Association between aortic valvular calcification and characteristics of the aortic valve in patients with bicuspid aortic valve stenosis

Abstract

Background

Aortic valve calcification quantification using cardiac computed tomography (CCT) is a reliable marker for aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) disease.

Purpose

To determine the association of Agatston aortic valve calcium score (AVCS) with morphological and hemodynamic characteristics of BAV and define cut-off AVCS for optimizing the grade of AS in patients with bicuspid AS.

Material and Methods

This study included 161 BAV patients with AS regardless of aortic regurgitation who underwent transthoracic echocardiography and CCT. BAVs were classified according to orientation of cusps and presence of raphe. Associations of AVCS with characteristics of BAV morphology and functional variables were determined by linear regression analysis. Area under the receiver operating characteristic curve (AUC) was used to determine the cut-off AVCS greater than which the diagnosis of severe AS was optimized.

Results

AVCS was significantly different according to sex (P < 0.001), AS severity (P < 0.001), type of valvular dysfunction (P = 0.011), and orientation of cusps (P = 0.028). Multiple linear regression showed that AVCS was significantly associated with sex (estimate = −0.583, P < 0.001) and AS severity (estimate = 0.817, P < 0.001). AVCS was a predictor for severe AS with AUC of 0.80 in both women (P = 0.002) and men (P < 0.001). Its cut-off value was 1423 Agatston unit (AU) in women and 2573 AU in men.

Conclusions

In patients with bicuspid AS, AVCS was significantly higher in men and those with severe AS. However, AVCS was not significantly associated with morphological characteristics of BAV or the type of valvular dysfunction.

Keywords

Aortic valve aortic valve stenosis calcium echocardiography multidetector computed tomography

Introduction

Aortic valve calcification (AVC), a typical feature of aortic stenosis (AS), is caused by active inflammatory process in aortic valve cusps (1). Echocardiography, the gold standard to assess the severity of valvular stenosis, can provide semi-quantitative grading for AVC severity. However, echocardiography has several limitations such as high inter-observer variability, poor acoustic window, and poor resolution in detecting early subtle AVC (2 –6). In contrast, cardiac computed tomography (CCT) allows for precise detection, localization, and quantification of AVC. CCT calcium score, generally described using Agatston units (AU), is linked to hemodynamic severity of AS. It is considered an imaging marker to predict disease progression and prognosis (7). Severe AVC is associated with worse morbidity and mortality in patients with AS, including those with low-gradient and low-flow severe AS (5).

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. Its prevalence is in the range of 0.5–2% in the general population (8 –12). Patients with BAV have high risk for AS and aortic regurgitation (AR) as well as aortic wall abnormalities such as ascending aorta dilatation, aneurysm, and dissection (13). Differences in BAV morphology according to the presence of raphe and orientation of cusps are significantly associated with valvular dysfunction and aortopathy (14). AS is the most common complication of BAV. AS in patients with BAV is characterized by an earlier onset, a higher prevalence, and a higher rate of progression than that in patients with tricuspid aortic valve (TAV) (15,16). In patients with BAV, calcific change can develop early in life and progress after the fourth decade. Hope et al. demonstrated that AVC is found 14 years earlier in patients with BAV than that in patients with TAV (15). It is more severe and strongly linked to AS in patients with BAV than that in patients with TAV (15). However, studies on the association between AVC and characteristics of BAV for identifying the importance of AVC in patients with bicuspid AS are lacking. Therefore, the objectives of the present study were: (i) to evaluate the relationship of AVC with morphological and hemodynamic characteristics of BAV; and (ii) to define the cut-off Agatston aortic valve calcium score (AVCS) for optimizing the grade of AS in patients with bicuspid AS.

Material and Methods

Patient population

Our Institutional Review Board approved this retrospective study. The requirement of informed consent was waived due to its retrospective nature. A computerized search of medical and radiological records from January 2008 to February 2017 identified 261 patients with BAV who underwent both transthoracic echocardiography (TTE) and CCT within four weeks without interval change in clinical status or cardiovascular event at our institution. Patients (n = 100) who had no AS on TTE were excluded. Finally, 161 patients with AS (without AR or with mild to severe AR) were enrolled. Their baseline clinical characteristics and detailed information on surgery were obtained from medical and radiological records. CCT was performed to evaluate preoperative coronary artery anatomy, aortic valve morphology, the presence and extent of aortic valve cusp calcification, and ascending aorta dimensions.

