of habitual smoking at any age. References [ll Murdoch JL, Walker BA, Halpern BL et al. Life expectancy and causes of death in the Marfan syndrome. N Eng J Med 1972;286:804-808.
Dl Silverman DI, Burton KJ, Gray J et al. Life expectancy in the Marfan syndrome. Am J Cardiol 1995;75:157-160. Coselli, JS and LeMaire SA. Prog Pediatr Cardiol 1996;5:189-203 t41 Cameron, DE. Prog Pediatr Cardiol 1996;5;151-157. [51 Pyeritz, RE. Prog Pediatr Cardiol 1996;5;151-157. bl Phomaphutkul C, Rosenthal A, Nadas AS. Cardiac manifestations of Marfan syndrome in infancy and childhood. Circulation 1973;47:587-596. [71 Sisk HE, Zahka KG, Pyeritz RE. The Marfan syndrome in early childhood: analysis of 15 patients diagnosed at less than 4 years of age. Am J Cardiol 1983;52:358-358. [8I Gillan JE, Costigan DC, Keeley FW et al. Spontaneous dissecting aneurysm of the ductus arteriosus in an infant with Marfan syndrome. J Pediatr 1984;105:952-955. [91 Geva T, Hegesh J, Frand M. The clinical course and echocardiographic features of Marfan’s syndrome in childhood. Am J Dis Child 1987;141:1179-1182. Morse RP, Rockenmacher S, Pyeritz RE et al. Diagnosis and [lOI management of infantile Marfan syndrome. Pediatrics 1990;86:888-895. [ill Tayel S, Kurczynski TW, Levine M et al. Etiologic heterogeneity and cardiac findings. Am J Dis Child 1991;145:90-93. [I21 El Habbal MH. Cardiovascular manifestations of Marfan’s syndrome in the young. Am Heart J 1992;123:752-757. t131 Gross DM, Robinson LK, Smith LY et al. Severe perinatal Marfan syndrome. Pediatrics 1989;84:83-89. Dietz HC. Prog Pediatr Cardiol 1996;5;159-166. [I41 [151 Pyeritz RE. The Marfan syndrome. In: Royce PM and Steinmann B, editors. Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects. New York: Wiley-L& 1993;437-468. 1161Yin FCP, Brin KP, Ting CP et al. Arterial hemodynamic indexes in Marfan’s syndrome. Circulation 1989;79:854-862. [171 Geva T, Sanders SP, Diogenes MS et al. Two-dimensional and Doppler echocardiographic and pathologic characterist31
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tics of the Infantile Mar-fan syndrome. Am J Cardiol 1990;65:1230-1237. Ml Ose L, McKusick VA. Prophylactic use of propranolol In the Marfan syndrome to prevent aortic dissection. Birth Defects 1977;13:163-169. [191 Simpson CF, Boucek RJ, Noble NL. Influence of D-, L- and p-L-propranolol and practolol on P-amniopropropionitrile-induced aortic rupture in turkeys. Toxic01 Appl Pharmacol 1976;38:169-175. [201 Prokop EK, Palmer RF, Wheat MW Jr. Hydrodynamic forces in dissecting aneurysms. In-vitro studies in a tygon model and in dog aortas. Circ Res 19X$27:121-127. 1211Milewicz DM, Pyeritz RE, Crowford ES et al. Marfan syndrome: defective synthesis, secretion and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J Clin Invest 1992;89:79-86. P21 Dietz HC, Pyeritz RE, Francomano CA et al. Marfan phenotype variability in a family segregating a missense mutation in the EGF-like motif of the fibrillin gene. J Clin Invest 1992;89: 1674-1680. WI Dietz HC, Francomano CA, Kendzior RJ et al. Skipping a consecutive exons in vivo induced by a nonsense mutation. Science 1993;259:680-683. [241 Hirata K, Triposkiadis F, Sparks E et al. The Marfan syndrome: Abnormal aortic elastic properties. J Am Coll Cardiol 1991;18:57-63. La Savolainen A, Keto P, Hekali P et al. Aortic distensibility in children with the Marfan syndrome. Am J Cardiol 1992;70: 691-693. [261 Reed CM, Fox ME, Alpert BS. Aortic biochemical properties in pediatric patients with the Marfan syndrome, and the effect of atenolol. Am J Cardiol 1993;71:606-608. WI Reed CM, Alpert BS. Assessment of ventricular performance after chronic beta adrenergic blockade in the Marfan syndrome. Am J Cardiol 1992;70:541-542. LB1 Pyeritz RE. Predictors of dissection of the ascending aorta in Mat-fan syndrome. Circulation 1991;84(II Suppl):II-351. 1291Roman MJ, Rosen SE, Kramer-Fox R et al. Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. J Am Coil Cardiol 1993;22:1470-1476. [301 Pyeritz RE. Propranolol retards aortic root dilation in the Marfan syndrome (abstract). Circulation 1983;68:111-365.
