Outcomes in Adults
With Bicuspid Aortic Valves
Nikolaos Tzemos, MD Judith Therrien, MD James Yip, MD George Thanassoulis, MD Sonia Tremblay, MD Michal T. Jamorski, BSc Gary D. Webb, MD Samuel C. Siu, MD, SMB
ICUSPID AORTIC VALVE IS THEmost common congenital car-diac anomaly in the adult population.1-3 Prior studies have reported significant mortality and morbidity in patients with bicuspid aor-tic valve related to the development of aortic valve dysfunction, endocardi-tis, and dissection.1,4,5It is uncertain whether these prior findings, based on necropsy and surgical series from ear-lier eras, can be applied to a contem-porary patient population.1,6,7The pur-pose of this cohort study was to examine the cardiac outcomes and dis-ease progression in a large contempo-rary group of adults with bicuspid aor-tic valve followed up over a prolonged period of observation.
METHODS
This cohort study examined a referral population of consecutive adults with bi-cuspid aortic valve assessed at the Uni-versity Health Network (Toronto Gen-eral and Toronto Western Hospitals, Toronto, Ontario, Canada) ambulatory cardiac clinics from 1994 through 2001. Patients were identified using the hos-pital’s echocardiography and congeni-tal cardiac databases. The University Health Network is the main congenital cardiac center for the city of Toronto. The
inclusion criteria were bicuspid aortic valve documented on transthoracic ech-ocardiography and the absence of
com-plex congenital cardiac defects. We ex-cluded 260 patients who were referred for cardiac surgery, catheter-based
treat-Author Affiliations:Peter Munk Cardiac Centre and Toronto Congenital Cardiac Centre for Adults, Uni-versity Health Network, UniUni-versity of Toronto, Toronto, Ontario, Canada (Drs Tzemos and Siu and Mr Jamor-ski); Department of Cardiology, National University Hospital, Singapore (Dr Yip); Sir M. B. Davis Jewish General Hospital, Department of Medicine, McGill Uni-versity, Montreal, Quebec, Canada (Drs Therrien, Tha-nassoulis, and Tremblay); Philadelphia Adult Congenital
Heart Center, Children’s Hospital of Philadelphia, De-partment of Medicine, University of Pennsylvania, Philadelphia (Dr Webb); and Division of Cardiology, University of Western Ontario, London, Ontario, Canada (Dr Siu).
Corresponding Author:Samuel Siu, MD, SM, C6-005, University Hospital, 339 Windermere Rd, London, Ontario, Canada N6A 5A5 (Samuel.Siu@lhsc .on.ca).
Context Bicuspid aortic valve is the most common congenital cardiac anomaly in the adult population. Cardiac outcomes in a contemporary population of adults with bi-cuspid aortic valve have not been systematically determined.
Objective To determine the frequency and predictors of cardiac outcomes in a large consecutive series of adults with bicuspid aortic valve.
Design, Setting, and Participants Cohort study examining cardiac outcomes in 642 consecutive ambulatory adults (mean [SD] age, 35 [16] years; 68% male) with bi-cuspid aortic valve presenting to a Canadian congenital cardiac center from 1994 through 2001 and followed up for a mean (SD) period of 9 (5) years. Frequency and predictors of major cardiac events were determined by multivariate analysis. Mortality rate in the study group was compared with age- and sex-matched population estimates. Main Outcome Measures Mortality and cause of death were determined. Pri-mary cardiac events were defined as the occurrence of any of the following compli-cations: cardiac death, intervention on the aortic valve or ascending aorta, aortic dis-section or aneurysm, or congestive heart failure requiring hospital admission during the follow-up period.
Results During the follow-up period, there were 28 deaths (mean [SD], 4% [1%]). One or more primary cardiac events occurred in 161 patients (mean [SD], 25% [2%]), which included cardiac death in 17 patients (mean [SD], 3% [1%]), intervention on aortic valve or ascending aorta in 142 patients (mean [SD], 22% [2%]), aortic dissec-tion or aneurysm in 11 patients (mean [SD], 2% [1%]), or congestive heart failure requiring hospital admission in 16 patients (mean [SD], 2% [1%]). Independent pre-dictors of primary cardiac events were age older than 30 years (hazard ratio [HR], 3.01; 95% confidence interval [CI], 2.15-4.19;P⬍.001), moderate or severe aortic stenosis (HR, 5.67; 95% CI, 4.16-7.80;P⬍.001), and moderate or severe aortic regurgitation (HR, 2.68; 95% CI, 1.93-3.76;P⬍.001). The 10-year survival rate of the study group (mean [SD], 96% [1%]) was not significantly different from population estimates (mean [SD], 97% [1%];P=.71). At last follow-up, 280 patients (mean [SD], 45% [2%]) had dilated aortic sinus and/or ascending aorta.
Conclusions In this study population of young adults with bicuspid aortic valve, age, severity of aortic stenosis, and severity of aortic regurgitation were independently as-sociated with primary cardiac events. Over the mean follow-up duration of 9 years, survival rates were not lower than for the general population.
ment, or obstetric care, and those from outside of Ontario. The study popula-tion was comprised of 642 patients. There were 148 patients who were origi-nally included in a preliminary ancil-lary echocardiographic study of aortic di-latation, which excluded clinical outcomes and had a short duration of fol-low-up.8The study protocol was ap-proved by the research ethics board of the University Health Network, which enabled access to health records and imaging data as well as telephone con-tact with patients and their physicians for determination of outcomes. Verbal in-formed consent was obtained in pa-tients in whom clinical follow-up data were obtained by telephone.
Assessments
Baseline data were obtained from the rec-ord of the patient’s first visit to the am-bulatory cardiac clinic. Baseline data in-cluded age, sex, prior cardiac procedures, coronary risk factors, cardiac medica-tions, symptomatic status, and echocar-diographic parameters. Follow-up data up to December 2007 were obtained by review of health records, which in-cluded summaries of ambulatory clinic visits, procedures, and hospital admis-sions. For those patients who were not scheduled or were unable to return for evaluation during the 2007 calendar year, follow-up information was obtained by a scripted telephone interview with the patients or their physicians.
Comprehensive transthoracic echo-cardiography was performed at the first ambulatory visit and again at the most recent follow-up visit. Bicuspid aortic valve was diagnosed when only 2 cusps were clearly identified in the short axis view. Aortic stenosis was classified as mild (valve area⬎1.5 cm2; peak gradi-ent⬍36 mm Hg), moderate (valve area, 1.0-1.5 cm2; peak gradient, 36-64 mm Hg), or severe (valve area⬍1.0 cm2; peak gradient⬎64 mm Hg).9Aortic re-gurgitation was classified as mild, mod-erate, or severe using an integrated ap-proach incorporating the following color and continuous flow Doppler criteria: ra-tio of regurgitant jet height to left ven-tricular outflow tract height, ratio of
re-gurgitant jet area to left ventricular outflow tract area, regurgitant jet decel-eration rate (pressure half-time), and presence of pandiastolic retrograde flow in the descending aorta.10This inte-grated approach accounts for the known difficulties in using a single method in the assessment of eccentric or multiple regurgitant jets. In those patients who had not undergone prior intervention on the aortic valve and in whom leaflet ori-entation could be visualized, the spatial orientation of bicuspid aortic valve leaf-lets was classified into either right-left (from right noncoronary cusps fusion) or anterior-posterior (usually from right-left coronary cusps fusion and rarely from left noncoronary cusps fusion) (FIGURE1).11,12End diastolic measure-ments of aortic sinus (at the sinus of Valsalva level) and proximal ascend-ing aortic dimensions were per-formed.13Dilated aortic sinus and as-c e n d i n g a o r t a w e r e d e f i n e d b y dimensions of greater than 35 mm and greater than 34 mm, respectively.14Left ventricular ejection fraction was cal-culated.15Significant coarctation of the aorta was diagnosed based on stan-dard criteria.5
A subset of patients underwent car-diac magnetic resonance (CMR) as part of the recently implemented (since 2001) follow-up template for patients with bicuspid aortic valve and/or coarcta-tion. Aortic dimensions were assessed using standardized CMR pulse sequence protocols as reported previously.16For patients in whom CMR was contrain-dicated, chest computed tomography (CT) was performed. For the purpose of this analysis, CMR and CT results were combined and the threshold for the diag-nosis of aortic sinus and ascending aorta dilation was the same as in echocardi-ography (⬎35 mm for aortic sinus and
⬎34 mm for ascending aorta).17-19 Fol-low-up CMR or CT studies were per-formed using the same modality as the baseline examination.19
Outcome Measures
Mortality was determined and causes of deaths were classified as cardiac or noncardiac based on review of health
records and/or death certificates. Pri-mary cardiac events were defined as sur-gery on the aortic valve or ascending aorta, percutaneous aortic valvotomy, aortic complications (dissection or an-eurysm development), congestive heart failure requiring hospital admission, or cardiac death during the follow-up pe-riod. All cardiac events were verified by review of health records, operative re-ports, or hospital discharge summa-ries. Our recommended follow-up schedule for clinical reassessment of asymptomatic patients with bicuspid aortic valve and without valvular dys-function is every 3 to 5 years. The stan-dard of practice at our institution is to intervene on aortic stenosis or aortic re-gurgitation primarily on the basis of symptoms. Potential candidates for sur-gical or percutaneous interventions are reviewed at a weekly combined medi-cal-surgical conference. Asymptom-atic patients with severe aortic regur-gitation or dilated aortic sinus or ascending aorta are referred for sur-gery when thresholds for intertions are reached (end diastolic left ven-tricular dimension ⬎75 mm, left ventricular ejection fraction⬍55%, or aortic sinus/ascending aorta dimen-sion⬎50 mm).9,20Aortic valve bacte-rial endocarditis and cardiac arrhyth-mia were considered to be secondary cardiac events.
Statistical Analysis
Data analysis was performed using SPSS version 15.0 (SPSS Inc, Chicago, Illi-nois). Data were presented as mean and standard deviation (SD) or proportion (SD); median values with range and/or interquartile range (IQR) were pro-vided when data was not normally dis-tributed. Mortality rate during fol-low-up was determined using the Kaplan-Meier method. Means and pro-portions were compared using thet,2, and Fisher exact tests wherever appro-priate. Unless otherwise stated, the 2-sided level of significance was .05.
Sex-specific mortality rates for each of 20 age groups (⬍1, 1-4, 5-9, 1-14 . . .ⱖ90 years) were derived from vital statistics data collected by the Of-1318 JAMA,September 17, 2008—Vol 300, No. 11(Reprinted) ©2008 American Medical Association. All rights reserved.
fice of the Registrar General, Ontario, Canada, during the period from 1996 through 1997 (population of Ontario, 11.2 million).2 1 , 2 2 Age- and sex-specific life expectancies were then cal-culated as previously described.21,22The life expectancy of a population of 642 adults with identical age and sex dis-tribution as the study group was then calculated. The survival estimate of this population comparison group was com-pared with that of the study group using the log-rank test.
Potential predictors of primary car-diac outcome were evaluated by uni-variate Cox regression analyses; data were censored at the time of the first primary cardiac event. Candidate vari-ables with aPvalue of less than .05 on univariate analysis were entered into a multivariate Cox regression model; highly correlated variables (r⬎0.70) were combined prior to entry into the multivariate model. A stepwise, back-ward-elimination algorithm was used and a conservative significance level of less than .01 was chosen for inclusion in the multivariate model. Indepen-dent predictors were assessed for time dependency and then cross-validated for the entire study group with boot-strapping (Stata version 8.2, Stata-Corp, College Station, Texas).
The frequency of progression to moderate or severe aortic stenosis or re-gurgitation was determined in pa-tients in whom the latest follow-up echocardiogram was obtained prior to any primary cardiac event. The rate of change in peak aortic valve gradient and aortic root was calculated by dividing the difference between the baseline and latest examinations by the time be-tween evaluations.
RESULTS
Baseline characteristics are shown in TABLE1. All patients were ambulatory and asymptomatic; mean (SD) age was 35 (16) years (median, 31 years; range, 16-78 years). Two hundred patients (31%) had 1 or more coronary risk fac-tors (hypertension, hyperlipidemia, dia-betes mellitus, cigarette smoking, or family history of coronary artery
dis-ease in first-degree relatives). All pa-tients with hypertension or hyperlip-idemia were receiving pharmacological treatment. The type of cardiac medica-tions included (not mutually exclu-sive) were -adrenergic antagonist (19%), angiotensin-converting
en-zyme inhibitor (13%), aspirin (8%), statins (6%), calcium channel antago-nist (4%), and/or diuretics (1%). Al-most all patients with aortic coarcta-tion had undergone successful prior percutaneous or surgical therapy (150/ 159 patients); the severity of coarcta-Figure 1.Echocardiograms of Patients With Bicuspid Aortic Valve
A Heart anatomy in short axis plane B Short axis echocardiography view
C Phenotypic variations in bicuspid aortic valve anatomy
Right-left orientation
Anterior-posterior orientation
Anterior cusp
Posterior cusp
Right cusp Left cusp
Right cusp Left cusp Right coronary artery Right coronary artery Left coronary artery Left coronary artery Pulmonary artery Right atrium (RA) Right ventricle (RV)
Left atrium (LA) Tricuspid valve
Bicuspid aortic valve
R V L A R A L A R V R A Anterior cusp Posterior cusp Pulmonary valve Right atrium Right ventricle Bicuspid aortic valve
Left atrium Pulmonary artery
H E A R T
A, Schematic view of the spatial location of the short axis echocardiographic imaging plane relative to the heart anatomy. B, Parasternal short axis echocardiographic image demonstrating spatial relationship of aortic valve in relation to the RA, LA, RV, main pulmonary artery, tricuspid valve, and pulmonary valve. C, Parasternal short axis echocardiographic images and schematic views showing right-left and anterior-posterior orienta-tions in bicuspid aortic valve and the relaorienta-tionship of the valve cusps relative to other cardiac structures, includ-ing the origins of the coronary arteries.
tion was below the threshold for inter-vention in the remaining patients. Forty patients (6%) had undergone surgical or percutaneous treatment of intracar-diac shunts, subaortic stenosis, mitral regurgitation, or pulmonic stenosis in childhood and have no hemodynamic residua. Overall, 406 patients (63%) in the study group did not have signifi-cant aortic stenosis (mild or less than mild) and regurgitation at baseline (TABLE2); this group included 122 pa-tients with aortic peak gradient of less than 25 mm Hg and no aortic regurgi-tation. Eleven patients (2%) had small intracardiac shunts or mitral valve pro-lapse at the time of their baseline echo-cardiogram.
Primary Outcomes
Follow-up, which consisted of sur-vival status and documentation of car-diac events, was obtained for all pa-tients with a mean (SD) duration of 9 (5) years (median, 8 years; range, 2-26 years; IQR, 5-12 years). Total fol-low-up time was 5797 patient-years with 41% of the study group having at least 10 years of follow-up. There was a total of 28 deaths (mean [SD], 4% [1%]); of which, 17 were cardiac-related (mean [SD], 3% [1%]) and 11 were not related to a cardiac etiology (2 cases of thrombotic stroke, 7 cases of malignancy, 1 case of pneumonia, and 1 suicide). In 9 of 12 heart failure deaths, the underlying cause was either ischemic or nonischemic left ventricu-lar dysfunction that developed during the follow-up period. In the 15 deaths that were not related to aortic dissec-tion, 8 patients had moderate aortic ste-nosis at baseline and 2 patients had se-vere aortic stenosis at baseline.
The cardiac mortality rate was 0.3% per patient-year of follow-up. When compared with age- and sex-matched population estimates, the over-all mortality was not significantly dif-ferent between the bicuspid aortic valve group and the population estimates (P= .71). The 5-year mean (SD) sur-vival was 97% (1%) in both the bicus-pid aortic valve group and in the popu-lation estimates. The 10-year survival Table 1.Baseline Characteristics
No. (%) of Participantsa P Value Primary Cardiac Event (n = 161) No Primary Cardiac Event (n = 481) Age, mean (SD), y 40 (17) 33 (15) ⬍.001 Age⬎30 y 103 (64) 228 (47) ⬍.001 Male sex 128 (80) 309 (64) .001 Hypertension 61 (38) 109 (23) ⬍.001 Hyperlipidemia 19 (12) 18 (4) ⬍.001 Diabetes mellitus 3 (2) 9 (2) .99 Smoking 3 (2) 0 .02
Family history of coronary artery disease (n = 159) 4 (3)
(n = 427) 19 (4)
.35
Body mass index, mean (SD)b (n = 149)
25 (4)
(n = 427) 25 (4)
.56
Prior diagnosis of aortic coarctation 17 (11) 142 (30) ⬍.001
Prior aortic valvuloplasty or valvotomy in childhood 24 (15) 26 (5) ⬍.001
Prior pregnancy 3 (2) 19 (4) .32
Right-left leaflet orientation (n = 104)
36 (35)
(n = 406) 92 (23)
.01 Peak aortic velocity, mean (SD), m/s 3.0 (0.8) 2.1 (0.6) ⬍.001 Aortic valve area, mean (SD), cm2 (n = 126)
1.3 (0.5)
(n = 257)
1.6 (0.5) ⬍
.001
Moderate or severe aortic stenosis 89 (55) 51 (11) ⬍.001
Moderate or severe aortic regurgitation 61 (38) 71 (15) ