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Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease: A Five-year Prospective Study
Accepted Manuscript Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a Five-Year Prospective Study Sriya A. Avadhani, MD, William Martin-Doyle, MD, MPH, Amir Y. Shaikh, MD, Linda A. Pape, MD PII:
S0002-9343(15)00075-3
DOI:
10.1016/j.amjmed.2014.12.027
Reference:
AJM 12847
To appear in:
The American Journal of Medicine
Received Date: 6 December 2014 Revised Date:
31 December 2014
Accepted Date: 31 December 2014
Please cite this article as: Avadhani SA, Martin-Doyle W, Shaikh AY, Pape LA, Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a Five-Year Prospective Study, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2014.12.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a FiveYear Prospective Study Authors: Sriya A. Avadhani, MD1; William Martin-Doyle, MD, MPH2; Amir Y. Shaikh, MD3;
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Linda A. Pape, MD3
1. Department of Medicine, State University of New York (SUNY) Downstate Health Science Center, Brooklyn, NY
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2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA
Type of Study: Clinical Research Study
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3. Department of Medicine, University of Massachusetts Medical School, Worcester, MA
Corresponding author: Linda A. Pape, MD
Division of Cardiology, Department of Medicine, University of Massachusetts Medical School,
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55 Lake Ave N, Worcester, MA 01655 Tel: 508-856-3050, Fax: 508-856-4571 Email: [email protected]
Echocardiography
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Keywords: Aortic dilation; Bicuspid aortic valve; Aortic stenosis; Aortic regurgitation;
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Word count: 2893 (excluding abstract, clinical significance, acknowledgments, references, tables, and figures)
Number of figures: 2; Number of tables: 2 Funding: Department of Medicine, University of Massachusetts Medical School Conflicts of Interest: None Disclosure: All authors had access to data and were involved in writing the manuscript.
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ABSTRACT Background: Bicuspid aortic valves are associated with aortic dilation and dissection. There is a paucity of prospective studies evaluating changes in aortic size over time in adult subjects with
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bicuspid aortic valves.
Methods: A total of 115 subjects with asymptomatic bicuspid aortic valves were enrolled from 2003-2008 and followed prospectively over 5 years. Clinical and family histories as well as
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transthoracic echocardiograms were obtained at baseline and echocardiograms were performed annually thereafter.
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Results: Mean age of subjects was 41.8± 12.8 years, 61% male. Ascending aortic size at baseline averaged 35.5±5.6 mm and increased in 71.1% of subjects (mean 0.66±0.05 mm/year; range 0.2-2.3 mm/yr) over an average of 4.8 years. In 15.6% of subjects, the rate of change exceeded 1mm/yr. The average rate of ascending aortic dilation for all subjects was 0.47±0.05
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mm/ year (p<0.001). Family history of aortic valve disease was associated with progression in both unadjusted (p=0.029) and logistic regression analysis adjusted for age, gender, and body surface area (OR 13.7, p=0.021). Multivariate analysis did not find leaflet orientation or
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moderate to severe aortic valve dysfunction as independent predictors of aortic dilation. Conclusion: In conclusion, we found that in bicuspid aortic valve subjects, studied
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prospectively, there was an annual rate of ascending aortic dilation of 0.47 mm/year. In contrast to previous reports, leaflet orientation and aortic valve dysfunction were not independent predictors of aortic dilation. Family history of aortic valve disease was associated with significantly increased risk of increasing ascending aortic size.
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INTRODUCTION Bicuspid aortic valve, the most common congenital cardiac abnormality in adults, is estimated to be present in 0.5 -1.5% of the population. While survival among subjects with bicuspid aortic
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valves in published studies is similar to that of the general population, there is a greater incidence of cardiac and aortic complications.1 The clinical presentation of bicuspid aortic valve disease ranges from asymptomatic subjects to those with aortic stenosis and or insufficiency,
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endocarditis, aortic dilation and aortic dissection.1-3 Aortic stenosis is the most common reason for aortic valve replacement among bicuspid aortic valve patients.4
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An important non-valvular association of bicuspid aortic valve is thoracic aortic dilation, in the past referred to as post-stenotic dilation.1 4 While hemodynamic factors such as shear stress likely play a role, there is growing recognition that bicuspid aortic valve associated aortopathy has genetic causes and cannot be accounted for by hemodynamic factors alone.5 6 Because as a
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group, bicuspid aortic valve patients have been shown to have larger aortic diameters than controls,5 and because bicuspid aortic valve patients have approximately an 8 times greater risk of aortic dissection2 than the normal population, predictors of aortic dilation have been sought.
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Most of the data, however, on bicuspid aortic valve associated aortic complications comes from retrospective studies involving subjects who are surgical candidates or have
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significant coexistent valve dysfunction.2 3 7 In 2003 our group showed, in a retrospective study, that many bicuspid aortic valve patients with nearly normal baseline valve function have progression of aortic dilation similar to bicuspid aortic valve patients with valve dysfunction.8 There are few prospective studies of the progression of aortic disease in asymptomatic bicuspid aortic valve subjects.1 Some have tried to demonstrate a correlation between valve morphology and aortic dilation.7 9 Until genetic testing is available to identify those at greatest risk for aortic
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complications, having clinical predictors of these complications might be useful. The objective of the current study was to evaluate prospectively possible clinical and echocardiographic predictors of progressive aortic dilation among asymptomatic adult subjects with bicuspid aortic
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valves.
METHODS
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This study was approved by the institutional review board of the University of
Massachusetts Medical School. Between 2003 and 2008, 115 asymptomatic subjects with the
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echocardiographic diagnosis of bicuspid aortic valve and no prior cardiac surgery were recruited at the University of Massachusetts Medical School. Subjects gave written informed consent, and underwent baseline and yearly echocardiography for five years. Clinical information was obtained from patient interviews at the time of enrollment and at least at the first follow-up
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appointment.
Baseline data included age, sex, body surface area (BSA), cardiac medications, cardiac symptoms, prior cardiac interventions, family history of aortic valve disease, other
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congenital/valvular disease, and coronary risk factors. Standard transthoracic echocardiograms were performed; bicuspid aortic valve morphology and cusp orientation were confirmed in short
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axis views. Aortic root measurements were made inner edge to inner edge in the parasternal long axis view; the sinuses of Valsalva at end diastole and the ascending aorta at end systole. We have previously demonstrated that maximal ascending aortic size in bicuspid aortic valve patient with aortic dilation usually occurs at least 2-3 centimeters above the sinotubular junction and that a greater length of aorta can usually be imaged at end systole.10 In cases with effacement or poor imaging of the sinotubular junction the ascending aorta was measured 4 cm above the valve
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plane. The largest ascending aortic diameter was recorded at baseline and at follow-up. For purposes of this analysis, we compared the initial measurement with the final measurement.
stenosis (AS) and/or aortic insufficiency (AI).