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[311 Alpert BS, Reed CM, Ward WJ et al. Atenolol reduces aortic growth in the Marfan syndrome. Pediatr Res 1991;70:14A. WI Alpert B, Reed C, Ward J et al. Beta blockade reduces aortic growth rate in Marfan syndrome. Cardiol Young 1993;3(1 Supplk25. [331 Hwa J, Richards JG, Huang H et al. The natural history of aortic dilation in Marfan syndrome. Med J Aust 1993;158: 558-562. [341 Tahernia AC. Cardiovascular anomalies in Marfan’s syndrome: The role of echocardiography and @-blockers. South Med J 1993;86:305-310. I351 Shores J, Berger KR, Murphy EA et al. Progression of aortic dilation and the benefit of long-term /3-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994;330:1335-1341. [361 Josephson ME, Horowitz LN, Kastor JA. Paroxysmal supraventricular tachycardia in patients with mitral valve prolapse. Circulation 1978;57:11 l-1 15. [371 Salim MA, Alpert BS, Ward JC et al. Effect of &adrenergic blockade on aortic root rate of dilation in the Marfan syndrome. Am J Cardiol 1994;74:629-633. I381 Beighton P, de Paepe A, Danks D et al. International nosology of heritable disorders of the connective tssue, Berlin, 1986. Am J Med Genet 1988;29:581-594. [391 Pyeritz RE, McKusick VA. The Marfan syndrome: Diagnosis and management. N Eng J Med 1979;300:772-777. asI401 Sheil MLK, Jenkins 0, Sheller GF. Echocardiographic sessment of aortic root dimensions in normal children based on measurement of a new ratio of aortic size independent of growth. Am J Cardioi 1995;75:711-715. [411 Sahn DJ, DeMaria A Kisslo J et al. Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1083. [421 Schaefer S, Peshock RM, Malloy CR et al. Nuclear magnetic resonance imaging in Marfan’s syndrome. J Am Colt Cardiol 1987;9:70-74. [431 Gott VL, Pyeritz RE, Cameron DE. Composite graft repair of Marfan aneurysm of the ascending aorta: results in 100 patients. Ann Thorac Surg 1991;52:38-45. WI Finkbonhner R, Johnston D, Crawford ES et al. Marfan syndrome, Long term survival and complications after aortic aneurysm repair. Circulation 1995;91:728-733.
Pediatric Cardiology Progress in Pediatric Cardiology 5 (1996) 167-174
Medical management of young patients with the Marfan syndrome Mubadda A. Salim* , Bruce S. Alpert The Depamnent
of Pediatrics,
Division
of Cardiology,
The University of Tennessee, TN 38105, USA
777 Washington
Avenue,
Suite 215, Memphis,
Abstract The Marfan syndrome can be associatedwith high morbidity and reduced survival, primarily from cardiovascular complications.Thesemanifestationsinclude abnormalitiesof the mitral valve and progressivedilation of the proximal aorta. In recent yearsmedicaland surgicaladvanceshave dramatically improved the outlook for patientswith the Marfan syndrome. Acute medicaltreatment of the Marfan syndromeusually involves managingcomplicationssuchasheart failure from severe mitral and/or aortic valve regurgitation. The long term treatment involves the use of &adrenergic blockade to retard progressivedilation of the aortic root and to prevent dissection.The efficacy of this therapy hasbeen documentedin several prospectivetrials. Echocardiographyor magneticresonanceimagingis usedto evaluate the sizeof the aortic root, allowingfor frequent non-invasive follow-up. These techniques can also be used to gauge the effectiveness of pblockade, detect cardiovascularcomplications,and help to determinethe optimal timing for surgicalinterventions. Compositegraft repair of the aortic valve and ascendingaorta is a life-savingprocedure in patients with the Marfan syndromewith severedilation of the aortic root. P-adrenergicblockade should be continued after surgery to protect againstarterial dilation and dissection elsewhere. Keywords:
Marfan syndrome;Padrenergic blockade;Atenolol; Aorta; Pediatrics
1. Introduction
In patients with the Marfan syndrome premature death is largely due to cardiovascular complications. A quarter of a century ago, life expectancy was markedly reduced by about one-third in both male and female patients [l]. At that time a 40-year-old man with the syndrome had only a 32% probability of living another 20 years. In cases where the cause of death could be identified, cardiovascular problems were responsible in over 90% of patients. Most of the deaths were from aortic complications and occurred between the second and fifth decades. Survival was somewhat better in women than in men. By 1993 the overall survival had improved consider*Corresponding author, Tel.: + 1 901 5723380;fax: + 1 901 5725107.