Image acquisition and CT protocols

All CT examinations were performed using a dual-source CT scanner (Somatom Definition, Siemens Medical Solutions, Forchheim, Germany). AVC was defined as calcification involving the aortic valve leaflets, points of attachment as well as the aortic wall immediately connected to the calcified leaflets, as previously described (17). Generally, the protocol is the same for calculation of AVCS as used in coronary artery calcium score which is electrocardiography-gated non-contrast CT scans. The AVCS area of interest comprised the sinotubular junction (STJ), valve cusp, aortic annulus, and left ventricle outflow tract. The start of acquisition was placed from the bottom of the valve to the level of the STJ (18). The specific scanning parameters and contrast medium administration of CT are described in the supplementary material.

CT image analysis

Ten transaxial CCT datasets were reconstructed at an increment of 10% of the cardiac cycle, in the range of 0–90% of the R-R interval for each patient. CCT images were reconstructed with a slice thickness of 1.0 mm. Reconstruction increment was set at 0.5 mm. Non-enhanced CT images were reconstructed with section thickness of 3 mm and reconstruction internment of 1.5 mm to quantify AVCS. After reconstruction, all datasets were transferred to a post-processing workstation (Vitrea 2, Vital Images, Plymouth, MN, USA). Aortic valve calcium burden was quantified by a standard Agatston methodology with a threshold for calcium detection set at 130 Hounsfield Units (HU) (19). AVCS was evaluated using dedicated analysis software (VScore, Vital Images, Minnetonka, MN, USA). A representative example of AVCS assessment is shown in Fig. 1. Cross-sectional transverse images during whole cardiac cycle were reconstructed for morphological aspects of aortic valve using oblique coronal and oblique sagittal planes along the left ventricular outflow tract with an additional oblique transverse plane parallel to the aortic valve (Fig. 2).

Fig. 1.

Representative case of AVCS calculation by using non-contrast ECG-gated cardiac CT in a 55-year old man with BAV with severe AS. (a) Calcification of cusps of BAV (arrows). (b) AVCS was 4452 AU. (c) Multiplanar reformatted coronal image of aortic valve for displaying the sliced images used for AVCS calculation. (d–f) The AVCS area of interest included calcification involving the aortic valve cusps (e) between sinotubular junction (d) and aortic annulus (f) and the aortic wall immediately connected to the calcified cusps.

Fig. 2.

Representative case of type I BAV and raphe- in a 51-year-old man with severe aortic valve calcification and severe AS. (a) The grade of aortic valve calcification was considered severe and aortic valve calcium score was 5544 AU. (b) Double oblique CT reconstruction parallel to the aortic valve during systole demonstrating a BAV with AP orientation of the free edge of cusps without raphe. (c) Double oblique coronal CT reconstruction through the left ventricular outflow tract during systole showing 41.9 mm in diameter at sinus of Valsalva and 44.2 mm in diameter at tubular portion. (d) Transthoracic Doppler echocardiography image demonstrating severe AS with aortic valve area of 0.9 cm², peak aortic velocity of 5.2 m/s, and mean pressure gradient of 56 mmHg. (e) Parasternal long axis transthoracic echocardiography showing a regurgitant jet flow (arrow) from the aorta into the left ventricle with vena contracta width of 2 mm² and pressure half-time of 629 ms, corresponding to a mild degree of aortic regurgitation.

The presence of BAV was confirmed after visualizing two cusps and commissures with or without a raphe in both systole and diastole. BAV was classified as type I (anterior-posterior orientation of the free edge of cusps with or without fusion of the right and left coronary cusps; AP) or type II (right-left orientation of the free edge of cusps with or without fusion of the right or left coronary cusp and non-coronary cusps; RL) and divided into raphe+ (presence of raphe) and raphe- (no raphe) (20). The assessment of ascending aorta dimensions and classification of ascending aorta phenotype are described in the supplementary material (21).