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Other echocardiographic data included ejection fraction (EF), presence and degree of aortic
Two observers, blinded to patient information, measured aortic diameters and cusp fusion independently. Inter-observer reliability was assessed by the intraclass correlation
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coefficient.
Aortic stenosis was graded based on the peak systolic gradient. Mild aortic stenosis was
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defined as a peak pressure gradient less than 25 mm Hg, moderate between 25-36 mm Hg, and severe as 36-64 mm Hg. Aortic regurgitation was graded based on Doppler criteria including jet height/left ventricle outflow tract height ratio in parasternal long-axis views, jet area/left ventricle outflow area ratio and pressure halftime by spectral Doppler. Aortic insufficiency was
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graded as mild, moderate or severe. Cusp orientation was classified as either right-left (R-L) cusp fusion or right-noncoronary (R-N) cusp fusion. A blinded observer determined the presence and grade of aortic stenosis and aortic insufficiency, and cusp orientation.
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Outcomes used included a) annual rate of aortic dilation, estimated as the difference between final aortic diameter and baseline aortic diameter, divided by number of years of follow-
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up, and b) presence of any aortic size progression: subjects with no increase in aortic diameter from baseline to follow-up were considered to have no progression, and subjects with any increase in aortic diameter >0 mm were considered to have progression. Statistical analysis was performed using Stata (Version 12, StataCorp, College Station,
Texas). Baseline statistics are presented as mean ± standard deviation (continuous variables) or as proportions (binary and categorical variables). In univariate analyses, differences in
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proportions of subjects with any progression were tested using Fisher’s exact test and differences in means for annual rate of change by two-sample t-tests with unequal variances. Multivariate analysis by linear regression of annual rates of change, and logistic regression models predicting
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presence of any aortic progression were used to identify independent predictors of aortic dilation. Variables associated with progressive aortic dilation (p<0.05) in univariate analysis were entered into multivariate models controlling for age, gender, and baseline body surface area as a priori
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clinically relevant potential confounding variables. Variables considered as potential predictors are shown in Table 1. Missing data was addressed by complete case analysis, including patients
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lost to follow-up. Multilevel linear regression and logistic regression analyses were also conducted as a sensitivity analysis, using random effects to account for correlation in aortic diameter over time within individuals. A p value <0.05 was considered significant.
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RESULTS
Of the 115 subjects originally enrolled, 18 were excluded because of aortic valve replacement within 3 years of enrollment and 7 were excluded for <3 years of follow-up data
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(lost to follow-up). Ninety subjects had 3-5 years of follow-up data and no prior aortic valve replacement. Of these 90 subjects, 6 had subsequent valve replacements after enrollment, but had
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at least three annual echocardiograms prior to surgery and were included in the analysis. The inter-observer reliability for measurement of aortic diameter, assessed by the intraclass correlation coefficient, was 97.5% (95% CI: 95.6%-98.6%). Average age at diagnosis was 41.8 years and mean follow-up was 4.8 years (median 5
years, range 3-5 years). The average baseline ascending aortic diameter was 35.5mm (±5.6mm). Sixty-nine subjects (77%) had right-left cusp fusion, 21 (23%) had right-noncoronary cusp
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fusion, 15 (17.6%) had moderate to severe aortic insufficiency, and 13 (14%) had moderatesevere aortic stenosis. Baseline characteristics are described in Table 1. Aortic size increased in 64 (71%) subjects (mean 0.66±0.05 mm/yr; range 0.2-2.3 mm/yr)
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over a mean follow up of 4.8 years (median follow up 5 years). In 14 (15.6%) subjects the rate of change exceeded 1mm/yr (Figure 1). The average rate of ascending aortic dilation for all subjects was 0.47±0.05 mm/year (p<0.001). Although a history of hypertension was inversely associated
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with ascending aortic dilation (0.54 mm/yr with hypertension vs. 0.30 mm/yr without, p=0.022), it was not an independent predictor (p=0.159). Family history of aortic valve disease (self-
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reported family history of bicuspid aortic valve, aortic valve surgery, aortic stenosis, aortic insufficiency, or thoracic aortic aneurysm) was associated with progression in both unadjusted (p=0.03), and logistic regression analysis adjusted for age, gender, and body surface area (OR 13.6, p=0.023) (Table 2).
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As a sensitivity analysis, we also evaluated multilevel linear regression models of aortic diameter over time, as well as multilevel logistic regression models predicting presence or absence of progression of aortic dilation, with random effects to account for intra-subject
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correlation over time. Results (not shown) were similar to non-multilevel results presented in Tables 1 and 2, with family history of aortic valve disease emerging as the only significant
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predictor of progression.
Patients with right-noncoronary cusp fusion (N=21) had higher baseline ascending aortic
diameters compared to those with right-left cusp fusion (37.6 mm versus 34.9 mm; p=0.049), but no difference was observed in rate of aortic dilation. In these two groups, unadjusted rates of aortic dilation were 0.47 mm/year for subjects with right-left cusp fusion, vs. 0.46 mm/year for those with right-noncoronary cusp fusion, p=0.95 (Figure 2). There was no significant
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association between family history of aortic valve disease and cusp morphology (p=0.78). Multivariate analysis did not find leaflet orientation or the presence of moderate to severe aortic
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valve dysfunction as independent predictors of aortic dilation.
DISCUSSION
The large number of studies published in recent years on the subject of aortic dilation in
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bicuspid aortic valve patients attests to the growing awareness of, and interest in predicting aortic complications in these patients. The 2008 guidelines for surgical repair of aortic dilation with
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bicuspid aortic valves include an aortic diameter of >5cm or diameter >4.5cm and a yearly dilation rate >0.5cm/yr.11 Other indications include aortic diameter >4cm in a patient undergoing elective aortic valve replacement.11 However these guidelines are not supported by strong evidence and are based on expert opinion alone. There has been considerable controversy about
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these guidelines which are similar to those for Marfan syndrome and are not widely accepted as appropriate for bicuspid aortic valve patients whose rate of aortic complications, while much greater than the general population, are much less than for Marfan syndrome patients.12 Thus, the
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2014 guidelines were changed back to 5.5 cm for bicuspid aortic valve patients.13 Since the ascending aorta is the segment in bicuspid aortic valve subjects that most often
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develops aneurysmal dilation or, rarely dissection, requiring surgery, we were most interested in assessing in a prospective manner factors that might predict progressive dilation of this segment. Could we eventually determine which subjects with bicuspid aortic valves are at risk for aortic complications and need close follow up and, on the other hand, which patients might be reassured that their risk is low?
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In this prospective study evaluating the progression of aortic size in asymptomatic subjects with bicuspid aortic valves, we found an overall annual rate of 0.47 mm/year; a rate which is in agreement with the range of progression found in earlier retrospective studies,
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reported to be between 0.18-1.0 mm/year,3 14 15 and lower than the rate of 0.9 mm/year reported in our own previous retrospective study.8 The aortas of 30% of subjects did not increase in size over the study period similar to the 32% reported in Della Corte et al.’s study.7 In only 14
not predict progression, nor did valve dysfunction.