ably for both sexes. More than 80% of men with the Marfan syndrome were likely to survive to 60 years of age [21. Nonetheless, cardiovascular complications continued to be the chief cause of death and morbidity remained high, with at least one-quarter of patients requiring cardiovascular surgery. As documented elsewhere in this review, [3,4] advances in surgical technique and postoperative care have contributed to a marked improvement in survival after elective repair of the dilated aortic root and the mitral valve. It has also become obvious, however, that mildly affected patients were often not included in earlier surveys, and that reports of a lengthened life-expectancy may be exaggerated. It cannot be denied, however, that patients with the Marfan syndrome have benefitted significantly from the early diagnosis and aggressive medical management demonstrated during the past several decades. This review focuses on this early diagnostic and medical management.
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2. The Marfan
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syndrome in infancy
The cardiovascular manifestations of the Mar-fan syndrome can present at any age from infancy to late adulthood [S-131. When its manifestations are detected in infancy the child is usually severely affected or diagnostic evaluation is requested because of concern by a parent or relative with the Marfan syndrome. In many cases the most severely affected infants have no identifiable relative with the syndrome, and their abnormalities represent new mutations in fibrillin-1 [14]. In infants the cardiovascular manifestations of the Marfan syndrome include prolapse and regurgitation of the mitral and tricuspid valves and dilation of the aortic root, especially at the level of the sinuses of Valsalva. The prevalence rates of these abnormalities can be as high as 80% in infants diagnosed with the syndrome [7,10]. These lesions, especially those producing mitral valve regurgitation, can be fatal at a very young age [lo]. For example, of 22 patients with the infantile Marfan syndrome reported by Morse et al. [lo] three (13.6%) died during the first year of life from aortic dissection, cardiopulmonary failure, and after mitral valve replacement. Sisk et al. [7] reported on the longitudinal follow-up of 15 children who were diagnosed with the Marfan syndrome before 4 years of age. At follow-up all of them had dilation of the aortic root. Mitral valve function was diminished at later follow-up examinations in nine patients, four of whom, all with a negative family history, required mitral valve replacement between 11 months and 12 years of age. 2.1. Cardiac arrhythmia
Cardiac arrhythmia can be a manifestation of the Marfan syndrome. Paroxysmal atria1 tachycardia was observed in one child who was thought to have ‘no significant heart disease’ and atria1 fibrillation and multiform ventricular extra systoles were observed in three others with mitral valve regurgitation [6]. These arrhythmias were probably related to the functional abnormalities of the mitral valve with dilation of the left atrium rather than to specific structural cardiovascular abnormalities of the Mar-fan syndrome. The Wolff-Parkinson-White syndrome has also been reported in children with the syndrome [12]. 2.2. Congenital heart disease
The significance of an association between the Marfan syndrome and congenital heart disease remains controversial [6,12]. In El Habbal’s report of 186 Mar-fan patients younger than 20 years of age, the incidence of bicuspid aortic valve, atria1 septal defect,
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and tetralogy of Fallot was 9.7%, 2.7%, and l.l%, respectively [12]. These rates are significantly higher than those reported for these defects in the general population (2%, 0.06%, and 0.03%, respectively). El Habbal also reported that bicuspid aortic valve was associated with an increased incidence of severe cardiovascular sequelae in Marfan patients, and he hypothesized that flow through the two cusps produced turbulence in the ascending aorta which contributed to elevated aortic wall stress and an increase in the rate of aortic dilation. Other authors have not confirmed an increased incidence of congenital heart defects in patients with the syndrome [15]. 2.3. Survival in childhood