Echocardiographic evaluation

Aortic valve morphology and the presence and severity of valvular dysfunction were obtained from patient’s medical records documented by cardiologists. Two-dimensional TTE was performed with a Vivid 7 device (GE Healthcare; Wauwatosa, WI, USA) and an Acuson Sequoia C512 apparatus (Siemens, Erlangen, Germany) with 2.5–3.5-MHz imaging transducers. AS severity (mild, moderate, or severe) was determined using variable parameters (valve area, mean transvalvular gradient, or peak transvalvular velocity) according to American College of Cardiology/American Heart Association guidelines (22).

Statistical analysis

Continuous variables are presented as mean ± standard deviation (SD) or median. Categorical variables are summarized as frequencies. Independent samples t-test and analysis of variance (ANOVA) were used to compare differences in AVCS according to morphological and functional characteristics of BAV. AVCS was log-transformed and analyzed due to its skewed distribution. The relationship between AVCS and associated variables was evaluated by simple linear regression analysis. Variables with a P value < 0.05 on simple linear regression analysis were included into multivariable model to identify significant clinical factors. Receiver operative characteristic (ROC) curve was used to determine the cut-off AVCS greater than which the diagnosis of severe AS was optimized. All statistical analyses were performed using SPSS, version 24.0 (SPSS Inc., Chicago, IL, USA) and R program version 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was considered at P < 0.05.

Results

Patient characteristics

Of 161 patients with AS (13 mild, 26 moderate, 122 severe) on TTE, a total of 39 (24.2%) patients had discordant parameters (valve area and mean transvalvular gradient) of AS severity. Seventy-eight (48.4%) patients also had AR (62 mild, 14 moderate, 2 severe) while 145 patients (90.1%) had dilated ascending aorta, including 41 (25.5%) patients who had ascending aorta aneurysm (Table 1). To correct defective aortic valve and/or pathology involving the ascending aorta, open heart surgery was done in 133 (82.6%) patients.

Table 1.

Baseline characteristics of patients included in this study.

Variables
Patients (n)	161
Age (years), range	58.9 ± 10.6 (31–81)
Male sex (n (%))	103 (64)
Body surface area (m²), range	1.7 ± 0.2 (1.1–2.2)
NYHA functional class (n (%))
I/II/III/IV	59 (36.6)/65 (40.4)/ 34 (21.1)/3 (1.9)
COPD (n (%))	7 (4.3)
Hypertension (n (%))	61 (37.9)
Diabetes mellitus (n (%))	16 (9.9)
CAD (n (%))	43 (26.7)
Hyperlipidemia (n (%))	32 (19.9)
Smoking (n (%))	54 (33.5)
Echocardiographic data
AS/ASR (n (%))	83 (51.6)/78 (48.4)
Dimension of sinus (mm), range	38.0 ± 5.8 (26.1–74.2)
Dimension of tubular portion (mm), range	44.6 ± 6.8 (29.6–70.4)
AA types
Normal aorta (n (%))	16 (9.9)
Tubular (n (%))	51 (31.7)
Dilated root (n (%))	6 (3.7)
Combined root and tubular (n (%))	88 (54.7)
Aortic aneurysm (n (%))	41 (25.5)
LVEF (%), range	64.9 ± 12.8 (21.8–88.7)
Aortic valve calcium score, median (range)	2456 (63–14,073)
Coronary calcium score, median (range)	0 (0–1756)
BAV morphology
Type I (AP)/Type II (RL) (n (%))	83 (51.6)/78 (48.4)
Raphe+/Raphe- (n (%))	75 (46.6)/86 (53.4)

AA, ascending aorta; AP, anterior-posterior orientation; AS, aortic stenosis; ASR, aortic stenosis and regurgitation; AV, aortic valve; BAV, bicuspid aortic valve; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CT, computed tomography; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RL, right-left orientation.

Detailed surgical findings regarding BAV morphology were available for 133 patients. CCT was used to assess BAV morphology in 28 patients not treated surgically due to insignificant valvular dysfunction. Type I BAV was present in 83 (51.6%) patients while raphe+ was present in 75 (46.6%) patients.