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(15.6%) of our patients did growth equal or exceed 1 mm/year. Baseline aortic size in itself did
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Retrospective study populations will differ from prospective ones. For example: in our retrospective study8 the rate of aortic size increase was twice that in the current prospective study. Differences in patient selection among study populations, pre-surgical patients, community studies, symptomatic, asymptomatic, echo database searches, etc. will account for
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some of the differences in results and conclusions.
Della Corte et al recently reported a retrospective series of 133 bicuspid aortic valve patients, 48% of whom were referred for symptoms, with mean and median follow up of 4 and 3
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years respectively.7 Fifty percent of the patients had ≥moderate aortic stenosis or insufficiency and 40% underwent aortic and/or aortic valve surgery. The male to female ratio was 3:1. That
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study concluded that aortic phenotype predicted complications. Thanassoulis et al., in a retrospective study of 156 patients, 60% of whom had moderate aortic regurgitation or stenosis with 3.8 years mean follow up, found that right-left cusp orientation was associated with rapid aortic growth.3
Our patients, on the other hand, were asymptomatic at enrollment and followed prospectively; mean and median follow up were 4.8 and 5 years respectively. Only 31% had
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≥moderate valve dysfunction and only 6 (6%) underwent aortic valve replacement. The male to female ratio in our study was 3:2, lower than the generally reported ratio of 2:1. Also in contrast to Della Corte et al.7, we found that patients with right-noncoronary cusp fusion at baseline had
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greater ascending aortic size than patients with right-left cusp fusion. We found that cusp orientation did not predict an increase in aortic size; only family history predicted progressive enlargement.
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Cusp orientation is thought to arise from different developmental mechanisms associated with possibly different aortic vulnerability. Cusp fusion morphology has been shown by recent
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elegant 3 and 4D magnetic resonance imaging (MRI) studies to determine flow pattern and wall shear stress, and thus likely impacts aortic pathology.16 In contrast to prior studies,2 3 we did not identify aortic valve dysfunction or cusp morphology as significant predictors of the rate of progressive aortic dilation. Hemodynamic factors related to valve function and morphology have
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been associated with a faster rate of aortic dilation in some bicuspid aortic valve subjects. The correlation of severe aortic insufficiency with aortic root dilation is thought to be due to higher wall tension and larger stroke volumes.6 There is also speculation that since stenotic aortic valves
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increase shear stress on the aortic wall, stenosis increases the likelihood of aortic dilation; however, there is conflicting evidence17 for the correlation of bicuspid aortic valve cusp
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morphology and aortic dilation.3 18 None of these hemodynamic factors alone are clearly predictive of aortic dilation with bicuspid aortic valves. Familial clustering and genetic studies identify a high prevalence of bicuspid aortic valve
disease among first degree relatives of affected members.19 Bicuspid aortic valve disease is inherited in an autosomal dominant pattern with variable expressivity. Up to one-third of family members of bicuspid aortic valve patients have been shown to have aortic dilation even with
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tricuspid aortic valves. The presence of aortic dilation in the absence of valve dysfunction and its persistence after aortic valve replacement suggests that aortic dilation may be independent of hemodynamic factors.15 20 Deficiency of fibrillin-1 gene and increased activity of MMP-1 gene
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have been identified in bicuspid aortic valve subjects resulting in a fragile aorta, less suited to deal with stress associated with valvular dysfunction.21 Numerous genes and genetic syndromes are associated with the bicuspid aortic valve and/or thoracic aortic dilation. Mutations in the
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TGFBR1 and 2 genes, ACTA2 gene, and multiple single nucleotide polymorphisms have been implicated in thoracic aneurysm formation in bicuspid aortic valve subjects.22 23
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We found that family history of aortic valve disease (including bicuspid aortic valves, aortic valve replacements, aortic stenosis, aortic insufficiency or thoracic aortic disease) was reported by 21% of our patients and was an independent predictor for progressive aortic dilation. While it is known that approximately 10% of bicuspid aortic valve cases are familial, ours is the
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first study we are aware of that has shown family history to be a significant predictor of increased risk of progressive aortic dilation. While family history was a significant predictor of any progression of aortic dilation in logistic regression, we did not find that family history
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predicted the annual rate of aortic dilation in linear models. However, it is not clear that a relationship between family history and aortic dilation should be expected to be linear,
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potentially limiting the sensitivity of linear regression to detect an association. Limitations
This study had relatively modest sample size and therefore somewhat limited power to
detect significant predictors of the rate of aortic dilation. Unlike other reports it is unique in being a prospective study of asymptomatic patients, the majority of whom had little or no valve dysfunction at the time of enrollment. The effects we observed for candidate predictors such as
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age, body surface area, gender, aortic insufficiency, aortic stenosis, and aortic valve leaflet orientation were small and did not approach significance. Effects of these candidate predictors were small enough that if these results were to be reproduced in a larger study, we would need to
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enroll more than 600 patients in order to detect a significant effect of the strongest predictors in our current study (age and gender); effects of other potential predictors were even weaker, suggesting that the variables we measured may not have a large influence on the rate of aortic
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dilation in this asymptomatic bicuspid aortic valve population. The family history of aortic valve disease was self-reported and not independently verifiable and likely overestimated the
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prevalence of bicuspid aortic valves among family members.
CONCLUSIONS
We found that among asymptomatic subjects with bicuspid aortic valves, studied
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prospectively, there was an annual rate of ascending aortic dilation of 0.47 mm/year, consistent with rates previously described.3 12 14 Given the prospective design of our study in a pre-defined population of asymptomatic bicuspid aortic valve patients, these results are perhaps more
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generalizable within this population than those of previous retrospective reports, which may have associated biases. The majority of patients’ aortas progressed at a modest rate <1mm/year, 30%
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showed no increase in ascending aortic size and only 15.6% showed ≥ 1mm/year growth. We found, in contrast to previous reports,2 3 that leaflet orientation or aortic valve dysfunction were not independent predictors of aortic dilation. We also observed a higher proportion of women among the right-noncoronary cusp orientation phenotype compared with the more common right-left type (57% vs. 33%; p=0.05). Family history of aortic valve disease and thoracic aortic
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disease was associated with significantly increased risk of progressive aortic dilation, an
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observation that warrants further investigation.