In children with the Mar-fan syndrome the survival rate is lower than that in normal children. Reported mortality rates range from 1.6% 191 to 44% [16]. Most of the deaths occurred in infants during the first year of life, and were caused by heart failure from mitral and/or aortic valve insufficiency. Postoperative death after valve surgery was also an important cause. 3. Medical
therapy
3.1. Padrenergic
blockade
In 1977 Ose and McKusick were the first to report a trial of /3-adrenergic blockade to try to prevent aortic dissection in patients with the Marfan syndrome [17]. Twenty-five patients were treated with propranolol for 14 months to 5 years. Five died during follow-up, all from dissecting aortic aneurysm or its complications. The dose of propranolol ranged from 120-160 mg/day in adults and from 40-80 mg/day in children. The results of treatment were inconclusive, probably because the method of analysis was not able to measure a significant progression of aortic root dilation, and also because some of the patients had marked aortic dilation when treatment was started. A more recent study of Marfan patients with a dilated aorta has measured an increase in vascular impedance with acute @blockade treatment begun after nitroprusside therapy [ 181. 3.2. Eqerimental
work
An experimental model of the aortic pathology found in the Marfan syndrome was created in broadbreasted turkeys who developed aortic rupture when they were fed amniopropionitrile [19]. When the turkeys were fed amniopropionitrile supplemented with L- or D-L-propranolol, aortic rupture did not develop. Practolol, a cardioselective P-blocker, produced a similar effect with rupture in only 13.1% of
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birds. The use of the o-isomer of propranolol had no significant effect on the incidence of aortic rupture (62.4%) as compared to control animals (54.2%). The efficacy of the therapy correlated with the reduction in the maximum rate of pressure rise (dP/dt) in the carotid artery. Moreover, histologic examination of the aorta in turkeys who did not receive L- or D-L-propranolol revealed extensive degeneration of elastic fibers and disappearance of the internal elastic membranes, whereas these changes were very mild in turkeys fed L- or DL-propranolol [19]. In an in-vitro study of dogs, Prokop et al. [201 showed that only pulsatile flow in the aorta contributed to the dissecting forces in the presence of an intimal tear, whereas nonpulsatile flow produced no aneurysms, even at aortic pressures as high as 400 mmHg. The extent of dissection for each pulsation was related to the maximum rate of pressure rise in the aorta (dP/dt,,,). These animal studies and other investigations have led to several therapeutic trials of p-adrenergic blockade in patients with the Marfan syndrome. The abnormal mechanical properties of the ascending aorta relate to the structural defects of the aortic wall. Abnormalities in fibrillin synthesis and deposition in the extracellar matrix appear to explain the wide array of ocular, skeletal and cardiac abnormalities found in the Marfan syndrome [14,21-231. In patients with the syndrome the ascending aorta and the abdominal aorta have been shown to have decreased distensibility and increased stiffness as compared to these sites in normal individuals, [24-261 and these abnormalities did not change after therapy with atenolol [27]. The pulsatile burden of left ventricular ejection and the reduced elasticity of the aorta produce shear forces that diminish the integrity of the aortic wall and lead to dilation. The reduction in left ventricular contractile force after p-adrenergic blockade may be important in slowing the rate of dilation of the ascending aorta and its consequent complications [271. Factors that predict an increased risk of aortic dissection and death include an aortic root diameter of 60 mm or more and a family history of death from a dissecting aortic aneurysm in a close relative under 40 years of age 1281. The configuration of the aortic root at the initial evaluation is another predictor of aortic dilation and of its complications - subsequent severe dilation, need for aortic surgery, and severe aortic valve regurgitation [24]. In patients with dilation localized to the sinuses of Valsalva, significantly less progression of aortic root dilation has been seen, as compared to those with generalized dilation extending beyond the sinuses of Valsalva to the supraaortic ridge and proximal ascending aorta [29]. padrenergic blockade has not been shown to protect indefinitely from aortic dilation and dissection [28,29].
