angiotensin converting enzyme inhibitors ( acei ) have been shown to decrease agv in marfan syndrome ( mfs ) . we sought to compare the effect of -blockers and acei on aortic growth velocity ( agv ) in mfs . we reviewed retrospectively all data from all patients with mfs seen at arkansas children s hospital between january 1 , 1976 and january 1 , 2013 . generalized least squares were used to evaluate agv over time as a function of age , medication group , and the interaction between the two . a mixed model was used to compare agv between medication groups as a function of age , medication group ( none , -blocker , acei ) , and the interaction between the two . a total of 67 patients with confirmed mfs were identified ( 34/67 , 51% female ) . mean age at first encounter was 13  10 years , with mean follow - up of 7.6  5.8 years . there were 839 patient encounters with a median of 10 ( range 242 ) encounters per patient . agv was nearly normal in the -blocker group , and was less than either the acei or untreated groups . the agv was higher than normal in acei and untreated groups ( p<0.001 for both ) . we performed a retrospective review of all patients with mfs seen at arkansas children s hospital between january 1 , 1976 and january 1 , 2013 . patients with mfs were identified using multiple institutional databases including those from the echocardiography and cardiac catheterization laboratories , the cardiology clinic , all cardiothoracic surgeries , and the division of genetics . echocardiograms were performed with the patient in the supine position using commercially available ultrasound machines ( siemens acuson sequoia 512 with 10 , 7 , 5 , and 3 mhz probes and philips ie33 with 12 , 8 , and 5 mhz probes ) . two - dimensional measurements were made in accordance with the recommendations of the american society of echocardiography using parasternal long - axis views of the aortic annulus , aortic sinus of valsalva , sinotubular junction and ascending aorta . measurements were made from inner edge to inner edge during ventricular systole . the decision to initiate pharmacologic therapy was primarily based on the presence of aortic measurements above the normal range reported by roman et al or accelerated progressive dilation . the selection of a pharmacologic agent and the dose were provider dependent ; there were no formal algorithms . after the report from our institution by yetman et al , the use of acei as primary therapy at our institution increased . anthropometric data were used to calculate the body surface area ( bsa ) at each patient encounter using the dubois formula . a normative control comparison dataset for aortic dimension and growth rate was created by using the calculated bsa of each patient with mfs at each encounter using the formula : aortic root dimension = 24.0(bsa in m ) + 0.1(age )  4.3 . this normative control dataset was then compared against actual measured aortic dimensions in the patient cohort . summary statistics were expressed as frequency and percentage for categorical variables , and as mean  standard deviation for continuous variables , except for the ages of the treatment groups , which are expressed as mean with first ( q1 ) and third ( q3 ) quartiles . to compare aortic growth velocities between medication groups , a mixed model was developed for the aortic dimension as a function of age , medication group ( none , -blocker , acei , or normative control ) , and the interaction between the two . a restricted cubic spline was used for age when fitting the mixed model with regard to the non - linear relationship between aortic dimension and age . a compound symmetry variance matrix was used to take into account the correlated measurements from the same patient . additional mixed models were fitted for blood pressures and heart rates to assess their differences among three medication groups ( none , -blocker , or acei ) . all the data were analyzed using statistical software sas 9.4 ( sas institute inc . , summary statistics were expressed as frequency and percentage for categorical variables , and as mean  standard deviation for continuous variables , except for the ages of the treatment groups , which are expressed as mean with first ( q1 ) and third ( q3 ) quartiles . to compare aortic growth velocities between medication groups , a mixed model was developed for the aortic dimension as a function of age , medication group ( none , -blocker , acei , or normative control ) , and the interaction between the two . a restricted cubic spline was used for age when fitting the mixed model with regard to the non - linear relationship between aortic dimension and age . a compound symmetry variance matrix was used to take into account the correlated measurements from the same patient . additional mixed models were fitted for blood pressures and heart rates to assess their differences among three medication groups ( none , -blocker , or acei ) . all the data were analyzed using statistical software sas 9.4 ( sas institute inc . , a total of 67 patients with confirmed mfs were identified ( 34/67 , 51% female ) . the mean  sd age at first encounter was 13  10 years , with a mean followup length of 7.6  5.8 years . there were 839 patient encounters with a median number of 10 ( range 242 ) encounters per patient . for