Scholarly article on topic 'Association between leaflet fusion pattern and thoracic aorta morphology in patients with bicuspid aortic valve'

Association between leaflet fusion pattern and thoracic aorta morphology in patients with bicuspid aortic valve Academic research paper on "Clinical medicine"

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Academic research paper on topic "Association between leaflet fusion pattern and thoracic aorta morphology in patients with bicuspid aortic valve"

JOURNAL OF MAGNETIC RESONANCE IMAGING 40:294-300 (2014)

Original Research _

Association Between Leaflet Fusion Pattern and Thoracic Aorta Morphology in Patients With Bicuspid Aortic Valve

Bryce A. Merritt, BA,1* Alexander Turin, BS,1 Michael Markl, PhD,1,2

S. Chris Malaisrie, MD,3,4 Patrick M. McCarthy, MD,3,4 and James C. Carr, MD1,4,5

Purpose: To determine if patients with certain bicus- Key Words: BAV; CMR; thoracic aorta

pid aortic valve (BAV) phenotypes are predisposed to j. Magn. Reson. Imaging 2014;40:294-300. particular morphological abnormalities of the thoracic @ 2013 Wiley PeriodicalS Inc aorta.

Materials and Methods: One hundred ninety-two patients with BAV who underwent magnetic resonance angiography between January 2007 and July 2010 were retrospectively identified. Aortic morphology was examined through measurements of aortic size index at nine levels along the thoracic aorta, three-dimensional volume of the ascending aorta, vessel asymmetry, and assessment of aortic root morphology.

Results: We found 140 patients (73%) with right and left coronary cusps (R-L) fusion, 46 patients (24%) with R-N fusion, and 6 patients (3%) with left and noncoronary cusps (L-N) fusion. Mean aortic volume in the proximal ascending aorta was significantly greater in R-L patients (0.93 versus 0.60 cm3/m2; P < 0.01). R-N patients possessed greater aortic size index at the distal ascending aorta and proximal aortic arch, and were also significantly more likely to have Type 2 patterns of aortic dilatation.

Conclusion: Our results suggest that BAV with R-L fusion is associated with increased dimensions of the aortic root, while BAV with R-N fusion is associated with increased dimensions of the distal ascending aorta and proximal arch. Our findings illustrate the morphological heterogeneity that exists among BAV phenotypes.

1Northwestern University, Feinberg School of Medicine, Department of Radiology, Chicago, Illinois, USA.

2Department of Biomedical Engineering, Northwestern University, Chicago, Illinois, USA.

3Northwestern University, Feinberg School of Medicine, Division of Cardiac Surgery, Chicago, Illinois, USA.

4Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, Chicago, Illinois, USA.

5Northwestern University, Feinberg School of Medicine, Department of Medicine, Chicago, Illinois, USA.

»Address reprint requests to: B.A.M., 420 E. Ohio Street, #23D, Chicago, IL 60611. E-mail: bryce-merritt@fsm.northwestern.edu Received March 7, 2013; Accepted August 5, 2013. DOI 10.1002/jmri.24376

View this article online at wileyonlinelibrary.com.

BICUSPID AORTIC VALVE (BAV) is the most common congenital heart defect, affecting 0.5-2.0% of the general population (1). This condition may be responsible for more deaths and morbidity than the combined effects of all other congenital heart defects, and is the most common underlying cause for aortic valve replacement in the United States (2,3). While the influence of BAV on valvular disorders such as aortic regurgitation and aortic stenosis has been extensively documented (2,4,5), this condition is increasingly recognized as a disease of the entire aortic root, ascending aorta, and the aortic arch (6).

BAV is associated with a high risk of aortic dilation (7-11), and patients with BAV have larger diameters and a higher prevalence of aortic root and ascending thoracic aortic dilation than those with tricuspid aortic valve (12). It is widely known that with increasing size of an ascending aortic aneurysm, the risk of aortic dissection and aneurysm rupture increases (1). Furthermore, autopsy reports of patients with aortic dissection demonstrate BAV in 7-9% of cases and BAV has been shown to occur in as many as 28% of aortic dissection cases in patients <40 years of age (1). Aortic dilatation in the presence of BAV may be an indication for earlier surgical intervention compared with thoracic aortic aneurysm with a normal tri-leaflet valve (13).

BAV can be subdivided into a set of rather unique morphological phenotypes (14,15). Phenotypes are most often classified based on the pattern of cusp fusion, involving either the right and left coronary cusps (R-L), the right and noncoronary cusps (R-N), and the left and noncoronary cusps (L-N) (3). Recently, cardiac MR (CMR) has been shown to be successful in classifying BAV phenotypes (6). While echocardiographic examinations have been used in previous studies to assess the dimensions of the thoracic aorta (3,7,9,13,16-18), CMR has been

© 2013 Wiley Periodicals, Inc.

Table 1

Summary of Image Analysis Methods

Measure Description

Aortic Diameter - Measured at 9 levels along the thoracic aorta, from aortic annulus to

the distal descending aorta (Figure 1)

- Two perpendicular measurements taken at each level to obtain value

for vessel eccentricity

Ascending Aortic Volume - Ascending aorta was divided into four elliptical cone frustums (Figure 2)

- Provides volume estimation for four segments of ascending aorta

Aortic Morphology - Four aortic morphology phenotypes were defined as follows (Figure 3):

Type 0: Normal aorta

Type 1: Dilated aortic root

Type 2: Aortic enlargement involving the tubular portion of the

ascending aorta

Type 3: Diffuse involvement of both the entire ascending aorta and

the transverse aortic arch

Summary of image analysis methods used to assess thoracic aorta morphology.

recommended as the preferred method for the evaluation of aortic dilation in BAV, and has been shown to be superior to two-dimensional (2D) echocardiography in determining the presence of BAV (6,19-21).

Given that BAV can manifest as one of multiple unique phenotypes, it may be relevant to determine if specific cusp fusion patterns have a causative relationship to different types of aortic dilatation. For example, aortic root aneurysms may have a greater association with certain BAV types compared with more distally located aneurysms of the ascending aorta. The size and location of such aneurysms may have an impact on the timing and type of surgical intervention. Previous studies have attempted to show a relationship between BAV morphology and characteristics of aortic dilation (3,6,11,16,18,22), however, results were variable and used a variety of imaging techniques (6). Most prior investigations have relied on echocardiography to assess aortic dimensions, which limits the ability to characterize involvement of the entire aorta. These studies depended largely on 2D measurements of aortic diameter to assess morphological differences between BAV phenotypes. The present study uses methods to characterize aortic shape and size in addition to conventional measures of aortic diameter.

The purpose of this study was to retrospectively assess whether there is any relationship between BAV phenotype and thoracic aortic morphology and size.

METHODS Patients

We retrospectively identified 211 patients with BAV diagnosed by cardiac MRI and MR angiography (MRA) of the chest between January 2007 and July 2010. Patients with a history of an aortic valve replacement were excluded. In 2 patients, classification of the aortic valve was not possible due to poor image quality. In 3 patients, a complete set of images (i.e., aortic valve images and MRA of thoracic aorta) could not be retrieved. In 6 patients, data on height and weight could not be obtained. 8 patients had an indetermi-

nate BAV fusion pattern, and could not be accurately classified into any of the three phenotypes and, therefore, were excluded. This left a total study group of 192 patients with BAV who were eligible for inclusion in the study. Patient age, gender, height, weight, body surface area, pattern of fusion, diabetes mellitus history, smoking history, blood pressure, and primary indication at the time of the MRA were recorded from the medical record. Hypertension was defined as systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg. Patients were selected retrospectively according to an IRB-approved protocol and informed consent was waived.

MR Imaging Protocol

All studies were carried out on a 1.5 Tesla (T) Siemens Avanto scanner (Siemens Medical Solutions).

For imaging of the thoracic aorta, electrocardiograph (ECG) -gated contrast enhanced magnetic resonance angiography (CEMRA) was carried out during an intravenous injection of 0.2 mmol/kg of Gadolinium-DTPA (Magnevist, Bayer Pharmaceuticals) in a sagittal oblique orientation (23). The basic pulse sequence was a 3D fast low angle shot (FLASH) with the following imaging parameters: repetition time/echo time (TR/TE): 2.5/1.2 ms; flip angle: 25 degrees; field of view: 300 x 400 mm; matrix: 320 x 512; slice: 1.1 mm; voxel size: 0.9 x 0.8 x 1.1 mm; GRAPPA acceleration x 2; 6/8 partial Fourier in x-y and z axes; acquisition time: 18-20 s. The acquisition was gated to diastole to minimize motion artifact at the aortic root. Precontrast and one postcontrast 3D data sets were acquired for automatic image subtraction to remove background signal calculation of maximum intensity projection (MIP) views.

ECG-gated cine 2D balanced steady state free precession (SSFP) imaging of the bicuspid aortic valve was performed. The imaging plane was carefully angulated to be orthogonal to the aortic root at the level of the aortic valve. Imaging parameters were as follows: TR/ TE: 3.2/1.6 ms; flip angle: 70 degrees; field of view: 350 x 250 mm; matrix: 192 x 150; slice: 8 mm; pixel size: 1.8 x 1.7 mm; iPAT, acceleration x 2.

Aortic Dimensions

Aortic diameter was measured at nine levels: aortic annulus, sinus of Valsalva, sinotubular junction, proximal ascending aorta (along the inferior border of the pulmonary artery, orthogonal to the ascending aorta), mid-ascending aorta (at the level of the pulmonary artery), distal ascending aorta (along the superior border of the pulmonary artery, orthogonal to the ascending aorta), proximal arch (at the innominate artery, or common trunk in case of a bovine arch), distal arch (at the left subclavian artery), and distal descending aorta (at the level of the diaphragm). All measurements were made in the orthonormal plane to the aorta at end-diastole, and were normalized to body surface area (BSA) (24). Aortic size index was calculated as aortic diameter (cm) divided by body surface area (m2) (Fig. 1).

At each level, two perpendicular measurements were recorded to quantify vessel asymmetry. Measurements were taken as a ratio between the maximum aortic diameter and the corresponding perpendicular diameter, and asymmetric segments were defined as having a major/minor diameter ratio > 1.10.

For volume estimation, the ascending aorta was divided into four elliptical cone frustums each defined by specific anatomical boundaries as shown in Figure 2. Using the cross-sectional dimensions collected for each level of the ascending aorta, the volume of each cone frustum was calculated using the equation:

Figure 1. Cardiac MRI annotated to illustrate the nine levels at which the aortic diameter was measured. All measurements were taken in the orthonormal plane. 1. Aortic annu-lus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proximal Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm

Image Analysis

Image analysis methods are summarized in Table 1. Data collection was performed by two observers (B.M., A.T.) who were blinded to the BAV phenotype of each subject.

BAV Leaflet Morphology

Cine SSFP images of the aortic valve were evaluated for the pattern of BAV disease. BAV phenotype was classified using criteria defined by Schaefer et al (3).

BAV phenotype was classified as: R-L when there was fusion of the right and left coronary cusps, R-N when there was fusion of the right and noncoronary cusps, and R-L when there was fusion of the left and noncoronary cusps.

V — — p[ab + cd + y/abcd]

Where h is the curvilinear distance from the inferior to superior boundary along the midline of the ascending aorta, a/b are the perpendicular diameter measurements for the inferior boundary, and c/d are the perpendicular diameter measurements for the superior boundary. Total ascending aortic volume was calculated as the sum of the four subvolumes, yielding an approximated volume for the aorta extending from the sinotubular junction to the proximal innominate artery (Fig. 2).

Aortic Root Morphology

Aortic root morphology was classified into four distinct types based on patterns of aortic dilatation (25) (Fig. 3): Type 0, normal aorta; Type 1, with exclusive dilation of the aortic root; Type 2, with aortic dilation involving only the tubular portion of the ascending aorta; and Type 3, with diffuse dilation of both the entire ascending aorta and the transverse aortic arch.

An aortic segment (root, ascending aorta, transverse arch, etc.) was considered dilated if a diameter of >4 cm was found.

Statistical Analysis

For continuous variables, Student's t-test /analysis of variance were used for single/multiple variables with normal distribution. x2 tests were performed to compare frequencies between groups. Categorical data are given as total number (relative frequency). Continuous

Figure 2. Cardiac MRI annotated to illustrate the measurements used to estimate the volume of the ascending aorta, from the sinotubular junction to the proximal innominate trunk. Cross-sectional images show the two diameter measurements used for each aortic level.

data are given as mean ± standard deviation. Statistical significance was defined as a value of P < 0.05.

RESULTS

Patient Characteristics

There were 139 males and 53 females and the mean age was 45.8 ± 13.1 years (range: 20-79 years). Mean body surface area was 1.98 ± 0.23m2 (range: 1.422.70 m2). The patterns of cusp fusion were as follows: 140 patients (73%) were classified as R-L, 46 patients (24%) were classified as R-N, and 6 patients (3%) were classified as L-N. As L-N BAV was rare, no conclusions could be drawn from this data and thus these patients were excluded from analysis. A total of 20 (10.4%) of

patients possessed a bovine arch. Of those patients with bovine arches, 15 (75%) had R-L valves and 5 (25%) had R-N valves. There were no significant differences in gender (P = 0.93), age (P = 0.064), or BSA (P = 0.28) among the three BAV phenotypes. No significant differences existed between groups in three additional risk factors for aortic dilation: smoking history, diabetes mellitus history, and hypertension (Table 2).

Aortic Dimensions

When all BAV phenotypes were compared, R-N patients were shown to have significantly greater aortic size indices (cm/m2) at the distal ascending aorta (P = 0.014) and proximal aortic arch (P = 0.011). Additionally, R-L patients were shown to have significantly

Figure 3. Cardiac MRIs illustrating each of the four aortic morphologies classified in the study.

Table 2

Patient Characteristics

R-L R-N L-N Total

n 140 (73%) 46 (24%) 6 (3%) 192

Age (years) 47.1 42.7 39.4 45.8 ± 13.11

Males (%) 101 (72%) 34 (74%) 4 (67%) 139 (72%)

Body SA (m2) 1.97 2.03 2.04 1.98 ± .23

Smokers (%) 28 (32%) 11 (34%) 1 (25%) 40 (33%)

n = 87 n = 32 n = 4 n = 123

Diabetes (%) 2 (1%) 2 (4%) 0 (0%) 4 (2%)

n = 134 n = 45 n = 6 n = 185

Hypertension (%) 16 (13%) 5 (12%) 1 (17%) 22 (13%)

n = 126 n = 42 n = 6 n = 174

Clinical and demographic characteristics of the study population.

Table 3

BAV Phenotype vs. Aortic Size Index (cm/m2)

1 2 3 4 5 6 7 8 9

R-L R-N 1.60* 1.49 1.97z 1.77 1.82* 1.71 2.03 1.97 2.01 2.03 1.78 1.91y 1.65 1.77+ 1.27 1.22 1.15* 1.07

*P < 0.05 yP < 0.01 zP < 0.001

1. Aortic annulus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proxmial Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm Variations in aortic diameter with bicuspid aortic valve fusion pattern type.

greater aortic size indices at the aortic annulus (P = 0.032), sinus of Valsalva (P = 0.00002), sinotubular junction (P = 0.013), and distal descending aorta (P = 0.025) (Table 3). R-N patients were more likely to possess an asymmetric sinus of Valsalva compared with R-L patients (P = 0.00002) (Table 4).

There was no significant difference in total ascending aortic volume between fusion phenotypes. However, when regions were analyzed individually, region 1 volume (cm3/m2), from STJ to proximal ascending aorta, was significantly greater in R-L patients compared with R-N (P = 0.0097) (Table 5).

Aortic Morphology

Overall, 52 patients (28%) had Type 0 morphology, 42 patients (23%) had Type 1 morphology, 40 patients

(22%) had Type 2 morphology, and 52 patients (28%) had Type 3 morphology. Comparing R-L and R-N fusion phenotypes showed a significantly greater percentage of R-L patients with Type 1 morphology (P = 0.009). R-N patients were more likely to have Type 2 aortic morphology (P = 0.035) (Table 6).

DISCUSSION

Overall, our results suggest that BAV with fusion of the right and left coronary cusps (R-L) is associated with increased dimensions of the aortic root, while BAV with fusion of the right and noncoronary cusps (R-N) is associated with increased dimensions of the distal ascending aorta and proximal arch. Furthermore, the present study finds greater morphological differences between BAV phenotypes than has been reported in previous research.

In our measurements of aortic size indices, R-L patients showed significantly increased dimensions at each level of the aortic root when compared with R-N patients. These results are in accordance with the findings of prior studies showing significantly larger mean aortic root diameters in those with R-L fusion (3,26). The results of our ascending aortic volume measurements agree with this data, with R-L patients shown to have increased aortic volume from the sino-tubular junction to the proximal ascending aorta. Our findings provide further evidence that disproportionate dilation of the root is more common among patients with R-L fusion pattern.

There was a reversing trend in aortic dimensions more distally along the thoracic aorta, with R-N

Table 4

BAV Phenotype vs. Rate of Vessel Asymmetry

1 2 3 4 5 6 7 8 9

R-L (%) 75.7 22.9 12.1 7.9 i 6.4 5.7 7.1 17.1 10.0

(n = 140) (n = 106) (n = 32) (n = 17) (n = 11) (n = 9) (n = 8) (n = 10) (n = 24) (n = 14)

R-N (%) 80.4 56.5z 17.4 4.3 6.5 0 8.7 13.0 17.4

(n = 46) (n = 37) (n = 26) (n = 8) (n = 2) (n = 3) (n = 0) (n = 4) (n = 6) (n = 8)

*P < 0.05 yP < 0.01 zP < 0.001

Variations in aortic vessel asymmetry with bicuspid aortic valve fusion pattern type. 1. Aortic annulus; 2. Sinus of Valsalva; 3. Sinotubular junction; 4. Proximal Ascending Aorta; 5. Mid-Ascending Aorta; 6. Distal Ascending Aorta; 7. Proximal to the innominate trunk (proximal aortic arch); 8. Distal to the left subclavian artery (distal aortic arch); 9. Descending aorta at the level of the diaphragm.

Table 5

BAV Phenotype vs. Ascending Aortic Volume (cm3/m2)

Region 1 Region 2 Region 3 Region 4 Total Volume

R-L 0.93y 0.86 0.66 0.64 3.08

R-N 0.60 0.88 0.70 0.68 2.86

*P < 0.05 yP < 0.01

Variations in ascending aortic volume with bicuspid aortic valve fusion pattern type. Region 1: Sinotubular Junction to Proximal Ascending Aorta; Region 2 Proximal Ascending Aorta to Mid-Ascending Aorta; Region 3: Mid-Ascending Aorta to Distal Ascending Aorta; Region 4: Distal Ascending Aorta to Proximal Aortic Arch.

patients displaying significantly larger aortic diameters at the distal ascending aorta and the proximal aortic arch. These findings substantiate the trend reported in earlier literature that R-N shows greater arch dimensions than R-L (3,11,27). While certain publications have failed to show an association between fusion phenotypes and differing patterns of dilation, such studies have either only used echocardiography (16,18) or failed to comprehensively assess the ascending aorta and arch (6). We suggest that fusion pattern should be taken into consideration when approaching aortic resection in patients with BAV, as R-N patients are more likely to involve repair of the distal ascending aorta and proximal arch.