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and functional
im-
3.3. Clinical efficacy of /3-adrenergic blockade
The earliest, albeit preliminary, report of the benefit of propranolol in the preventive treatment of patients with the Marfan syndrome was in 1983 [30]. Thereafter, additional sporadic reports of a decrease in the progression of aortic dilation appeared, usually as abstracts or as a part of a larger series of patients, most of whom did not receive therapy [9,31-341. Two prospective studies have evaluated the efficacy of P-adrenergic blockade in patients with the Marfan syndrome. Shores et al. [351 reported the results of a randomized, open-label study of patients between 12 and 50 years of age [35]. There were 32 patients in the treatment group and 38 patients in the control group. Patients were followed every 6-12 months to detect and evaluate aortic valve regurgitation with echocardiographic evaluations including measurements of the aortic root diameter. The initial dose of propranolol used was 10 mg four times a day. Thereafter the dose was increased until the heart rate after moderate exercise was below 100 beats/min or the left ventricular systolic time interval (PEP/ET) was increased by 30%. At the start of the study the control and treatment groups were comparable in blood pressure, resting heart rate, systolic time intervals, and aortic diameter. Because of a wide range of ages, the ratio of the actual aortic root diameter to the diameter predicted by age, height, and weight was used for statistical comparisons. The rate of dilation, as indicated by plotting the slope of this ratio against the length of follow-up, was significantly lower in the treatment group. The rate of change was not related to the aortic diameter at the beginning of study in either the treatment or the control groups. There were several clinical end points: voluntary withdrawal, death, aortic dissection, aortic regurgitation audible by auscultation, cardiovascular surgery, congestive heart failure, or an intractable adverse reaction to propranolol. A clinical end point was reached by five patients in the treatment group, two of whom did not comply with therapy. Acute aortic dissection occurred in two, aortic valve regurgitation developed in two, and one child developed an aortic root diameter greater than 60 mm. In the control group two patients died suddenly, four developed acute aortic dissection, two had aortic valve regurgitation, and one patient had progressive aortic root dilation to greater than 60 mm. Control and treatment groups were followed for a mean of 9.3 years and 10.7 years, respectively. Although the two groups were not significantly different for survival without reaching a clinical end
170
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point at the end of follow-up, the survival rate without reaching a clinical end point was significantly different at intermediate follow-up periods between 3.5 and 6 years and 7-9 years. Neither of the two deaths in the control group was caused by aortic dissection [35]. The absence of sudden death in the treated patients was thought to be due, at least in part, to the antiarrhythmic effects of propranolol. The two patients with sudden death had a history of paroxysmal supraventricular tachycardia, and one of them had the Wolff-Parkinson-White syndrome. Mitral valve prolapse, a common abnormality in the Marfan syndrome, has been associated with supraventricular tachycardia and with an atrioventricular bypass tract
DA. In another study, we examined both the general effect of /3-adrenergic blockade on the rate of aortic root dilation and the specific effect of the dose-response relationship [37]. This study included patients from the Johns Hopkins Hospital (JHH) and the LeBonheur Children’s Medical Center at the University of Tennessee (UT). Charts were reviewed of all patients diagnosed with the Marfan syndrome who were initially evaluated at the JHH between 1978 and 1990, were treated with P-blockade, and who were re-evaluated at least once between 1991 and 1992. Patients who had their first visit after 21 years of age were excluded. None of the selected patients participated in the randomized, prospective trial of propranolo1 presented above [351. The patients in the UT group were evaluated prospectively between 1986 and 1992. Each received /3-adrenergic blockade and biannual follow-up evaluations. A control group was not formed because of ethical considerations. During these time periods, all patients with the diagnosis of the Marfan syndrome were considered for chronic P-adrenergic blockade therapy. Several criteria were used to withhold P-blockade therapy: a history of bronchospasm which required treatment on two or more occasions in 1 year; diabetes mellitus under treatment; signs of severe ventricular dysfunction; a resting bradycardia below 50 beats/min; and patients or parents who refused the treatment. The JHH treatment protocol used a starting dose of the p-blocker of 0.5-1.0 mg/kg/day. The dose was increased in increments of 20-40 mg of propranolo1 or 12.5-25 mg of atenolol until adequate blockade was demonstrated by exercise testing. Patients older than 5 years were asked to run up and down two flights of stairs and the heart rate was measured at the end of this stressor. A heart rate greater than 110 beats/min immediately after exercising indicated a need for an increase in the dose of the p-blocker. During the initial period of treatment, follow-up every 4-6 weeks was required to determine the optimal dose.