Differences of AVCS according to variables

Mean AVCS was 2912 ± 2381 AU and median AVCS was 2456 AU. There was significant (P < 0.001) difference in AVCS between women (1740 ± 1085 AU) and men (3572 ± 2649 AU). Patients with severe AS had significantly (P < 0.001) higher AVCS (3349 ± 2463 AU) than those with moderate AS (1892 ± 1550 AU) or mild AS (849 ± 782 AU) (Table 2, Fig. 3).

Table 2.

Difference in aortic valve calcium score according to variables.

	AVCS	Log (AVCS)	P value
Sex			<0.001
Male (n = 103)	3572 ± 2649	7.82 ± 1.02
Female (n = 58)	1740 ± 1085	7.18 ± 0.88
Raphe			0.129
Absence (n = 75)	2551 ± 2128	7.47 ± 0.97
Presence (n = 86)	3325 ± 2594	7.71 ± 1.07
BAV type			0.028
I (AP, n = 83)	3334 ± 2652	7.76 ± 0.98
II (RL, n = 78)	2463 ± 1974	7.40 ± 1.04
Valvular dysfunction			0.011
AS (n = 83)	2249 ± 1705	7.39 ± 0.91
ASR (n = 78)	3617 ± 2276	7.80 ± 1.09
Aorta aneurysm			0.125
Absence (n = 120)	3069 ± 2505	7.66 ± 0.96
Presence (n = 41)	2453 ± 1927	7.37 ± 1.17
Ascending aorta			0.177
Normal (n = 16)	2279 ± 1918	7.33 ± 1.10
Mild-ascending (n = 51)	2320 ± 1735	7.41 ± 1.07
Dilated root (n = 6)	4299 ± 2235	8.05 ± 0.54
Combined (n = 88)	4048 ± 3012	7.70 ± 0.98
AS severity			<0.001
Mild (n = 13)	849 ± 782	6.26 ± 1.10
Moderate (n = 26)	1892 ± 1550	7.17 ± 1.02
Severe (n = 122)	3349 ± 2463	7.82 ± 0.88

Data are presented as means ± standard deviation. P values < 0.05 were considered statistically significant.

AP, anterior-posterior orientation; AS, aortic stenosis; ASR, aortic stenosis and regurgitation; AVCS, aortic valve calcium score; BAV, bicuspid aortic valve; RL, right-left orientation.

Fig. 3.

Graph showing box plots of AVCS in relation to stenosis severity determined by echocardiography, including median (horizontal line within box) and 25th–75th percentiles. Bars above and below boxes indicate minimum and maximum scores, respectively. Circle, mild outliers.

Patients with type I BAV and patients with combined AS and AR (ASR) had significantly (P = 0.028 and P = 0.011, respectively) higher AVCS than those with type II BAV and pure AS. AVCS values were not significantly different among patients regardless of the presence of aortic aneurysm or raphe or the phenotype of aortopathy (Table 2).

Regression model between AVCS and variables

In simple linear regression analysis between AVCS and variables, sex (P < 0.001), variables assessed with TTE (such as AS severity [P < 0.001] and type of valvular dysfunction [P = 0.011]), and variables assessed with CCT (such as phenotype of BAV [P = 0.028] and sinus diameter [P = 0.039]) showed significant association with AVCS. There was no significant association between AVCS and variables such as age (P = 0.103), diabetes mellitus (P = 0.768), coronary artery disease (P = 0.627), coronary calcium score (P = 0.167), the presence of raphe (P = 0.129), aorta aneurysm (P = 0.125), or ascending aorta phenotype (P = 0.064) in simple linear regression analysis.

In multiple linear regression analysis (Table 3), AVCS was associated with sex and AS severity. No significant association was observed between AVCS and type of valvular dysfunction, cusp orientation (type I vs. II), or sinus diameter assessed by CCT in bicuspid AS.

Table 3.

Multivariate linear regression analysis between aortic valve calcium score and variables.

