Aortic stiffness and diameter predict progressive aortic dilatation in patients with Marfan syndrome

Gijs J. Nollena, Maarten Groeninka, Jan G.P. Tijssena, Ernst E. van der Wallb and Barbara J.M. Muldera,*

a Department of Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
b Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

* Corresponding author. Tel.: +31-20-5-662-193; fax: +31-205-666-809
E-mail address: b.j.mulder{at}amc.uva.nl

Received 2 January 2004; revised 20 April 2004; accepted 29 April 2004

Abstract

Aim Patients with Marfan syndrome may develop dissection due to progressive dilatation in the entire aorta, which is not always predictable by mere anatomic assessment of the aortic diameter, especially of the descending aorta. The aim of this study was to identify the predictive value of aortic stiffness on the occurrence of dissection and progressive aortic dilatation.

Methods and results In 78 non-operated patients with Marfan syndrome (mean age 31±8 years, mean aortic root diameter 43±6 mm, range 31–55 mm) aortic stiffness and diameters were assessed by magnetic resonance imaging (MRI) at multiple levels. After a median follow-up of 71 months (25–75%: 68–72 months) a second MRI was performed and the incidence of aortic dissection and progressive aortic dilatation, defined as mean aortic diameter increase 1 mm/year was determined.

During follow-up, 4 (5%) of 78 patients developed an aortic dissection (1 type A, 2 type B, and 1 infra-renal dissection). Twenty (26%) of the 78 patients had progressive aortic root dilatation. There were 5 (6%) patients with progressive descending thoracic aortic dilatation and 6 (7%) with progressive abdominal aortic dilatation. Multivariate logistic regression analysis revealed that local distensibility was an independent predictor of progressive thoracic descending aortic dilatation (OR=4.14, 95% CI, 1.02–16.7). For progressive aortic root and abdominal aortic dilatation local initial diameter appeared to be the major predictor (OR=1.37, 95% CI, 1.16–1.62; OR=1.36, 95% CI, 1.09–1.69, respectively).

Conclusion In patients with Marfan syndrome both aortic diameter and aortic distensibility are independent predictors of progressive aortic dilatation. For optimal risk assessment and monitoring of patients with Marfan syndrome, both aortic stiffness and diameter should be assessed at least annually.

Key Words: Aorta • Elasticity • Magnetic resonance imaging • Aneurysm

Introduction

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the gene encoding the microfibrillar protein fibrillin-1 with an estimated incidence of 1/5000, and probably over 25% sporadic mutations.1,2 The syndrome involves many systems but the prominent manifestations are of skeletal, ocular and cardiovascular origin.3 The leading cause of premature death in patients with Marfan syndrome is aortic dissection due to progressive dilatation of the aortic root.4 It has been recommended to replace the aortic root with a composite-graft conduit before the diameter exceeds 5.0–5.5 cm.5–7 In approximately 15% of patients with Marfan syndrome, initial operation concerns the descending aorta.8 Moreover, it has been shown that after aortic root replacement, aortic operation in the descending aorta is required in 50% of patients over a mean period of 26 years.8 There are no clear guidelines for intervention of descending aortic complications in patients with Marfan syndrome.9 The risk of aortic dissection rises with increasing aortic diameter, but it may also occur in non-dilated aortas.6,10,11 For this reason aortic stiffness as a potential predictor of aortic dissection and aortic dilatation has been investigated in patients with Marfan syndrome.12 Aortic stiffness can be calculated at a regional level by distensibility or over a larger aortic segment by flow wave velocity. Several studies have demonstrated increased aortic stiffness assessed by echocardiography and MRI in patients with Marfan syndrome.12–15 However, the predictive value of aortic stiffness on progressive aortic dilatation has not yet been investigated. If increased aortic stiffness precedes progressive aortic dilatation, stiffness measurement could be a useful tool for the identification of patients at risk. The aim of the present study was to identify the predictive value of aortic stiffness on aortic dissection or progressive aortic dilatation in patients with Marfan syndrome.

Methods

Patients
From September 1996 to May 1997, 78 consecutive adult patients with Marfan syndrome (age range 18–50 years) were included in the Academic Medical Center and the Leiden University Medical Center. Patients were eligible for inclusion when (1) diagnosis of Marfan syndrome had been established according to the Ghent criteria16, (2) no substantial aortic regurgitation was present, and (3) no history of aortic dissection, aortic surgery, or aortic aneurysm distal to the aortic root was present. In all patients baseline measurement of aortic stiffness and aortic diameters by cardiac magnetic resonance imaging (MRI) was assessed. From September 2002 to January 2003, 70 (90%) of the initial 78 patients with Marfan syndrome underwent a successful follow-up MRI in the Academic Medical Center. In two patients triggering problems occurred during image acquisition, 4 patients refused further MRI, and 2 patients had become claustrophobic. The median duration of follow-up was 71 months (25–75%: 68–72 months). In the beginning of 2000, additional midterm MRI analysis of aortic diameter and stiffness was performed in 19 patients to determine early changes in aortic stiffness and the consistency of the measurements. The primary outcome event of this study was progressive aortic dilatation defined as a mean aortic diameter increase of over 1 mm/year. This is a substantial increase since The Framingham Heart Study revealed 0.8 (men) and 0.9 mm (women) increases in aortic root dimensions for each advancing decade of age17 and Sonesson et al.,18 reported an increase of abdominal aortic diameter of 24% between 25 and 70 years (i.e., from 20 to 25 mm). Aortic diameters were measured at least annually by means of MRI or echocardiography. The increase in aortic diameter was studied between baseline and last MRI before surgery, dissection or end of follow-up, whichever came first. The primary outcome was related to its location in the aortic root/ascending aorta, and descending thoracic aorta, and abdominal aorta. Each subject provided informed written consent to participate in the study, which was approved by our institutional review board.

Magnetic resonance imaging
MRI was performed with a 1.5 Tesla MR system (either Philips ACS-NT15, Philips Medical Systems, Best, the Netherlands, or Magnetom Vision, Siemens Medical Systems, Erlangen, Germany) using similar pulse sequences. Image acquisition was triggered on the electrocardiogram. Axial localiser images were used to identify the position of the ascending and descending aorta. Oblique sagittal spin echo images were then acquired to visualise the entire aorta in the long axis. Next, a high resolution gradient echo pulse sequence with a velocity encoding gradient was applied perpendicular to the aorta at 4 levels as indicated in Fig. 1. The first level was the ascending, the second was the descending thoracic aorta at the level of the bifurcation of the pulmonary artery, the third was the descending aorta at the level of the diaphragm, and the fourth was the abdominal aorta just above the aortic bifurcation. Maximal velocity encoding was chosen at 150 cm/s and was increased to a maximum of 250 cm/s when aliasing occurred. This resulted in multi-phase image pairs of modulus and velocity encoded images with a temporal resolution of approximately 25 ms through the cardiac cycle and a spatial resolution of approximately 1 pixel/mm. Distances between the levels were measured on the console of the MR system by drawing a line through the middle of the aortic lumen on the oblique sagittal images. During each flow measurement, the brachial artery systolic and diastolic blood pressures were measured three times by means of a sphygmomanometer cuff and the average of the measurements was used for calculations.



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Fig. 1 Contrast-enhanced MR image showing the aorta in the long axis of a patient with Marfan syndrome. Levels perpendicular to the aorta applied for gradient echo MR imaging with velocity encoding. Distensibility and diastolic diameter were assessed at these 4 levels. Flow wave velocity between these levels was calculated.

 
Image analysis
A SUN Ultra Sparc workstation (Sun Microsystems, Mountain View, CA) and the FLOW image analysis software (Medis, Leiden, The Netherlands) were used for image analysis. Aortic contours were drawn manually on the modulus images of all cardiac phases and flow (ml/s) through each aortic level was calculated using the areas on the modulus images and the velocity values of the corresponding velocity encoded images.