Providing further illustration of the differing patterns of aortic dilation between fusion phenotypes, our aortic morphology classification showed patients with R-L fusion are more likely to have isolated dilation of aortic roots (Type 1 morphology). Conversely, R-N fusion is associated with enlargement of the tubular portion of the ascending aorta (Type 2 morphology), and this phenotype was also found more likely to possess vessel asymmetry at the sinus of Val-salva. Differences in aortic dimensions amongst BAV phenotypes may reflect differences in aortic hemody-namics associated with BAV geometry. Irrespective of the genetic origins of BAV, altered flow through a morphologically abnormal valve is likely to alter aortic flow patterns and thus viscous forces at the artery wall (28). These forces, known as wall shear stress (WSS), are a known pathophysiological stimulus cited to alter gene expression and promote endothelial remodeling (29). A recent study by Girdauskas et al (30) provides a comprehensive review of the clinical literature regarding BAV patient studies, including the recent work by Hope et al. using 4D flow MR imaging to show that different BAV fusion patterns result in different orientation of eccentric systolic flow jets (31).

Table 6

BAV Phenotype vs. Aortic Morphology

Type 0 (%) Type 1 (%) Type 2 (%) Type 3 (%)

R-L 38 (27.1) 38 (27.1)y 25 (17.9) 39 (27.9)

R-N 14 (30.4) 4 (8.7) 15 (32.6)* 13 (28.2)

*P < 0.05 yP < 0.01

Variations in aortic morphology with bicuspid aortic valve fusion pattern type.

These recent flow studies have reported high velocity flow jets in patients with R-L fusion that direct the maximal force at the right anterior of the aortic root and flow jets in patients with R-N fusion that create greater WSS more distally on the posterior aortic wall (31,32). These flow jet patterns, with R-L and R-N valves experiencing increased force at the aortic root and tubular ascending aorta, respectively, corresponds to the patterns of dilation demonstrated in the present study. Our findings, i.e., the differences in aortic shape and dimension for different BAV geometries support the role of hemodynamics in the aortic dilation seen in patients with BAV. However, further study is needed to explore the degree to which altered flow patterns are implicated in ascending aortic dilation. Our results suggest the need for considering differences in cusp fusion pattern when evaluating the influence of BAV on aortic disease.

To date, most studies have used only echocardiog-raphy to detect aortic dilatation in patients with BAV (1). While echocardiography allows accurate measurement of the proximal aorta, it has limitations in the assessment of ascending aorta and arch dimensions. The present study has shown that BAV phenotypes are associated with differences in aortic dilation that extend into the proximal aortic arch. For this reason, and due to the fact that the ascending aorta is usually the site of maximum dilation in patients with BAV (8,33,34), it has been argued that MR is a more appropriate tool for the assessment of aortic dilation in this population (6,10).

Our study was not without limitations. First, as this was a retrospective study, no follow up or longitudinal data could be obtained to evaluate the relationship between BAV fusion pattern and outcome/prognosis. Second, as our volume estimation equation relied on just five measurement levels for ascending aortic diameter, the values we obtained do not fully account for small fluctuations in vessel shape. In addition, the approximation as a sum over a small number of cone frustums represents an approximation of the true aortic volumes.

ACKNOWLEDGMENTS

We thank Ms. Jennifer McDonald, Dr. Ann Ragin, and Dr. Mauricio Galizia for their contributions to the data acquisition and statistical analysis.

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