	Estimate ± SE	β	P value
Sex (male 0, female 1)	−0.583 ± 0.152	−0.275	<0.001
TTE-AS severity	0.817 ± 0.107	0.495	<0.001
TTE- AS (0) or -ASR (1)	0.257 ± 0.135	0.126	0.059
BAV type (type I 0, type II 1)	−0.225 ± 0.134	−0.111	0.094
CT sinus diameter of AA	0.019 ± 0.012	0.106	0.132

Log-transformed AVCS values were used for analysis.

AS, aortic stenosis; ASR, aortic stenosis and regurgitation; AA, ascending aorta; BAV, bicuspid aortic valve; CT, computed tomography; SE, standard error; TTE, transthoracic echocardiography.

Diagnostic value of AVCS for identifying AS severity

AVCS was a possible predictor for severe AS, with area under the ROC curve (AUC) of 0.76 (P < 0.001) and cut-off value of 2573 AU (sensitivity = 59.8%, specificity = 87.2%) (Fig. 4a). AUC and cut-off values of AVCS for predicting moderate AS were 0.74 (P = 0.014) and 513 AU (sensitivity = 88.5%, specificity = 53.8%), respectively. ROC curve analyses in women and men separately showed that the best cut-off values to identify severe AS were AVC ≥ 2573 AU in men (sensitivity = 73.3%, specificity = 82.1%) (Fig. 4b) and 1423 AU in women (sensitivity = 68.1%, specificity = 90.9%) (Fig. 4c). AUC of AVCS for predicting severe AS were both 0.80 in women (P = 0.002) and in men (P < 0.001). When this sex-specific cut-off value of AVCS was applied to discordant cases described above, two discordant cases of suspected moderate AS upgrade to severe AS and nine discordant cases of suspected severe AS could be considered as severe AS.

Fig. 4.

ROC curves of AVCS for diagnosis of non-severe vs. severe AS without sex differentiation (a), non-severe vs. severe AS in men (b) and non-severe vs. severe AS in women (c).

Discussion

Major findings of this study are as follows. First, sex and AS severity were independently associated with AVCS on multivariate analysis. Second, AVCS did vary by AS severity. It was, in fact, influenced by several factors on simple linear regression analysis. Third, AVCS was a predictor for severe AS with a cut-off value of 2573 AU. It was particularly higher in men compared to that in women. Fourth, morphology of BAV such as cusp orientation or the presence of raphe was not significantly associated with AVCS.

CT calcium scoring of aortic valve could be used as an alternative marker of AS severity, demonstrating a good relationship with hemodynamic echocardiographic assessment (7,23). However, patients enrolled in these studies had TAV with or without BAV, not only BAV patients. There is limited evidence supporting that AVCS is diagnostic marker for AS severity in pure BAV patients. One study demonstrated that AVCS in patients with bicuspid AS is positively related to severe AS in patients with different degrees of AS severity (24), which is consistent with our study.

Several studies suggested the optimal AVCS for differentiating moderate AS from severe AS (5,7,24 –26). Optimal thresholds of AVCS have been reported to be in the range of 500–3700 AU. In our study, sex was an independent factor for AVCS on multivariate analysis. Furthermore, the cut-off value of AVCS in men (2573 AU) was higher than that in women (1423 AU). The AUC of AVCS for predicting severe AS according to sex showed higher sensitivity and specificity than that when data of men and women were combined. This result suggests that different gender-specific criteria of AVCS might be needed to predict severe AS. Clavel et al. also suggested well-defined cut-offs for severe AS in men (2065 AU) and women (1274 AU) (26,27). These thresholds independently predicted adverse events beyond clinical and Doppler echocardiographic assessment. However, cut-off values of AVCS in this study are higher than those in studies of Clavel et al. (26,27). This could be due to the fact that calcific change in aortic valve can develop early in patients with BAV. Therefore, higher cut-off value of AVCS to differentiate severe AS should be applied in bicuspid AS.

Accurate severity evaluation of AS is clinically important to obtain appropriate treatment option for aortic valvular dysfunction. In our study, AVCS was significantly associated with the severity of AS in patients with BAV. The cut-off value of AVCS can be used as an objective marker of severity in patients whose clinical assessment is confusing. It is highly challenging to diagnose severe AS for some patients who have discordant finding on TTE such as small AVA but low gradient (28). One study has emphasized the clinical yield of AVC quantification by CCT to diagnose and manage patients with severe AS but low mean gradient (27). In our study, 24.2% patients had discordant parameters of AS severity with an AV area and a transaortic mean pressure gradient. When we applied the cut-off value of AVCS according to sex, we could make more confident diagnosis of severe AS for these discordant cases. However, this hypothesis needs to be validated in further studies.

