Background The aortic root enlarges progressively in Marfan'ssyndrome, and this enlargement is associated with aortic regurgitationand dissection. Long-term treatment with -adrenergic blockade,by reducing the impulse (i.e., the rate of pressure change inthe aortic root) of left ventricular ejection and the heartrate, may protect the aortic root.
Methods We conducted an open-label, randomized trial of propranololin adolescent and adult patients with classic Marfan's syndrome(32 treated and 38 untreated [control] patients). Aortic-rootdimensions and clinical end points (aortic regurgitation, aorticdissection, cardiovascular surgery, congestive heart failure,and death) were monitored for an average of 9.3 years in thecontrol group and 10.7 years in the treatment group. All 70patients were included in the analysis according to the intention-to-treatprinciple.
Results The dose of propranolol was individualized; the mean(±SE) dose was 212 ±68 mg per day. The mean slopeof the regression line for the aortic-root dimensions, whichreflect the rate of dilatation, was significantly lower in thetreatment group than in the control group (0.023 vs. 0.084 peryear, P<0.001). Clinical end points were reached in fivepatients in the treatment group and nine in the control group.The Kaplan-Meier survival curve for the treatment group differedsignificantly from that for the control group during the middleyears of the trial and remained better for the treatment groupthroughout the study.
Conclusions Prophylactic -adrenergic blockade is effective inslowing the rate of aortic dilatation and reducing the developmentof aortic complications in some patients with Marfan's syndrome.
Of the many clinical manifestations of Marfan's syndrome,1 dilatationof the aorta is the most worrisome. Aortic dissection and regurgitation,first described 50 years ago,2,3 continue to account for a shorteningof life expectancy by about one third in untreated patients4,5,6.The occurrence of both dissection and regurgitation is directlyrelated to the relative size of the aortic root,7,8 althoughsome dissections of the ascending aorta occur with minor enlargement9,10.Dilatation is usually confined to the proximal ascending aorta.It may be evident at birth, but may not exceed the upper 95percent confidence limit for values expressed as a functionof age and body size until adulthood11,12,13. Aortic-root dilatationin Marfan's syndrome is progressive. Few longitudinal studieshave been conducted to determine either the rate of change inthe diameter or the risk factors for rapid dilatation, dissection,or regurgitation9.
Replacement of the aortic root with a composite graft has becomethe standard procedure for managing acute dissection of theascending aorta in Marfan's syndrome and most other conditionswith this feature14,15,16. Prophylactic repair when the aortic-rootdiameter reaches 55 mm during adulthood has also become an acceptedapproach, but dissection may occur in the ascending aorta beforethe diameter reaches that critical size, or may involve thedescending aorta16. Accordingly, a medical approach to protectingthe aorta in Marfan's syndrome would be valuable.
In 1971, Halpern et al.17 suggested that -adrenergic blockademight reduce the risk of aortic dissection. Their surmise wasbased on several lines of evidence. First, in patients withmalignant hypertension, reducing blood pressure to normal butnot reducing the rate of change in the central arterial pressurewith respect to time (designated as dP/dt, or the impulse ofleft ventricular ejection) did not prevent aortic dissectionbut apparently increased its risk18. Second, -adrenergic blockadehad been shown to be effective in the medical management ofaortic dissection19 and remains a mainstay today20. Third, turkeysprone to spontaneous aortic rupture had much improved survivalwhen propranolol was added to their feed21,22. Finally, studiesof model systems suggested that reducing dP/dt was much moreprotective than reducing mean blood pressure23. However, anuncontrolled study of a few asymptomatic patients with Marfan'ssyndrome treated briefly with low doses of oral propranololdemonstrated little overt benefit24.
We instituted a randomized trial of -adrenergic blockade inadolescent and adult patients with classic Marfan's syndromeand mild-to-moderate dilatation of the aortic root.
Methods
Recruitment of Patients
All participants had been evaluated in the Medical GeneticsClinic of the Johns Hopkins Hospital within one year beforethe beginning of this study. Only patients who met the strict,internationally established diagnostic criteria for Marfan'ssyndrome were considered25,26. Patients were excluded if theywere less than 12 or more than 50 years old, were receivingongoing treatment with propranolol, or had any of the followingfeatures: aortic dissection; aortic regurgitation on auscultation;moderate or severe mitral regurgitation; previous cardiovascularsurgery; dyspnea during moderate exercise, orthopnea, or peripheraledema; a left ventricular ejection fraction of less than 50percent; atrioventricular conduction delay of any degree; anddisorders in which propranolol is contraindicated (diabetesmellitus or recurrent bronchospasm requiring medical treatment).