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ACKNOWLEDGMENTS AND STATEMENTS Acknowledgments: None Competing interests: None
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Contributorship:
1. Substantial contributions to the conception or design of the work; or the acquisition,
a. Conception and design: LAP b. Acquisition: LAP, SAA, AYS
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c. Analysis and interpretation: All authors
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analysis, or interpretation of data for the work
2. Drafting the work or revising it critically for important intellectual content a. Drafting: SAA
b. Critical revisions for important intellectual content: All authors
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3. Final approval of the version to be published: All authors
4. Agreement to be accountable for all aspects of the work: All authors Disclosures: None (all authors)
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Source of funding: Supported in part by a grant from the Department of Medicine at the
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University of Massachusetts Medical School
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REFERENCES:
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1. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008;300(11):1317-25. 2. Michelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri RM, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA 2011;306(10):110412. 3. Thanassoulis G, Yip JW, Filion K, Jamorski M, Webb G, Siu SC, et al. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med 2008;5(12):821-8. 4. Fedak PW, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106(8):9004. 5. Nistri S, Sorbo MD, Marin M, Palisi M, Scognamiglio R, Thiene G. Aortic root dilatation in young men with normally functioning bicuspid aortic valves. Heart 1999;82(1):19-22. 6. Keane MG, Wiegers SE, Plappert T, Pochettino A, Bavaria JE, Sutton MG. Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation 2000;102(19 Suppl 3):III35-9. 7. Della Corte A, Bancone C, Buonocore M, Dialetto G, Covino FE, Manduca S, et al. Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve. JACC Cardiovasc Imaging 2013;6(12):1301-10. 8. Ferencik M, Pape LA. Changes in size of ascending aorta and aortic valve function with time in patients with congenitally bicuspid aortic valves. Am J Cardiol 2003;92(1):43-6. 9. Kang JW, Song HG, Yang DH, Baek S, Kim DH, Song JM, et al. Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction and bicuspid aortopathy: comprehensive evaluation using MDCT and echocardiography. JACC Cardiovasc Imaging 2013;6(2):150-61. 10. Albano AJ, Mitchell E, Pape LA. Standardizing the method of measuring by echocardiogram the diameter of the ascending aorta in patients with a bicuspid aortic valve. Am J Cardiol 2010;105(7):1000-4. 11. Bonow RO, Carabello BA, Chatterjee K, De Leon AC, Jr., Faxon DP, Freed MD, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118(15):e523-661. 12. Guntheroth WG. A critical review of the American College of Cardiology/American Heart Association practice guidelines on bicuspid aortic valve with dilated ascending aorta. Am J Cardiol 2008;102(1):107-10. 13. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA, et al. 2014, AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary. J Am Coll Cardiol. 2014;63(22):2438-2488.
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14. Dore A, Brochu MC, Baril JF, Guertin MC, Mercier LA. Progressive dilation of the diameter of the aortic root in adults with a bicuspid aortic valve. Cardiol Young 2003;13(6):52631. 15. Yasuda H, Nakatani S, Stugaard M, Tsujita-Kuroda Y, Bando K, Kobayashi J, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve. Circulation 2003;108 Suppl 1:II291-4. 16. Mahadevia R, Barker AJ, Schnell S, Entezari P, Kansal P, Fedak PW, et al. Bicuspid Aortic Cusp Fusion Morphology Alters Aortic 3D Outflow Patterns, Wall Shear Stress and Expression of Aortopathy. Circulation 2013. 17. Novaro GM, Tiong IY, Pearce GL, Grimm RA, Smedira N, Griffin BP. Features and predictors of ascending aortic dilatation in association with a congenital bicuspid aortic valve. Am J Cardiol 2003;92(1):99-101. 18. Khoo C, Cheung C, Jue J. Patterns of aortic dilatation in bicuspid aortic valve-associated aortopathy. J Am Soc Echocardiogr 2013;26(6):600-5. 19. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol 1997;30(7):1809-12. 20. La Canna G, Ficarra E, Tsagalau E, Nardi M, Morandini A, Chieffo A, et al. Progression rate of ascending aortic dilation in patients with normally functioning bicuspid and tricuspid aortic valves. Am J Cardiol 2006;98(2):249-53. 21. Fedak PW, de Sa MP, Verma S, Nili N, Kazemian P, Butany J, et al. Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J Thorac Cardiovasc Surg 2003;126(3):797-806. 22. Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007;39(12):1488-93. 23. Pisano C, Maresi E, Balistreri CR, Candore G, Merlo D, Fattouch K, et al. Histological and genetic studies in patients with bicuspid aortic valve and ascending aorta complications. Interact Cardiovasc Thorac Surg 2012;14(3):300-6.
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FIGURE LEGENDS Figure 1: (A) Baseline and endpoint aortic diameter (mm) measured at end-systole (B) Annual rate of aortic dilation in the study population
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Figure 2: Univariate analysis of potential predictors (A) Annual rate of aortic dilation in mm/year (B) Percentage of subjects with aortic dilation >0mm/year HTN = hypertension, NS= non-significant
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Table 1: Baseline characteristics of the overall study population and by valve cusp fusion orientation
Age, yrs (N=90)
R-L cusp orientation (N=69) 41.8 ± 12.9
R-N cusp orientation (N=21) 41.9 ± 12.9
p value 0.97
35 (39)
23 (33)
12 (57)
0.050
1.9 ± 0.3
1.9 ± 0.3
1.8 ± 0.2
0.11
61 (72)
47 (71)
14 (74)
0.83
13 (15)
9 (14)
4 (21)
0.44
15 (18)
13 (20)
2 (11)
0.36
28 (35)
20 (33)
8 (42)
0.46
39 (49)
29 (48)
10 (53)
0.74
88 ± 8.2 16 (19)
89 ± 8.7 9 (14)
84 ± 4.3 7 (35)
0.29 0.034
34.9 ± 5.9
37.6 ± 3.9
0.050
Female (N=90) BSA, m2 (N=85)
Stenosis (≥moderate)
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Insufficiency (≥moderate) History of hypertension (N=80) Antihypertensive medication use (N=79) Mean arterial pressure (mm Hg) (N=84) Family history of aortic valve disease (self-reported) (N=85) Ascending aorta diameter, mm (N=90)
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Normal
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Valve function (N=90)
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Variable
All patients (N=90) 41.8 ± 12.8
35.5 ± 5.6
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35 ± 5.5 34.7 ± 5.8 35.9 ± 4 0.39 SoV diameter, mm (N=90) Values are mean ± SD or n (%). p-values are for R-L versus R-N (unpaired Student t or chi-square test). BSA = body surface area; R-L = right-left coronary cusp fusion; R-N = rightnoncoronary cusp fusion; SoV = Sinus of Valsalva
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Table 2: Multivariate analysis of potential predictors of progression – logistic regression Variable
Odds ratio
p-value
(95% confidence interval) 13.61 (1.42-130.12)
disease BSA
4.36 (0.31-60.52)
Age
0.95 (0.91-0.99) 0.60 (0.007-212.5)
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BSA = body surface area
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0.272
0.034
0.937
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Female gender
0.023
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Family history of aortic valve
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Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a Five Year Prospective Study
•
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CLINICAL SIGNIFICANCE
Progression of aortic dilation in asymptomatic patients with bicuspid aortic valves
Annual rate of ascending aortic dilation was 0.47 mm/ year
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In 15.6% of subjects, rate of ascending aortic dilation exceeded 1mm/year
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Family history of aortic valve disease is a predictor of progressive aortic dilation
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Previously reported predictors of aortic dilation (including leaflet orientation
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and valve dysfunction) were not significant
S0002-9343(15)00075-3
DOI:
10.1016/j.amjmed.2014.12.027
Reference:
AJM 12847
To appear in:
The American Journal of Medicine
Received Date: 6 December 2014 Revised Date:
31 December 2014
Accepted Date: 31 December 2014
Please cite this article as: Avadhani SA, Martin-Doyle W, Shaikh AY, Pape LA, Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a Five-Year Prospective Study, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2014.12.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a FiveYear Prospective Study Authors: Sriya A. Avadhani, MD1; William Martin-Doyle, MD, MPH2; Amir Y. Shaikh, MD3;
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Linda A. Pape, MD3
1. Department of Medicine, State University of New York (SUNY) Downstate Health Science Center, Brooklyn, NY
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2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA
Type of Study: Clinical Research Study
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3. Department of Medicine, University of Massachusetts Medical School, Worcester, MA
Corresponding author: Linda A. Pape, MD
Division of Cardiology, Department of Medicine, University of Massachusetts Medical School,
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55 Lake Ave N, Worcester, MA 01655 Tel: 508-856-3050, Fax: 508-856-4571 Email: [email protected]
Echocardiography
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Keywords: Aortic dilation; Bicuspid aortic valve; Aortic stenosis; Aortic regurgitation;
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Word count: 2893 (excluding abstract, clinical significance, acknowledgments, references, tables, and figures)
Number of figures: 2; Number of tables: 2 Funding: Department of Medicine, University of Massachusetts Medical School Conflicts of Interest: None Disclosure: All authors had access to data and were involved in writing the manuscript.
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ABSTRACT Background: Bicuspid aortic valves are associated with aortic dilation and dissection. There is a paucity of prospective studies evaluating changes in aortic size over time in adult subjects with
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bicuspid aortic valves.
Methods: A total of 115 subjects with asymptomatic bicuspid aortic valves were enrolled from 2003-2008 and followed prospectively over 5 years. Clinical and family histories as well as
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transthoracic echocardiograms were obtained at baseline and echocardiograms were performed annually thereafter.
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Results: Mean age of subjects was 41.8± 12.8 years, 61% male. Ascending aortic size at baseline averaged 35.5±5.6 mm and increased in 71.1% of subjects (mean 0.66±0.05 mm/year; range 0.2-2.3 mm/yr) over an average of 4.8 years. In 15.6% of subjects, the rate of change exceeded 1mm/yr. The average rate of ascending aortic dilation for all subjects was 0.47±0.05
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mm/ year (p<0.001). Family history of aortic valve disease was associated with progression in both unadjusted (p=0.029) and logistic regression analysis adjusted for age, gender, and body surface area (OR 13.7, p=0.021). Multivariate analysis did not find leaflet orientation or
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moderate to severe aortic valve dysfunction as independent predictors of aortic dilation. Conclusion: In conclusion, we found that in bicuspid aortic valve subjects, studied
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prospectively, there was an annual rate of ascending aortic dilation of 0.47 mm/year. In contrast to previous reports, leaflet orientation and aortic valve dysfunction were not independent predictors of aortic dilation. Family history of aortic valve disease was associated with significantly increased risk of increasing ascending aortic size.
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INTRODUCTION Bicuspid aortic valve, the most common congenital cardiac abnormality in adults, is estimated to be present in 0.5 -1.5% of the population. While survival among subjects with bicuspid aortic
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valves in published studies is similar to that of the general population, there is a greater incidence of cardiac and aortic complications.1 The clinical presentation of bicuspid aortic valve disease ranges from asymptomatic subjects to those with aortic stenosis and or insufficiency,
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endocarditis, aortic dilation and aortic dissection.1-3 Aortic stenosis is the most common reason for aortic valve replacement among bicuspid aortic valve patients.4
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An important non-valvular association of bicuspid aortic valve is thoracic aortic dilation, in the past referred to as post-stenotic dilation.1 4 While hemodynamic factors such as shear stress likely play a role, there is growing recognition that bicuspid aortic valve associated aortopathy has genetic causes and cannot be accounted for by hemodynamic factors alone.5 6 Because as a
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group, bicuspid aortic valve patients have been shown to have larger aortic diameters than controls,5 and because bicuspid aortic valve patients have approximately an 8 times greater risk of aortic dissection2 than the normal population, predictors of aortic dilation have been sought.
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Most of the data, however, on bicuspid aortic valve associated aortic complications comes from retrospective studies involving subjects who are surgical candidates or have
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significant coexistent valve dysfunction.2 3 7 In 2003 our group showed, in a retrospective study, that many bicuspid aortic valve patients with nearly normal baseline valve function have progression of aortic dilation similar to bicuspid aortic valve patients with valve dysfunction.8 There are few prospective studies of the progression of aortic disease in asymptomatic bicuspid aortic valve subjects.1 Some have tried to demonstrate a correlation between valve morphology and aortic dilation.7 9 Until genetic testing is available to identify those at greatest risk for aortic
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complications, having clinical predictors of these complications might be useful. The objective of the current study was to evaluate prospectively possible clinical and echocardiographic predictors of progressive aortic dilation among asymptomatic adult subjects with bicuspid aortic
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valves.
METHODS
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This study was approved by the institutional review board of the University of
Massachusetts Medical School. Between 2003 and 2008, 115 asymptomatic subjects with the
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echocardiographic diagnosis of bicuspid aortic valve and no prior cardiac surgery were recruited at the University of Massachusetts Medical School. Subjects gave written informed consent, and underwent baseline and yearly echocardiography for five years. Clinical information was obtained from patient interviews at the time of enrollment and at least at the first follow-up
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appointment.
Baseline data included age, sex, body surface area (BSA), cardiac medications, cardiac symptoms, prior cardiac interventions, family history of aortic valve disease, other
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congenital/valvular disease, and coronary risk factors. Standard transthoracic echocardiograms were performed; bicuspid aortic valve morphology and cusp orientation were confirmed in short
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axis views. Aortic root measurements were made inner edge to inner edge in the parasternal long axis view; the sinuses of Valsalva at end diastole and the ascending aorta at end systole. We have previously demonstrated that maximal ascending aortic size in bicuspid aortic valve patient with aortic dilation usually occurs at least 2-3 centimeters above the sinotubular junction and that a greater length of aorta can usually be imaged at end systole.10 In cases with effacement or poor imaging of the sinotubular junction the ascending aorta was measured 4 cm above the valve
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plane. The largest ascending aortic diameter was recorded at baseline and at follow-up. For purposes of this analysis, we compared the initial measurement with the final measurement.
stenosis (AS) and/or aortic insufficiency (AI).
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Other echocardiographic data included ejection fraction (EF), presence and degree of aortic
Two observers, blinded to patient information, measured aortic diameters and cusp fusion independently. Inter-observer reliability was assessed by the intraclass correlation
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coefficient.