No studies have reported the relationship between morphology of BAV and AVCS. Kang et al. reported that there is no significant difference in the grade of AVC between type I and type II groups (20). In our study, AVCS in type I group was higher than that in type II group. In addition, patients with raphe demonstrated higher AVCS than those without raphe. However, the association between AVCS and the presence of raphe or the orientation of BAV was not significant in simple or multiple linear regression analysis. These results suggest that BAV morphologies such as valve orientation and raphe might not be independent causes of AVC formation.

In terms of the relationship between the type of valvular dysfunction and AVCS, patients with combined AS and AR had higher AVCS than those with AS in our study. However, there was no significant association between AVCS and the type of valvular dysfunction in multiple linear regression analysis. Ren et al. (24) demonstrated that patients with AS and those with combined AS and AR have significantly higher AVCS than those with AR. In our study, patients with pure AR were excluded because patients with AS were our focus. Therefore, there was limited evidence about the association between AVCS and the type of valvular dysfunction in this study. Further study is needed to validate this association.

In those with BAV disease, the aortic annulus, sinus, and proximal ascending aorta are larger than those found in adults with TAV (29 –31). However, bicuspid aortopathy is heterogeneous. It is still insufficiently defined (32,33). Recent studies demonstrated that tubular aortic dilation phenotype is the most common form of bicuspid aortopathy (20,34). We found that the percentage of patients having tubular aortic dilatation (86.3%) was higher than that of patients having root dilatation (58.4%). However, our study showed that there was no significant association between AVCS and the type of aortopathy (P = 0.064) or tubular diameter of ascending aorta (P = 0.849) in simple linear regression analysis. This result needs to be confirmed in future studies.

Our study has several limitations. First, it was a single institutional retrospective study, although CCT and TTE were available for all patients. Second, although the sample size used in our study was not small, 75.8% of enrolled patients had severe AS and 48.4% of those included patients had ASR. We excluded patients with pure AR. This might have caused selection bias. Third, this study only included patients with BAV and AS. Accordingly, the impact of the study is slightly limited due to the strict selective criteria of BAV. Forth, the cut-off value of AVCS for differentiating severe AS from moderate AS in our study was quite high compared to those reported in previous studies with lower sensitivity. To determine the appropriate cut-off value of AVCS as a clinical marker to assess the severity of AS, more patients are needed for confirmation based on the same definition for severe AS. In addition, some patients might have a predominantly fibrotic response with little aortic valve disease. Therefore, this method could not be used on its own to exclude severe AS. Furthermore, some studies reported that CT calcium scoring can be used to predict disease progression in AS (35 –37), indicating that AVCS progresses the fastest in patients with the highest baseline calcium burden. Longitudinal follow-up is needed to determine whether high AVCS in patients with BAV and AS affects clinical outcomes.

In conclusion, AVCS calculated at CCT is a reliable marker for assessing AS severity in patients with BAV. AVCS was significantly higher in patients with severe AS and male patients with bicuspid AS. However, morphology of BAV, the type of valvular dysfunction, or aortopathy in patients with AS might not be significantly associated with AVCS. Hence, AVCS according to sex could be a potential marker to evaluate AS severity in patients with BAV regardless of the morphology of BAV or aortopathy. The new cut-off value of AVCS proposed in this study needs to be validated by future longitudinal studies with outcome data.

Supplemental Material

Supplemental material for Association between aortic valvular calcification and characteristics of the aortic valve in patients with bicuspid aortic valve stenosis

Supplemental material for Association between aortic valvular calcification and characteristics of the aortic valve in patients with bicuspid aortic valve stenosis by Bo Hwa Choi, Sung Min Ko, Je Kyoun Shin, Hyun Keun Chee, Jun Seok Kim and Jayoun Kim in Acta Radiologica

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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