Study Design
Of 117 patients considered for the study, 93 were found to beeligible and were asked to participate. Of those excluded, 12had aortic regurgitation, 5 poor left ventricular function,4 bronchospasm, and 3 atrioventricular conduction delay. Elevenof the 23 who declined to participate did so because they livedtoo far from the clinic. Seventy patients gave informed consent.The protocol was approved by the institutional review board.Once consent was obtained, a patient was assigned the next availablenumber from a list derived from a table of random numbers atthe beginning of the study; a patient with an even number receivedno treatment (control group), and a patient with an odd numberreceived propranolol (treatment group). No patient or investigatorwas blinded to the patient's status after assignment to a studygroup.
Patients remained in the study until one of the following endpoints was reached: voluntary withdrawal; death; aortic dissection;development of aortic regurgitation detectable by auscultation;cardiovascular surgery; congestive heart failure, indicatedby new-onset dyspnea, orthopnea, peripheral edema, or fatigabilityassociated with a left ventricular ejection fraction of lessthan 40 percent; or an intractable adverse reaction to propranolol.After 1982, aortic regurgitation detected by auscultation wasconfirmed by Doppler echocardiography, although two patientshad already been withdrawn from the trial because they had reachedthis end point. For conformity, given that one investigatorwas conducting all examinations, we elected to retain diagnosisby auscultation as the criterion.
The patients were evaluated every 6 to 12 months. At each visit,an interval history was obtained and a physical examination,electrocardiography, and echocardiography were performed. Until1982, only M-mode echocardiography was available. Thereafter,cross-sectional examinations were performed; however, in theinterests of conformity, only M-mode tracings of the aorticroot were analyzed13. Echocardiographic data were interpretedby the same investigator throughout the study, who did not knowthe patient's identity, age, or study group. The resting heartrate was measured while the patient stood; then the patientran up and down 44 steps as rapidly as possible, and the heartrate was measured as soon as the exercise was completed andone minute later. Patients in the treatment group were studiedtwo to three hours after their usual dose of propranolol; thedrug concentration was determined in venous blood. These patientsalso underwent phonocardiography during successive visits tomeasure the left ventricular systolic time interval (the ratioof the preejection period to the left ventricular ejection time,both measured in seconds),27 until the optimal dose of propranololwas determined.
The initial dose of propranolol was 10 mg given four times daily;the response of the heart rate to exercise and the systolicinterval were assessed after two to four weeks. The dose wasincreased until the heart rate remained below 100 beats perminute during exercise or the systolic time interval (correctedfor the heart rate) increased by 30 percent.
Statistical Analysis
All comparisons of the two study groups included all patients,according to the intention-to-treat principle. Echocardiogramswere interpreted without knowledge of the identity of the patient,and the series of studies in each patient were interpreted inrandom order. The aortic diameter, determined from M-mode tracingsby the leading-edge method,28 was usually greatest at the levelof the sinuses but occasionally at the sinotubular junction;the maximal diameters were measured in five consecutive cyclesand averaged. Mean values are presented with their standarderrors unless otherwise noted. Group means were compared bythe two-tailed t-test and the Mann-Whitney nonparametric rank-sumtest29.
The Choice of Model for Analysis
The change in the size of the aorta reflects two processes:growth of the body and aortic dilatation due to abnormal characteristicsof the aortic wall30. We dealt with both these variables bydividing the measured aortic diameter by the diameter predictedfrom the patient's height, weight, and age,12 thus obtainingan aortic ratio. Exploratory analysis indicated that the aorticratio tended to change in a linear manner over time. Accordingly,we used the slope of the regression of the aortic ratio on thetime elapsed since randomization as the outcome measure in thisstudy. Because differences between patients were overwhelminglythe most important source of variation, the patients' slopeswere given equal weight in subsequent analyses, even when basedon different numbers of observations. Although adjusting forheterogeneity in the variation in the initial size of the aortaby analysis of covariance made virtually no difference in thecomparison of the means of the regression slopes, we used theadjusted data.
Survival
Kaplan-Meier life-table analysis was performed, with death,congestive heart failure, and aortic regurgitation, aortic dissection,or cardiovascular surgery as the clinical end points31.