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On the first visit, patients following the UT protocol had a complete history and physical examination, a maximal exercise test, and comprehensive two-dimensional echocardiography. After follow-up visits at 6 week intervals, patients were reevaluated every 6 months. For patients over 6 years of age a maximal exercise test on a cycle ergometer was performed before starting therapy and at 12 month intervals thereafter. The initial dose of atenolol was 1 mg/kg/day divided into two doses. It was increased until the maximal exercise heart rate had decreased by 30-40 bpm or to about 80% of the pretreatment maximal heart rate. The goal was to increase the dose of atenolol to approximately 2 mg/kg/day. Atenolol dose was increased progressively until the patient reached this goal dose, had the targeted reduction in exercise heart rate, or developed clinically unacceptable drug side-effects. In the JHH control group, 13 patients who could or would not take the p-blockers were followed prospectively. Cross-sectional echocardiographic images were used to find the region of the aortic root with the greatest diameter and this dimension was measured from an M-mode tracing using the leading edge method. Computerized tomography or magnetic resonance imaging were used when thoracic deformity precluded accurate echocradiographic measurements. The results of this study are summarized in Table 1. There were 20 patients in the UT group, 80 patients in the JHH treatment group, and 13 patients in the JHH control group. All of the patients were younger than 21 years of age at entry into the study, and the follow-up duration was similar among the three groups. The rate of change in aortic dilation in the control group was 2.1 f 1.6 mm/year. This was not different from the results reported by Pyeritz in 1983 [30]. However, in the two treatment groups the rates of change of aortic dilation were significantly lower (UT 0.7 f 1.8 mm/year, JHH 1.1 L- 1.1 mm/year) than in those in the control group. The dose of P-adrenergic blockade used in the UT patients (1.9 f 0.6 mg/kg) was significantly larger than the dose used in the JHH patients (1.3 + 0.9 mg/kg; P < 0.008). Although the rate of aortic dilation was not significantly different between the two treatment groups, the UT group tended to have a lower mean rate of dilation. Patients in the JHH treatment group tended to be younger at the start of therapy, but they had aortic root diameters that were similar to those in the UT group. At the start of therapy, the aortic root dimension indexed to body surface area was significantly lower in the UT group than in both the JHH treatment and control groups. A faster rate of aortic root dilation was apparent during the childhood years, as shown in Fig. 1. The maximal rate of dilation was between 5 and 15 years
M.A.