Aortic stenosis was graded based on the peak systolic gradient. Mild aortic stenosis was
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defined as a peak pressure gradient less than 25 mm Hg, moderate between 25-36 mm Hg, and severe as 36-64 mm Hg. Aortic regurgitation was graded based on Doppler criteria including jet height/left ventricle outflow tract height ratio in parasternal long-axis views, jet area/left ventricle outflow area ratio and pressure halftime by spectral Doppler. Aortic insufficiency was
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graded as mild, moderate or severe. Cusp orientation was classified as either right-left (R-L) cusp fusion or right-noncoronary (R-N) cusp fusion. A blinded observer determined the presence and grade of aortic stenosis and aortic insufficiency, and cusp orientation.
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Outcomes used included a) annual rate of aortic dilation, estimated as the difference between final aortic diameter and baseline aortic diameter, divided by number of years of follow-
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up, and b) presence of any aortic size progression: subjects with no increase in aortic diameter from baseline to follow-up were considered to have no progression, and subjects with any increase in aortic diameter >0 mm were considered to have progression. Statistical analysis was performed using Stata (Version 12, StataCorp, College Station,
Texas). Baseline statistics are presented as mean ± standard deviation (continuous variables) or as proportions (binary and categorical variables). In univariate analyses, differences in
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proportions of subjects with any progression were tested using Fisher’s exact test and differences in means for annual rate of change by two-sample t-tests with unequal variances. Multivariate analysis by linear regression of annual rates of change, and logistic regression models predicting
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presence of any aortic progression were used to identify independent predictors of aortic dilation. Variables associated with progressive aortic dilation (p<0.05) in univariate analysis were entered into multivariate models controlling for age, gender, and baseline body surface area as a priori
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clinically relevant potential confounding variables. Variables considered as potential predictors are shown in Table 1. Missing data was addressed by complete case analysis, including patients
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lost to follow-up. Multilevel linear regression and logistic regression analyses were also conducted as a sensitivity analysis, using random effects to account for correlation in aortic diameter over time within individuals. A p value <0.05 was considered significant.
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RESULTS
Of the 115 subjects originally enrolled, 18 were excluded because of aortic valve replacement within 3 years of enrollment and 7 were excluded for <3 years of follow-up data
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(lost to follow-up). Ninety subjects had 3-5 years of follow-up data and no prior aortic valve replacement. Of these 90 subjects, 6 had subsequent valve replacements after enrollment, but had
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at least three annual echocardiograms prior to surgery and were included in the analysis. The inter-observer reliability for measurement of aortic diameter, assessed by the intraclass correlation coefficient, was 97.5% (95% CI: 95.6%-98.6%). Average age at diagnosis was 41.8 years and mean follow-up was 4.8 years (median 5
years, range 3-5 years). The average baseline ascending aortic diameter was 35.5mm (±5.6mm). Sixty-nine subjects (77%) had right-left cusp fusion, 21 (23%) had right-noncoronary cusp
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fusion, 15 (17.6%) had moderate to severe aortic insufficiency, and 13 (14%) had moderatesevere aortic stenosis. Baseline characteristics are described in Table 1. Aortic size increased in 64 (71%) subjects (mean 0.66±0.05 mm/yr; range 0.2-2.3 mm/yr)
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over a mean follow up of 4.8 years (median follow up 5 years). In 14 (15.6%) subjects the rate of change exceeded 1mm/yr (Figure 1). The average rate of ascending aortic dilation for all subjects was 0.47±0.05 mm/year (p<0.001). Although a history of hypertension was inversely associated
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with ascending aortic dilation (0.54 mm/yr with hypertension vs. 0.30 mm/yr without, p=0.022), it was not an independent predictor (p=0.159). Family history of aortic valve disease (self-
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reported family history of bicuspid aortic valve, aortic valve surgery, aortic stenosis, aortic insufficiency, or thoracic aortic aneurysm) was associated with progression in both unadjusted (p=0.03), and logistic regression analysis adjusted for age, gender, and body surface area (OR 13.6, p=0.023) (Table 2).
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As a sensitivity analysis, we also evaluated multilevel linear regression models of aortic diameter over time, as well as multilevel logistic regression models predicting presence or absence of progression of aortic dilation, with random effects to account for intra-subject
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correlation over time. Results (not shown) were similar to non-multilevel results presented in Tables 1 and 2, with family history of aortic valve disease emerging as the only significant
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predictor of progression.
Patients with right-noncoronary cusp fusion (N=21) had higher baseline ascending aortic
diameters compared to those with right-left cusp fusion (37.6 mm versus 34.9 mm; p=0.049), but no difference was observed in rate of aortic dilation. In these two groups, unadjusted rates of aortic dilation were 0.47 mm/year for subjects with right-left cusp fusion, vs. 0.46 mm/year for those with right-noncoronary cusp fusion, p=0.95 (Figure 2). There was no significant
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association between family history of aortic valve disease and cusp morphology (p=0.78). Multivariate analysis did not find leaflet orientation or the presence of moderate to severe aortic
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valve dysfunction as independent predictors of aortic dilation.
DISCUSSION
The large number of studies published in recent years on the subject of aortic dilation in
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bicuspid aortic valve patients attests to the growing awareness of, and interest in predicting aortic complications in these patients. The 2008 guidelines for surgical repair of aortic dilation with
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bicuspid aortic valves include an aortic diameter of >5cm or diameter >4.5cm and a yearly dilation rate >0.5cm/yr.11 Other indications include aortic diameter >4cm in a patient undergoing elective aortic valve replacement.11 However these guidelines are not supported by strong evidence and are based on expert opinion alone. There has been considerable controversy about
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these guidelines which are similar to those for Marfan syndrome and are not widely accepted as appropriate for bicuspid aortic valve patients whose rate of aortic complications, while much greater than the general population, are much less than for Marfan syndrome patients.12 Thus, the
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2014 guidelines were changed back to 5.5 cm for bicuspid aortic valve patients.13 Since the ascending aorta is the segment in bicuspid aortic valve subjects that most often
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develops aneurysmal dilation or, rarely dissection, requiring surgery, we were most interested in assessing in a prospective manner factors that might predict progressive dilation of this segment. Could we eventually determine which subjects with bicuspid aortic valves are at risk for aortic complications and need close follow up and, on the other hand, which patients might be reassured that their risk is low?
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In this prospective study evaluating the progression of aortic size in asymptomatic subjects with bicuspid aortic valves, we found an overall annual rate of 0.47 mm/year; a rate which is in agreement with the range of progression found in earlier retrospective studies,
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reported to be between 0.18-1.0 mm/year,3 14 15 and lower than the rate of 0.9 mm/year reported in our own previous retrospective study.8 The aortas of 30% of subjects did not increase in size over the study period similar to the 32% reported in Della Corte et al.’s study.7 In only 14
not predict progression, nor did valve dysfunction.
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(15.6%) of our patients did growth equal or exceed 1 mm/year. Baseline aortic size in itself did
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Retrospective study populations will differ from prospective ones. For example: in our retrospective study8 the rate of aortic size increase was twice that in the current prospective study. Differences in patient selection among study populations, pre-surgical patients, community studies, symptomatic, asymptomatic, echo database searches, etc. will account for
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some of the differences in results and conclusions.
Della Corte et al recently reported a retrospective series of 133 bicuspid aortic valve patients, 48% of whom were referred for symptoms, with mean and median follow up of 4 and 3
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years respectively.7 Fifty percent of the patients had ≥moderate aortic stenosis or insufficiency and 40% underwent aortic and/or aortic valve surgery. The male to female ratio was 3:1. That
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study concluded that aortic phenotype predicted complications. Thanassoulis et al., in a retrospective study of 156 patients, 60% of whom had moderate aortic regurgitation or stenosis with 3.8 years mean follow up, found that right-left cusp orientation was associated with rapid aortic growth.3
Our patients, on the other hand, were asymptomatic at enrollment and followed prospectively; mean and median follow up were 4.8 and 5 years respectively. Only 31% had
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≥moderate valve dysfunction and only 6 (6%) underwent aortic valve replacement. The male to female ratio in our study was 3:2, lower than the generally reported ratio of 2:1. Also in contrast to Della Corte et al.7, we found that patients with right-noncoronary cusp fusion at baseline had
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greater ascending aortic size than patients with right-left cusp fusion. We found that cusp orientation did not predict an increase in aortic size; only family history predicted progressive enlargement.
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Cusp orientation is thought to arise from different developmental mechanisms associated with possibly different aortic vulnerability. Cusp fusion morphology has been shown by recent
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elegant 3 and 4D magnetic resonance imaging (MRI) studies to determine flow pattern and wall shear stress, and thus likely impacts aortic pathology.16 In contrast to prior studies,2 3 we did not identify aortic valve dysfunction or cusp morphology as significant predictors of the rate of progressive aortic dilation. Hemodynamic factors related to valve function and morphology have
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been associated with a faster rate of aortic dilation in some bicuspid aortic valve subjects. The correlation of severe aortic insufficiency with aortic root dilation is thought to be due to higher wall tension and larger stroke volumes.6 There is also speculation that since stenotic aortic valves
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increase shear stress on the aortic wall, stenosis increases the likelihood of aortic dilation; however, there is conflicting evidence17 for the correlation of bicuspid aortic valve cusp
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morphology and aortic dilation.3 18 None of these hemodynamic factors alone are clearly predictive of aortic dilation with bicuspid aortic valves. Familial clustering and genetic studies identify a high prevalence of bicuspid aortic valve
disease among first degree relatives of affected members.19 Bicuspid aortic valve disease is inherited in an autosomal dominant pattern with variable expressivity. Up to one-third of family members of bicuspid aortic valve patients have been shown to have aortic dilation even with
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tricuspid aortic valves. The presence of aortic dilation in the absence of valve dysfunction and its persistence after aortic valve replacement suggests that aortic dilation may be independent of hemodynamic factors.15 20 Deficiency of fibrillin-1 gene and increased activity of MMP-1 gene
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have been identified in bicuspid aortic valve subjects resulting in a fragile aorta, less suited to deal with stress associated with valvular dysfunction.21 Numerous genes and genetic syndromes are associated with the bicuspid aortic valve and/or thoracic aortic dilation. Mutations in the
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TGFBR1 and 2 genes, ACTA2 gene, and multiple single nucleotide polymorphisms have been implicated in thoracic aneurysm formation in bicuspid aortic valve subjects.22 23
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We found that family history of aortic valve disease (including bicuspid aortic valves, aortic valve replacements, aortic stenosis, aortic insufficiency or thoracic aortic disease) was reported by 21% of our patients and was an independent predictor for progressive aortic dilation. While it is known that approximately 10% of bicuspid aortic valve cases are familial, ours is the
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first study we are aware of that has shown family history to be a significant predictor of increased risk of progressive aortic dilation. While family history was a significant predictor of any progression of aortic dilation in logistic regression, we did not find that family history
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predicted the annual rate of aortic dilation in linear models. However, it is not clear that a relationship between family history and aortic dilation should be expected to be linear,
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potentially limiting the sensitivity of linear regression to detect an association. Limitations
This study had relatively modest sample size and therefore somewhat limited power to
detect significant predictors of the rate of aortic dilation. Unlike other reports it is unique in being a prospective study of asymptomatic patients, the majority of whom had little or no valve dysfunction at the time of enrollment. The effects we observed for candidate predictors such as
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age, body surface area, gender, aortic insufficiency, aortic stenosis, and aortic valve leaflet orientation were small and did not approach significance. Effects of these candidate predictors were small enough that if these results were to be reproduced in a larger study, we would need to
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enroll more than 600 patients in order to detect a significant effect of the strongest predictors in our current study (age and gender); effects of other potential predictors were even weaker, suggesting that the variables we measured may not have a large influence on the rate of aortic
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dilation in this asymptomatic bicuspid aortic valve population. The family history of aortic valve disease was self-reported and not independently verifiable and likely overestimated the
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prevalence of bicuspid aortic valves among family members.
CONCLUSIONS
We found that among asymptomatic subjects with bicuspid aortic valves, studied
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prospectively, there was an annual rate of ascending aortic dilation of 0.47 mm/year, consistent with rates previously described.3 12 14 Given the prospective design of our study in a pre-defined population of asymptomatic bicuspid aortic valve patients, these results are perhaps more
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generalizable within this population than those of previous retrospective reports, which may have associated biases. The majority of patients’ aortas progressed at a modest rate <1mm/year, 30%
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showed no increase in ascending aortic size and only 15.6% showed ≥ 1mm/year growth. We found, in contrast to previous reports,2 3 that leaflet orientation or aortic valve dysfunction were not independent predictors of aortic dilation. We also observed a higher proportion of women among the right-noncoronary cusp orientation phenotype compared with the more common right-left type (57% vs. 33%; p=0.05). Family history of aortic valve disease and thoracic aortic
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disease was associated with significantly increased risk of progressive aortic dilation, an
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observation that warrants further investigation.