Results
Characteristics of the Patients
The two study groups were well matched for mean age (controlgroup vs. treatment group, 14.5 vs. 15.4 years), the proportionof patients less than 18 years old at entry (0.68 vs. 0.60),and sex (chi-square = 0.65). The number of patients in eachgroup (38 controls and 32 propranolol recipients) did not markedlydiffer from the expected total of 35 (z = 0.72). Table 1 showssome of the cardiovascular characteristics of the patients atthe start of the study. The only significant difference betweenthe male and female patients in each study group was a slowerresting heart rate in the male patients in the treatment group(P = 0.019). Patients who were eligible for this study but whochose not to participate did not differ appreciably in any ofthe characteristics from the patients in the control and treatmentgroups combined. The two groups did not differ significantlyin the prevalence of mitral-valve prolapse and mild mitral regurgitation,mean ventricular size, mean left ventricular systolic time interval,mean heart rate at rest or during exercise, and mean restingsystolic or diastolic blood pressure. The groups did differsignificantly in their initial aortic diameter (control groupvs. treatment group, 30.2 vs. 34.6 mm) but not in their meanaortic ratios (1.3 vs. 1.4). The initial aortic ratio was accordinglytreated as a covariable; any bias that resulted from this approachwould tend to underestimate the potential benefit of propranolol.
Table 1. Characteristics of the Patients in the Two Study Groups.
The mean (±SE) dose of propranolol was 212 ±68mg, given in four divided doses a day. The mean serum propranololconcentration after the optimal dose was reached was 135 ±80ng per milliliter (520 ±310 nmol per liter). The pharmacologiceffect of the drug was indicated by the reductions in heartrate and blood pressure in both the male and female patients(Table 1).
Rate of Increase of Aortic Diameter
Figure 1 shows the regression lines for the aortic ratio ineach patient during the study. The trend in the differencesis reflected in the broad sweep of the slopes (rates of change);the length of each line indicates the duration of follow-upin the patient. Two patients given propranolol did not complywith treatment (arrows).
Figure 1. Changes in the Aortic Ratio in the Treatment Group and the Control Group.
The aortic ratio is the ratio of the diameter of the aorta measured in a patient to the diameter expected in a subject with the same body-surface area and age. The ratio in each patient is presented here as a fitted regression line: the data points are not shown, but the length of each line indicates the length of follow-up. One patient in the control group had an exceptional aortic ratio (>3.4) at 100 months. Two patients in the treatment group (arrows) did not comply with propranolol therapy.
The slopes in each study group could be coherently summarizedas empirical (cumulative) distribution functions for the changein the aortic ratio, shown in Figure 2. The groups are clearlyseparated in that their curves do not intersect; indeed, thecurve for the treatment group has scarcely left the base lineat a point at which the curve for the control group has almostreached 100 percent.
Figure 2. Empirical Distribution Functions of the Rate of Change in the Aortic Ratio, According to Study Group.
The height of each curve at any point shows the proportion of patients with values at or below the value given on the x axis. There is little overlap between the two groups.
The mean slope of the aortic ratio plotted against time was0.023 per year in the treatment group and 0.084 per year inthe control group (t = 6.73, P<0.001; z = 6.64 by Mann-Whitneynonparametric rank-sum test, P<0.001).
The influence of the initial aortic diameter on the rate ofchange is shown in Figure 3. There is little if any relationbetween the rate of change and the initial diameter in thisscatter diagram, but the values for the control group clusterin the upper half of the figure and those for the treatmentgroup cluster in the lower half. There is negligible evidencethat any of the effect of treatment was due to a differencein the initial aortic diameter. Furthermore, analysis of covarianceshowed that adjustment for the initial aortic diameter had anegligible effect on the significance of the difference in therates of enlargement.
Figure 3. Rate of Change in the Aortic Ratio as a Function of the Initial Aortic Diameter.
Each larger circle represents two patients whose values were too close together to plot separately. There is little overall trend as the initial aortic diameter increases, but most of the symbols for the control group are clustered above those for the treatment group.
Analysis of Morbidity and Mortality
Five patients assigned to the treatment group reached a clinicalend point (death, congestive heart failure, or aortic regurgitation,aortic dissection, or cardiovascular surgery) (Table 2), buttwo of these five had never taken their propranolol. Nine patientsin the control group reached a clinical end point; the two patientswho died (a 14-year-old boy and an 18-year-old woman) had mitral-valveprolapse and a history of paroxysmal tachyarrhythmia (one hadthe Wolff-Parkinson-White syndrome), and postmorten examinationsshowed no aortic dissection or obvious cause of death. The patientsin both groups who reached an end point had higher average initialaortic ratios than the total study population.