Table 1 Demographic and echocardiographic
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findings [7] a
a vs. b
JHH
P
b
b vs. c P
(n = 80)
Male (%) Age at therapy start (year) Age at last follow up (year) Duration of follow up (year) Initial height (cm) Final height (cm) Initial weight (kg) Final weight (kg) Initial body surface area cm*) Final body surface area cm*) Initial aortic root diameter (mm) Final aortic root diameter (mm) Aortic root growth rate (mm/year) Initial aortic root indexed (mm/m*) Final aortic root indexed (mm/m*) Aortic root rate of growth (mm/year/
74
56 (70) 10.4 + 3.4 15.8 + 6.5 5.5 k 2.7 151 * 31 174 * 22 41.2 f 20.4 58.6 f 19.9 1.34 f 0.48 1.72 f 0.40 31.1 f 7.0 37.0 f 8.6 1.1 * 1.1 25.2 f 7.2 22.2 + 5.1 -0.7 + 1.0
NS
< 0.005 NS NS < 0.0009 NS < 0.0002 < 0.02 < 0.005 < 0.05 NS NS NS < 0.003 < 0.02 < 0.025
13 (651 14.1 + 3.4 18.5 * 4.8 4.2 + 2.1 177 + 18 181 + 16 61.3 f 19.6 71.3 f 26.1 1.70 * 0.53 1.92 + 0.37 34.0 f 5.4 35.5 + 7.4 0.7 + 1.8 19.7 f 4.1 19.0 f 4.6 0.0 f 1.5
NS
< 0.009 NS NS < 0.01 NS < 0.02 NS < 0.02 < 0.05 NS < 0.05 < 0.03 < 0.003 < 0.002 NS
a vs. c
C
Control (n = 13)
P
7 (54) 10.2 &- 4.6 15.7 f 4.3 5.7 + 1.8 146 * 37 149 f 69 37.8 + 20.9 61 .Of 24.4 1.27 + 0.41 1.66 f 0.33 31.3 f 7.4 42.4 + 11.1 2.1 f 1.6 26.5 + 7.9 26.0 * 6.8 0.0 f 1.2
NS NS NS NS NS < 0.04 NS NS NS NS NS
< 0.05 < 0.006 NS < 0.02 < 0.05
m*) Beta-blocker dose (mg/kg/day)
1.3 f 0.9
< 0.008
of age. This is in contrast to the rate of aortic growth in normal subjects [12]. This accelerated rate of dilation in childhood deserves special attention because aortic dilation in early life may make subsequent P-blockade ineffective in preventing complications. Patients who required aortic root surgery during follow-up had greater aortic root diameters at the time of initial evaluation. The indexed aortic root size
1.9 f 0.6
0
for the JHH treatment group decreased by 0.7 mm/year/m’ during the follow-up period. This reduction was not observed in either the UT treatment group or the control group. This finding raises the intriguing hypothesis that if P-adrenergic blockade is used early enough in patients with the Marfan syndrome, it can actually improve the tensile strength of the aortic wall, allowing it to withstand the hemody-
Fig. 1. The relationship between aortic root diameter (mean f SD.) and age in patients with the Marfan syndrome receiving Padrenergic blockade therapy [7].
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namic forces. Recall the animal data presented earlier that demonstrated an intact aortic elastic laminae in turkeys fed propranolol and disruption in those who did not receive it [19]. 4. Recommendations
for management
4.1. Infants
All infants with clinical signs or a family history of the Marfan syndrome should have a complete evaluation by a pediatric cardiologist and a geneticist [38,39]. The evaluation should include a systematic appraisal of the several non-cardiovascular systems that can be involved. The cardiac evaluation should include a detailed general physical evaluation and a cardiovascular examination to detect signs of heart failure from mitral valve disease. A comprehensive echocardiographic study should be performed as a baseline study to evaluate the competence of all valves and the diameter and shape of the aortic root. Criticism of the use of body surface area as an index for aortic root dimensions in children has led to an alternative suggestion that the diameter of the annulus of the aortic valve be used as an internal control for each patient [40]. The validity of this method in young Marfan patients deserves study. In the presence of signs and symptoms of heart failure or severe mitral regurgitation, the patient should be treated with anti-congestive measures, including digoxin, diuretics, and afterload reduction drugs [lo]. The timing of mitral valve surgery, thoroughly discussed elsewhere in this review, is important because a large portion of the deaths in infants with the Marfan syndrome is caused by mitral valve deformity and dysfunction. p-adrenergic blockade is indicated in infants who have a large and deformed aortic root without signs of heart failure or other drug contraindications. At the University of Tennessee, we begin treatment when the largest diameter of the aortic root is above the 95th percentile predicted for age. Other centers start therapy at the time the diagnosis is established, regardless of the diameter of the aorta. While this approach may be useful in preventing early stages of aortic root dilation, it can lead to the treatment of patients with only mild aortic involvement which may never cause morbidity or mortality. Atenolol is the current drug of choice because of its &-selective effect on the heart and its reduced pulmonary and central nervous system side effects. We advocate two doses a day to reduce the potential for lethargy when a single large daily dose is used. Propranolol is given four times a day, and it more readily crosses the blood-brain barrier. The initial
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dose of atenolol is 0.5-l mg/kg/day, divided into two doses. In young infants, monitoring should include assessment of the resting heart rate response and identification of side effects such as lethargy, poor feeding, and hypoglycemia. The first follow-up evaluation should be 4-6 weeks after starting therapy. Thereafter bi-annual follow-up is adequate. At each visit a complete physical examination should be made to search for signs of progressive mitral valve disease or heart failure; the diameter of the aortic root should be re-measured by echocardiography. Because systematic exercise testing is not feasible in infants and young children, criteria for adequate P-blockade are not available for these patients with the Marfan syndrome. However, adequate blockade can be inferred by noting a reduction in the resting heart rate below 100 beats/min or by a 20% reduction from the pretreatment rate. The families of children with the Marfan syndrome should also be evaluated for the condition because of its dominant inheritance transmission. This is especially important in the first-degree relatives of the index case [39]. Genetic counseling for the parents of an affected child should include a clear explanation of the 50% risk of the syndrome occurring in other offspring [39]. 4.2. Children atzd adolescents
The evaluation of the Marfan syndrome in children and adolescents is the same as in infants. p-blockade therapy is started either at the time of diagnosis or when the aortic root diameter is above the 95th percentile as predicted by body surface area in normal children. The initial dose of atenolol, 1 mg/kg/ day, is increased at subsequent visits in increments of 0.25-0.5 mg/kg/day until a final dose of 2 mg/kg/ day is reached or drug side-effects interfere with daily activity. At each follow-up visit a cardiovascular evaluation should include echocardiographic measurement of the aortic root diameter and shape. Adequate P-blockade is determined by the heart rate response to exercise testing. Testing can be performed either by running briskly up- and-down two flights of steps or by a more structured maximal test with a cycle ergometer or treadmill. The goal heart rate should be below 100 beats/min after running the stairs or a maximal exercise heart rate which is 20% or 30-40 beats/min less than the pre-treatment maximal rate. In most patients the dose of atenolol can be gradually increased to a goal level of 2 mg/kg/day without unacceptable side effects. At this dosage the major side effects include tiredness and easy fatigue. Side effects of propranolol reported by Shores et al. [35] included: lethargy, depression, insomnia, dream disturbance, mild bronchospasm, and accentuated ef-
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fects from alcohol. The dose of P-blocker had to be reduced in only one patient in this study who developed third degree atrioventricular heart block. Most patients tolerate the side effects, and bothersome symptoms frequently disappear during follow-up [30]. Some teenagers report falling asleep in school after the morning dose. In this case, a reduction in dosage can help to alleviate these symptoms and encourage compliance. In adolescents, careful and prompt attention to side effects and concerns can help to improve and maintain compliance. Moderate physical exercise is allowed in patients with the Marfan syndrome, but participation in most competitive sports is discouraged. Aerobic, non-contact forms of exercise are ideal for these children, because they allow for longer periods of activity without large changes in heart rate, arterial blood pressure, and coronary driving pressure. 4.3. Surgery
In the Marfan syndrome aortic valve regurgitation occurs as the aortic root dilates. P-adrenergic blockade retards the rate of aortic root dilation but it does not provide complete or indefinite protection. When the root diameter at the sinuses of Valsalva is twice the mean predicted diameter, follow-up evaluations should be increased to every 3 months. The practice of waiting to replace the dilated aorta until its diameter is 60 mm does not protect all patients from dissection [23]. In patients who developed aortic dissection, Fyeritz noted that the aortic root diameter measured 1 day to 1 year before dissection was < 60 mm in 15 (38%) of 40 patients [28]. Close follow-up should include frequent measurements of the aortic diameter by echocardiography or magnetic resonance imaging, [42] as discussed elsewhere in this review issue. In 100 consecutive JHH patients with the Marfan syndrome who underwent composite graft repair of the aortic valve and ascending aorta, the hospital mortality rate was only 1% [43]. The late mortality after surgery for aortic dilation and dissection is also encouragingly low [3,43]. 4.4. Post-operatiuecare
When patients are adequately anticoagulated, significant complications related to the prosthetic valve have not been reported. In the JHH experience the incidence of infective endocarditis was 6% [43] and it was 5.2% in patients reported from Houston’s Methodist Hospital [441. This risk of endocarditis with prosthetic valves has raised the issue of using homograft conduits for the repair. At this time, however, there are not sufficient data in patients with the Marfan syndrome for adequate evaluation.
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