the patients in the untreated group , the mean age was 9.8 years ( q1 : 3.9 years ; q3 : 17.2 years ) , which was lower than either the -blocker or acei groups ( p<0.001 ) . for those treated with -blocker therapy , the mean age was 16.9 years ( q1 : 12.1 years ; q3 : 22.2 years ) . -blockers used included daily atenolol ( 45.9% ) , twice daily metoprolol ( 48.5% ) , and thrice daily propranolol ( 5.6% ) . the mean dose per patient was 0.95  0.63 mg / kg ( total daily dose 47.3  23.5 mg ) . the mean systolic ( 109  16 mmhg ) and diastolic ( 67  8 mmhg ) blood pressures were not different from patients who were not treated with medication . the mean heart rate in the -blocker group ( 78  19 bpm ) was significantly lower compared with those who were untreated ( 90  24 bpm , p=0.001 ) . for those treated with acei therapy , the mean age was 16.8 years ( q1 : 10.7 years ; q3 : 24.4 years ) . aceis used included daily lisinopril ( 12.9% ) , twice daily enalapril ( 85.5% ) , and thrice daily captopril ( 1.6% ) . the mean acei dose per patient was 0.22  0.1 mg / kg ( total daily dose 12.7  6.9 mg ) . the mean systolic ( 113  16 vs. 106  20 mmhg , p=0.005 ) and diastolic ( 68  10 vs. 64  10 mmhg , p=0.005 ) blood pressures were significantly higher in the acei group compared with the untreated group . the mean heart rate in the acei group ( 83  17 bpm ) was significantly lower compared with the untreated group ( 90  24 bpm , p=0.003 ) . the systolic and diastolic blood pressures were higher in the acei group compared with the -blocker group ( p=0.015 and p=0.019 , respectively ) , and there was no difference in heart rate ( p=0.696 ) . the aortic size and agv for the three largest groups ( none , acei , and -blocker ) were determined ( figure 1 ) and intergroup comparisons were made , as well as comparisons with the calculated , expected normative control aortic root dimensions ( figure 2 ) . the aortic dimensions were significantly larger in all groups compared with the normative control dataset ( p<0.001 ) . at younger ages , the aortic dimensions in the -blocker group were significantly larger than the acei and untreated groups ( p<0.01 ; figure 1 ) . there was no difference between the acei and untreated groups with regard to aortic dimensions at younger ages ( p=0.636 ) . aortic growth velocity was significantly attenuated in the -blocker , and nearly approximated that in the normative control dataset . the attenuation of the agv in the acei group was less than that of the -blocker group compared with those not treated with medication . the median age at aortic root replacement was 17 years ( range 935 years ) . two patients experienced aortic dissections : one treated with metoprolol experienced acute dissection of the entire thoracic aorta and survived to surgery ; the other was treated with enalapril and found to have an asymptomatic dissection of the aortic root . of the 11 patients who underwent aortic surgery , pharmacologic treatment prior to surgery included : acei in 5 ; -blocker in 4 ; and no therapy in 2 . the present study demonstrates a significant attenuation of the agv in pediatric patients with mfs treated with -blocker therapy . in fact , the growth velocity was almost identical to the predicted normal growth velocity for the cohort . on average , the patients in the -blocker group began with a larger aortic dimension compared with the patients in the acei and untreated groups , and this difference resolved over time , a finding that may suggest that the early initiation of -blocker therapy should be considered in patients with mfs . this is a significant finding because aortic wall tension increases as the aortic diameter increases , which results in acceleration of aortic dilation at larger diameters . the expected result would then be that the agv should be faster in the -blocker group ; however , the opposite was found in the -blocker group indicating a definite mitigating effect on the agv in patients with mfs . recently , mueller et al demonstrated a decrease in agv in patients with mfs who were treated with either -blockers or angiotensin ii receptor blockers . however , other studies have suggested that -blocker therapy does not alter the agv or clinical outcomes in patients with mfs . gersony et al conducted a meta - analysis of six studies available at the time , and concluded that -blocker therapy was ineffective in patients with mfs . in the original studies used to conduct their meta - analysis , most of the original authors arrived at different conclusions than gersony et al . silverman et al showed that death was twice as common in the untreated versus the -blocker treated group . legget et al reported that aortic complications were more common in the -blocker treatment group ; however , the aortic complication group also had significantly larger aortas at the initiation of the study ( p<0.0001 ) . further , in that study patients were dichotomized , without clear delineation as to why , to those who had -blocker therapy for 1 year versus those who had therapy for < 1 year . similar to the work of silverman et al , roman et al reported that in 113 patients with mfs those who had aortic complications had larger aortic size at presentation ( p<0.005 ) , were significantly older ( p<0.01 ) , and had significantly faster agv ( p<0.05 ) ; however , -blocker therapy use only trended toward being more common in the complication group ( 86% vs 66% , p = non - significant ) . those authors stated that the trend toward increased -blocker use in the group with complications was because they started out with larger aortas , which represents a significant selection bias . salim et al reported that the aorta is dilated at young ages in mfs and showed that the agv was faster in those who were untreated . in that study , the 5 patients treated with -blocker therapy who underwent surgical intervention had larger aortas at the time of enrollment . in their randomized trial of propranolol therapy in mfs , shores et al reported in the propranolol group a decreased rate of aortic dilation , fewer deaths , and significantly fewer patients who reached one or more predetermined clinical end - points . finally , tahernia reported three patients who were treated with -blocker therapy and three who were not . with a mean follow - up of 3.3 years the three untreated patients had a mean follow - up of 3 years with a mean agv of 1.4 mm / year . in the consideration of studies evaluating agv , it is imperative to consider the size of the aorta at the time of the initiation of pharmacotherapy . in accordance with the law of laplace , when wall thickness and blood pressure are stable , wall tension in the aorta increases as the aortic diameter increases , resulting in acceleration of aortic dilation at larger diameters . to make a truly meaningful comparison between therapeutic groups , either both groups have to begin with the same diameters or the group that is shown to have a decreased growth rate must have begun at a larger diameter , thus showing a diminution of agv . if the aorta is larger in one group than the other , those patients are beginning the study at a different point in the aortic disease process than the group with the smaller diameter . the present study is not subject to this concern because those patients treated with -blocker therapy began , on average , with a larger aortic diameter than either the acei group or the untreated group and were still demonstrated to have a lower agv . the difference in results between the -blocker and acei groups in the present study seem to support the hypothesis that a decrease in myocardial contractility is the explanation for decreased agv in patients with mfs treated with -blockers . in the present study , there were no clinically significant differences in blood pressure or heart rate between the -blocker and acei groups ; however , the agv in the -blocker group was significantly less than either the acei or untreated groups . however , other explanations can not be ruled out , such as heretofore - unknown pleiotropic effects of -blockers . yetman et al demonstrated that there was a decrease in the agv and improvement in the aortic distensibility in patients with mfs treated with acei versus those treated with -blocker . the present study does not corroborate those findings . in the study by yetman et al , the subject ages and the doses of both medications were similar to those in the present study . the length of follow - up was shorter in that prior study ( 3.0  0.2 years ) compared with the present study ( 7.6  5.8 years ) . however , a previously published and validated formula for the determination of predicted aortic size was used in combination with the anthropometric data from the present study cohort to create a predicted  normal  aortic growth curve , which allowed for comparison of the study measurements against a unique dataset specific to the study cohort . the patients in the non - treatment group were younger than those in either the -blocker or acei group . an older population would be expected to have an increased agv , which if anything would blunt any effect of the medication on slowing agv . . early introduction of -blocker therapy in patients with mfs should be considered particularly even prior to the demonstration of aortic dilation .
objectivesangiotensin converting enzyme inhibitors ( acei ) have been shown to decrease agv in marfan syndrome ( mfs ) . 
 we sought to compare the effect of -blockers and acei on aortic growth velocity ( agv ) in mfs.study designwe reviewed retrospectively all data from all patients with mfs seen at arkansas children s hospital between january 1 , 1976 and january 1 , 2013 . 
 generalized least squares were used to evaluate agv over time as a function of age , medication group , and the interaction between the two . 
 a mixed model was used to compare agv between medication groups as a function of age , medication group ( none , -blocker , acei ) , and the interaction between the two.resultsa total of 67 patients with confirmed mfs were identified ( 34/67 , 51% female ) . 
 mean age at first encounter was 13  10 years , with mean follow - up of 7.6  5.8 years . 
 there were 839 patient encounters with a median of 10 ( range 242 ) encounters per patient . 
 agv was nearly normal in the -blocker group , and was less than either the acei or untreated groups . 
 the agv was higher than normal in acei and untreated groups ( p<0.001 for both).conclusions-blocker therapy results in near - normalization of agv in mfs . 
 acei did not decrease agv in a clinically significant manner .