Table 2. Numbers of Patients Who Reached Clinical End Points and Their Initial Aortic Ratios.
The survival of patients who did not reach a clinical end pointis shown in Figure 4. The standard error of the difference wasrecalculated whenever a patient reached an end point and wasremoved from analysis; the dashed lines bounded by asterisksat the top of the figure indicate the periods at which the 90percent confidence limits for the difference between the curvesdid not include zero. Survival was most improved during theintermediate years.
Figure 4. Kaplan-Meier Survival Analysis Based on the Clinical End Points in the Study (Death, Congestive Heart Failure, or Aortic Regurgitation, Aortic Dissection, or Cardiovascular Surgery).
The dashed lines at the top indicate the periods when the 90 percent confidence limits for the difference between the curves did not include zero. The curves diverge the most in the middle years but do not intersect at any point.
Adverse Effects of Long-Term -Adrenergic Blockade
Table 3 shows the number of patients complying with propranololtreatment who reported adverse effects. Because the study wasneither blinded nor placebo-controlled, the patients in thecontrol group were not queried systematically about similarsymptoms; none had atrioventricular conduction delay. Only inthe patient in whom third-degree atrioventricular block developeddid the dose of propranolol have to be reduced, from 80 mg to40 mg per day, at which point a stable first-degree block appeared.The other patients were able to tolerate the adverse effects;many found that the troublesome symptoms disappeared over time.
Table 3. Adverse Effects of Long-Term -Adrenergic Blockade in 30 Patients Complying with Propranolol Therapy.
Discussion
Patients with Marfan's syndrome and mild-to-moderate dilatationof the aortic root received long-term benefit from -adrenergicblockade with propranolol. Two types of benefit were evident.First, the rates of increase in the aortic ratios were lowerin the treated patients as a group and in most of them individuallythan the rates in the untreated patients. Second, fewer patientsin the treatment group reached a predetermined end point forwithdrawal from the study. Two patients in the treatment group(including one who never took propranolol) had acute ascending(type A) aortic dissection, as compared with four in the controlgroup. Neither of the two deaths in the study (both in the controlgroup) was due to dissection. Propranolol is known to be beneficialin controlling some of the rhythm disorders associated withmitral-valve prolapse, a condition that affects 60 percent ormore of patients with Marfan's syndrome.
The doses of the drug were relatively high since a negativeinotropic effect was being sought. However, the adverse effectswere generally well tolerated and necessitated a dose reductionin only one patient, whose aortic root changed little during11 years of therapy.
The initial study of propranolol therapy for Marfan's syndromeincluded a small number of patients who were treated with relativelylow doses (40 to 120 mg per day) and no controls; most of thepatients had considerable aortic-root dilatation and aorticregurgitation at the start of treatment24. There was no monitoringof aortic-root dimensions over time. Several of the patientsrequired aortic surgery for regurgitation or sustained aorticdissection while being treated. Four retrospective surveys,32,33,34,35each studying 10 or more patients treated mostly with atenolol,have been presented in preliminary form. Three studies founda reduced rate of aortic-root dilatation among children andadolescents,32,33,34 whereas one suggested this trend but didnot find a significant reduction35. All four studies used historicalrather than concurrent controls and followed the patients forfour to six years. A retrospective study of 12 children nottreated with -blockade reported that the rate of aortic-rootenlargement (due to both growth and dilatation) in 10 of thepatients was no different from that expected in normal subjects36.
If propranolol benefits the aorta through its negative chronotropicand inotropic actions, then the elastic properties of the aorticwall should improve. However, in two studies of patients undergoingcardiac catheterization, stiffness increased and distensibilitydecreased after short-term intravenous administration of propranolol37,38.At least two explanations are possible. First, to be beneficialpropranolol may have to be given orally, for prolonged periods,or both. Any reduction in elasticity might be more than balancedby a reduction in the dP/dt and heart rate over a period ofyears. Second, like the patients who underwent clinically indicatedcatheterization,37,38 patients with severely dilated aorticroots may have a response to acute -adrenergic blockade distinctlydifferent from the response of patients with normal-caliberor moderately dilated roots. A thin aortic wall, accentuatedfragmentation of the elastic fibers in the media, constrictionto normal caliber just at or above the sinotubular junction,and aortic regurgitation may all help offset the benefit affordedby reducing the dP/dt. A prospective investigation of the effectof long-term oral -adrenergic blockade on the elastic propertiesof the aorta in patients with Marfan's syndrome is needed.