Flow wave velocity
Flow wave velocity (m/s) was calculated as the ratio of the distance between 2 levels and the time difference between arrival of the flow wave at these levels. The flow wave was considered to arrive at a certain level when the flow reached half of its maximum value. Consequently, flow wave velocity was determined in three segments of the aorta: ascending and arch (level 1 to level 2), descending thoracic aorta (level 2 to level 3) and abdominal aorta (level 3 to level 4) (Fig. 1).

Aortic distensibility
Aortic distensibility at the 4 levels was calculated according to the following formula:

where =distensibility (mmHg–1), =maximal (systolic) aortic area (mm2), =minimal (diastolic) aortic area (mm2), pulse pressure=systolic blood pressure–diastolic blood pressure (mmHg).

Statistical analysis
Time intervals are expressed in medians and interquartile ranges (P25–P75). Univariate analysis for categorical variables was performed using the test or the Fisher exact test where appropriate. Continuous variables were expressed as mean±SD. To account for the inflation of Type I error, we used the false discovery rate introduced by Benjami and Hochberg19 for multiple comparisons. To assess and satisfy linearity, all continuous variables were divided into quartiles (20,19,19,20) reaching from low to high. All quartiles were entered in the multivariate logistic regression, and increasing odds ratios from first to last quartile were ascertained. All variables associated with progressive aortic dilatation in the univariate analysis with a significance level 0.20 were included in a multivariate logistic regression model. With a sample size of 78 patients we had 59% power to detect progressive aortic dilatation in 14% of patients with decreased local distensibility and 6% in patients without decreased local distensibility (odds ratio of 2.5) with 5% significance. Stepwise multivariate logistic regression analysis was used to identify independent predictors of the primary outcome. The criterion for entry of variables was set at 0.05 and removal at 0.10. The relative risks were expressed as odds ratios with corresponding 95% confidence intervals (CI). Differences in variables within the group were compared with the paired t test. All tests were two-tailed and a -value of 0.05 was considered statistically significant. The SPSS statistical package (SPSS 10.01, SPSS Inc., Chicago, IL) was used for analysis.

Results

Patient characteristics
The characteristics of the cohort at the time of inclusion are shown in Table 1.


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Table 1 Baseline characteristics

 
Clinical outcome
During the 71-month follow-up (25–75%: 68–72 months), 20 (26%) of the 78 patients had progressive aortic root dilatation 1 mm/year. Seventeen patients (22%) underwent prophylactic aortic root replacement, and one patient developed a type A dissection at an aortic root diameter of 44 mm and had to undergo emergency repair (Table 2). Time between the beginning of the study and time of surgery in the patients who underwent aortic root replacement was 36 months (25–75%: 23–46 months). No deaths were recorded.


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Table 2 Progressive aortic dilatation in 78 patients with Marfan syndrome

 
There were 5 (6%) of the 78 patients with progressive descending thoracic aortic dilatation, of whom 1 patient (1%) underwent prophylactic intervention. Two patients (3%) developed a type B dissection from the subclavian artery to the aortic bifurcation, and subsequently required repair surgery (Table 2).

Progressive abdominal aortic dilatation was seen in 6 other patients (7%) of whom 1 patient (1%) underwent prophylactic intervention and 1 patient (1%) had surgery for a dissection of the infra-renal abdominal aorta (Table 2).

Progressive aortic dilatation was present in both aortic root and descending aorta in 6 (8%) patients; in 3 (4%) patients progressive aortic root dilatation preceded progressive abdominal aortic dilatation, in 2 (3%) patients progressive descending thoracic aortic dilatation. In 1 (1%) patient progressive aortic root dilatation was demonstrated after progressive descending thoracic aortic dilatation.

The relatively small number of patients with a dissection in the various segments of the aorta precluded any relevant statistical analysis.

Predictors of progressive aortic dilatation
We investigated the possible influences of gender, family history, ß-blocker use, age, pulse pressure, local diameter and distensibility, and segmental wave flow velocity for all three aortic segments by univariate and multivariate analyses.

Univariate analysis showed that younger age (), increased aortic root diameter (), and decreased ascending aortic distensibility (), all measured at baseline, were predictive of progressive aortic root dilatation (Table 3). The descending thoracic distensibility was predictive of progressive descending thoracic dilatation () (Table 3). A univariate predictor of progressive abdominal aortic dilatation was the abdominal aortic diameter (). There was also a trend towards a predictive value of decreased abdominal aortic distensibility () (Table 3).


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Table 3 Univariate analysis: predictors of progressive aortic dilatation

 
Multivariate analysis identified the aortic root diameter as the strongest predictor of progressive aortic root dilatation, followed by younger age (Table 4). Progressive aortic root dilatation was not seen in patients older than 40 years of age.


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Table 4 Multivariate analysis: predictors of progressive aortic dilatation

 
Decreased distensibility of the descending thoracic aorta had independent predictive value for progressive descending thoracic aortic dilatation. A reduction of one 10–3 mmHg–1 in distensibility was associated with a 4-fold increase in risk, independent of aortic diameter (Table 4). None of the patients with a descending thoracic distensibility > mmHg–1 had progressive descending thoracic aortic dilatation. If distensibility of mmHg–1 was used as a cut-off value, sensitivity was 100% and specificity 56%.

Increased abdominal aortic diameter had an independent predictive value of progressive abdominal aortic dilatation. (Table 4) An increase in diameter of 1 mm of the abdominal aorta at baseline was associated with a 36% increase in risk for progressive aortic dilatation. Flow wave velocity was not associated with progressive aortic dilatation. No correlation was observed between aortic stiffness and the time between onset of the study and prophylactic aortic root replacement.

Changes in aortic stiffness at follow-up
Aortic stiffness was assessed at 71-month follow-up MRI in 48 (91%) of 53 patients without, and 22 (88%) of 25 patients with, progressive aortic dilatation. Aortic stiffness of 48 patients without progressive aortic dilatation was compared with aortic stiffness at baseline. Table 5 shows changes in aortic diameters and aortic stiffness over time. A larger aortic root diameter and decreased distensibility of the ascending aorta were shown ( and , respectively). Flow wave velocity did not change significantly during follow-up.


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Table 5 Comparison of variables between first and second MR imaging in the 48 patients without progressive aortic dilatation

 
In 22 patients with progressive aortic dilatation, only a significantly decreased ascending aortic distensibility was observed at follow-up (from to mmHg–1, ). This observation can be explained by the replacement of the native ascending aorta by a stiff tube graft in 18 (81%) of 22 patients.

Reproducibility of measurements
Measurement of aortic diameters, distensibility, and flow wave velocity has been proven to be reproducible, as described extensively in a previous report.12

Additional mid-term analysis after 37 months (25–75%: 35–38 months) in 19 patients demonstrated consistency with the initial and final measurements. Five (26%) of the 19 patients studied at mid-term had progressive aortic dilatation; 4 patients of the aortic root, and 1 patients of the abdominal aorta. Compared to the initial measurements only distensibility of the ascending aorta (level 1) was significantly decreased ( mmHg–1 versus 2.7±0.9 10–3 mmHg–1 at baseline, ), similar to the results of the final follow-up MRI.

Discussion

Our study demonstrated that in patients with Marfan syndrome, descending thoracic aortic distensibility was the strongest predictor of progressive descending thoracic aortic dilatation. Aortic diameter was the strongest independent predictor of progressive dilatation in the aortic root and abdominal aorta. To our knowledge, this is the first study that evaluated aortic stiffness in patients with Marfan syndrome over a long follow-up period.