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ACKNOWLEDGMENTS AND STATEMENTS Acknowledgments: None Competing interests: None
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Contributorship:
1. Substantial contributions to the conception or design of the work; or the acquisition,
a. Conception and design: LAP b. Acquisition: LAP, SAA, AYS
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c. Analysis and interpretation: All authors
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analysis, or interpretation of data for the work
2. Drafting the work or revising it critically for important intellectual content a. Drafting: SAA
b. Critical revisions for important intellectual content: All authors
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3. Final approval of the version to be published: All authors
4. Agreement to be accountable for all aspects of the work: All authors Disclosures: None (all authors)
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Source of funding: Supported in part by a grant from the Department of Medicine at the
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University of Massachusetts Medical School
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REFERENCES:
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1. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008;300(11):1317-25. 2. Michelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri RM, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA 2011;306(10):110412. 3. Thanassoulis G, Yip JW, Filion K, Jamorski M, Webb G, Siu SC, et al. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med 2008;5(12):821-8. 4. Fedak PW, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106(8):9004. 5. Nistri S, Sorbo MD, Marin M, Palisi M, Scognamiglio R, Thiene G. Aortic root dilatation in young men with normally functioning bicuspid aortic valves. Heart 1999;82(1):19-22. 6. Keane MG, Wiegers SE, Plappert T, Pochettino A, Bavaria JE, Sutton MG. Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation 2000;102(19 Suppl 3):III35-9. 7. Della Corte A, Bancone C, Buonocore M, Dialetto G, Covino FE, Manduca S, et al. Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve. JACC Cardiovasc Imaging 2013;6(12):1301-10. 8. Ferencik M, Pape LA. Changes in size of ascending aorta and aortic valve function with time in patients with congenitally bicuspid aortic valves. Am J Cardiol 2003;92(1):43-6. 9. Kang JW, Song HG, Yang DH, Baek S, Kim DH, Song JM, et al. Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction and bicuspid aortopathy: comprehensive evaluation using MDCT and echocardiography. JACC Cardiovasc Imaging 2013;6(2):150-61. 10. Albano AJ, Mitchell E, Pape LA. Standardizing the method of measuring by echocardiogram the diameter of the ascending aorta in patients with a bicuspid aortic valve. Am J Cardiol 2010;105(7):1000-4. 11. Bonow RO, Carabello BA, Chatterjee K, De Leon AC, Jr., Faxon DP, Freed MD, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118(15):e523-661. 12. Guntheroth WG. A critical review of the American College of Cardiology/American Heart Association practice guidelines on bicuspid aortic valve with dilated ascending aorta. Am J Cardiol 2008;102(1):107-10. 13. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA, et al. 2014, AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary. J Am Coll Cardiol. 2014;63(22):2438-2488.
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14. Dore A, Brochu MC, Baril JF, Guertin MC, Mercier LA. Progressive dilation of the diameter of the aortic root in adults with a bicuspid aortic valve. Cardiol Young 2003;13(6):52631. 15. Yasuda H, Nakatani S, Stugaard M, Tsujita-Kuroda Y, Bando K, Kobayashi J, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve. Circulation 2003;108 Suppl 1:II291-4. 16. Mahadevia R, Barker AJ, Schnell S, Entezari P, Kansal P, Fedak PW, et al. Bicuspid Aortic Cusp Fusion Morphology Alters Aortic 3D Outflow Patterns, Wall Shear Stress and Expression of Aortopathy. Circulation 2013. 17. Novaro GM, Tiong IY, Pearce GL, Grimm RA, Smedira N, Griffin BP. Features and predictors of ascending aortic dilatation in association with a congenital bicuspid aortic valve. Am J Cardiol 2003;92(1):99-101. 18. Khoo C, Cheung C, Jue J. Patterns of aortic dilatation in bicuspid aortic valve-associated aortopathy. J Am Soc Echocardiogr 2013;26(6):600-5. 19. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol 1997;30(7):1809-12. 20. La Canna G, Ficarra E, Tsagalau E, Nardi M, Morandini A, Chieffo A, et al. Progression rate of ascending aortic dilation in patients with normally functioning bicuspid and tricuspid aortic valves. Am J Cardiol 2006;98(2):249-53. 21. Fedak PW, de Sa MP, Verma S, Nili N, Kazemian P, Butany J, et al. Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J Thorac Cardiovasc Surg 2003;126(3):797-806. 22. Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007;39(12):1488-93. 23. Pisano C, Maresi E, Balistreri CR, Candore G, Merlo D, Fattouch K, et al. Histological and genetic studies in patients with bicuspid aortic valve and ascending aorta complications. Interact Cardiovasc Thorac Surg 2012;14(3):300-6.
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FIGURE LEGENDS Figure 1: (A) Baseline and endpoint aortic diameter (mm) measured at end-systole (B) Annual rate of aortic dilation in the study population
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Figure 2: Univariate analysis of potential predictors (A) Annual rate of aortic dilation in mm/year (B) Percentage of subjects with aortic dilation >0mm/year HTN = hypertension, NS= non-significant
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Table 1: Baseline characteristics of the overall study population and by valve cusp fusion orientation
Age, yrs (N=90)
R-L cusp orientation (N=69) 41.8 ± 12.9
R-N cusp orientation (N=21) 41.9 ± 12.9
p value 0.97
35 (39)
23 (33)
12 (57)
0.050
1.9 ± 0.3
1.9 ± 0.3
1.8 ± 0.2
0.11
61 (72)
47 (71)
14 (74)
0.83
13 (15)
9 (14)
4 (21)
0.44
15 (18)
13 (20)
2 (11)
0.36
28 (35)
20 (33)
8 (42)
0.46
39 (49)
29 (48)
10 (53)
0.74
88 ± 8.2 16 (19)
89 ± 8.7 9 (14)
84 ± 4.3 7 (35)
0.29 0.034
34.9 ± 5.9
37.6 ± 3.9
0.050
Female (N=90) BSA, m2 (N=85)
Stenosis (≥moderate)
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Insufficiency (≥moderate) History of hypertension (N=80) Antihypertensive medication use (N=79) Mean arterial pressure (mm Hg) (N=84) Family history of aortic valve disease (self-reported) (N=85) Ascending aorta diameter, mm (N=90)
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Valve function (N=90)
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Variable
All patients (N=90) 41.8 ± 12.8
35.5 ± 5.6
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35 ± 5.5 34.7 ± 5.8 35.9 ± 4 0.39 SoV diameter, mm (N=90) Values are mean ± SD or n (%). p-values are for R-L versus R-N (unpaired Student t or chi-square test). BSA = body surface area; R-L = right-left coronary cusp fusion; R-N = rightnoncoronary cusp fusion; SoV = Sinus of Valsalva
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Table 2: Multivariate analysis of potential predictors of progression – logistic regression Variable
Odds ratio
p-value
(95% confidence interval) 13.61 (1.42-130.12)
disease BSA
4.36 (0.31-60.52)
Age
0.95 (0.91-0.99) 0.60 (0.007-212.5)
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BSA = body surface area
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0.034
0.937
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Female gender
0.023
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Family history of aortic valve
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Predictors of Ascending Aortic Dilation in Bicuspid Aortic Valve Disease - a Five Year Prospective Study
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CLINICAL SIGNIFICANCE
Progression of aortic dilation in asymptomatic patients with bicuspid aortic valves
Annual rate of ascending aortic dilation was 0.47 mm/ year
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In 15.6% of subjects, rate of ascending aortic dilation exceeded 1mm/year
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Family history of aortic valve disease is a predictor of progressive aortic dilation
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Previously reported predictors of aortic dilation (including leaflet orientation
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and valve dysfunction) were not significant