Oral -adrenergic blockade reduces the rate of enlargement ofabdominal aortic aneurysms in humans39. Oral therapy with propranololreduces the rate of aortic rupture in strains of mice and turkeyseither naturally prone to arterial disruption or made susceptiblewith a lathyritic agent21,22,40.
Our study had some limitations. Administering a placebo andblinding patients to their group assignment would have beenimpracticable because the physiologic effects of propranololare distinctive and difficult to mask or to mimic with placebo.Throughout the study, the investigator interpreting the echocardiogramswas kept unaware of the identity of the patients and the sequenceof the multiple tracings.
We had no way of checking, other than by asking the patientsand measuring serum propranolol levels at the time of a clinicvisit, how well they complied with treatment, whether the controlstook medication surreptitiously, or whether the patients modifiedtheir dosage in response to perceived benefits and side effects.Logically, any such tampering with the study design would tendto lead to a misclassifying of subjects and hence would systematicallyobscure differences due to treatment. This would, if anything,reduce the statistical power of the test but would not createfalse differences.
Since this study was started, what was long suspected has beendemonstrated: there is great variation in the molecular basisand natural history of Marfan's syndrome41,42,43. Whether heterogeneityin cause will be reflected as a variation in response to treatmentis unclear, but this would be not at all surprising. The responsesshown in Figure 1 give some hints of heterogeneity, callingfor circumspect interpretation of our results. It is not clearhow much the variation from patient to patient is due to technicalor random error, and how much to true heterogeneity in causeand responsiveness. But the results are stated in broad enoughterms to be robust, and that is possible because the hypothesizedaction of the drug is rather mechanical and nonspecific. Forpractical purposes, we may assume that until proved otherwise,the conclusions apply to kindred but quite distinct disorders,such as several familial conditions involving aortic dilatationand dissection44. This surmise is warranted in part becauseour patients, with all their heterogeneity, were in fact balancedagainst each other by random assignment to the two study groups.
The rationale for the study was the effect of -blockade on arterialhemodynamic function. But that rationale does not guaranteethe logic, and there is nothing in the nature of the study thatdisproves that the observed benefits were not mediated by someentirely different pathway, such as a chemical effect on theextracellular matrix. Propranolol increases cross-linking ofcollagen in animals bred to have a higher rate of aortic rupture,45,46reduces urinary levels of hydroxyproline (a product of collagendegradation) in patients with hyperthyroidism,47 and increasesdeposition of collagen in the lung48. Thus, there are good reasonsto explore factors other than negative inotropy and chronotropyas explanations for the beneficial clinical effects demonstratedin our study.
Although this study did not include young children, the resultsprovide a basis for considering instituting -adrenergic blockadeat an early age. In most patients with Marfan's syndrome, aortic-rootdilatation is present to some degree during the first few yearsof life49 and may be severe at birth50. In a nonrandomized,retrospective study of young children given atenolol, Zahkaand colleagues found evidence of a reduced rate of aortic-rootdilatation33.
When this study began, propranolol, a nonselective -adrenergicblocker, was the only preparation available for clinical use.As the study progressed, other preparations were approved. A1-selective agent with a longer therapeutic half-life and fewerside effects, such as atenolol, has potential advantages overpropranolol. Although no randomized trial of atenolol has beenconducted, many physicians now use it to treat patients withMarfan's syndrome, and there is some evidence that this drugalso protects the aorta32.
Supported by grants (AM-23066, HL-35877, and RR-00722) fromthe National Institutes of Health, by a grant (FD-R-692) fromthe Food and Drug Administration, and by the National MarfanFoundation.
We are indebted to M.H. Abbott, B.A. Bernhardt, J. Hennessey,B.J. Latrobe, L. Snyder, K. Supowitz, and J. Weiner for theirassistance in coordinating patient evaluations and counselingfamilies over the years, and to Professor Victor A. McKusickfor serving as our mentor, supporter, and colleague throughoutthis study.
Source Information
From the Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore.
Address reprint requests to Dr. Pyeritz at the Department of Human Genetics, Allegheny-Singer Research Institute, 320 E. North Ave., Pittsburgh, PA 15212-4772.
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