Aortic dissection type A and aortic rupture due to progressive aortic root dilatation are the leading causes of premature death in patients with Marfan syndrome.4,20 However, aortic aneurysms and dissection may also occur in the descending aorta both before and after aortic root replacement. In a study by Finkbohner et al., 31 (16%) of 191 patients with Marfan syndrome had initial aortic operations in the descending aorta due to dissection or aneurysm.8 Of the 161 patients who underwent primary aortic root replacement, 81 (50%) subsequently underwent descending aortic surgery. In contrast to the aortic root, there are no guidelines for maximum aortic diameters at which prophylactic descending aortic surgery should be performed in patients with Marfan syndrome.9 Aortic dissection and progressive aortic growth in the descending aorta are not always predictable by means of aortic diameters.21 The present study demonstrates that decreased descending thoracic aortic distensibility is an independent predictor of progressive descending thoracic aortic dilatation. No progressive aortic dilatation occurred in patients with a distensibility > mmHg–1, which is the lower limit of normal ( mmHg–1).12 We recommend annual assessment of aortic diameters and distensibility, and more frequent monitoring if there is an increase in aortic diameter or decrease in aortic distensibility.

In contrast to regional distensibility, segmental flow wave velocity did not predict descending thoracic aortic growth. This may be explained by the fact that distensibility represents purely regional aortic function, while flow wave velocity represents average stiffness over much longer aortic segments. In patients with Marfan syndrome, elastin fragmentation in the aortic media is scattered in an irregular pattern along the aorta.22 As a result, distensibility may relate to more affected or less affected segments of the aorta. Although several authors reported an inverse relation between distensibility and flow wave velocity13,14, Savolainen et al.,23 also observed a discrepancy between flow wave velocity and distensibility, similar to our findings. Furthermore, we recently showed that in patients with aortic root replacement distensibility of the graft was significantly lower than distensibility of the native aorta, while flow wave velocity showed no differences.24 Therefore, regional distensibility may be more sensitive in detecting regional variations in aortic stiffness, compared to flow wave velocity, over a longer aortic segment.

For the aortic root, we demonstrated that the diameter of the aortic root is the strongest predictor of aortic root growth. Distensibility of the ascending and abdominal aorta appeared not to be independent predictors of progressive aortic dilatation. However, univariate analysis showed P-values of 0.047 and 0.05 for local distensibility of progressive aortic dilatation in the root and abdominal aorta, respectively. Even so, In our study population, one type A dissection occurred in a 27-year old female patient with a mildly dilated aortic root diameter of 44 mm and a decreased ascending aortic distensibility of mmHg–1. This patient had a positive family history of aortic dissection, which was not an independent risk factor in our analysis, in contrast to a study by Silverman et al.25 This implies that, in patients with Marfan syndrome, several parameters should be determined for optimal risk assessment.

Younger age appeared to be an independent predictor of progressive aortic root dilatation, which occurred before the age of 40 years in each case in our adult population. This is consistent with previous studies where aortic root dissection and growth are usually reported to occur between 20 and 40 years.6,8,26

In patients without progressive aortic dilatation within 6 years of follow-up, a significant decrease in aortic distensibility was only found in the ascending aorta. This probably reflects the ratio of elastic fibre to collagen, which varies from 3.1:1 in the proximal ascending aorta, to 2.8:1 in the mid-thoracic region to 0.8:1 in the abdominal region.27 Thus, the progressive fragmentation of elastin that occurs throughout life may have a greater effect on the ascending aorta.

Limitations of the study
We used a non-invasive brachial cuff pressure measurement instead of a direct assessment of the aortic pulse pressure by a catheter. It has been shown that pulse pressure measured at the brachial artery over-estimates central pulse pressure 28. However, others have shown an excellent correlation (, ) of the calculated aortic distensibility using both invasive and non-invasive methods.29 A potential limitation is the small number of aortic dissections (only in 4 patients), which is caused by the successful implementation of the guidelines for prophylactic aortic root surgery (based on aortic root diameters) and treatment with ß-adrenergic blockade.11,30

Conclusion

In patients with Marfan syndrome, both aortic diameter and aortic distensibility are independent predictors of progressive aortic dilatation. For optimal risk assessment and monitoring of patients with Marfan syndrome, both aortic stiffness and diameters should be assessed at least annually.

Acknowledgments

This work was supported by a grant from the Netherlands Heart Foundation.

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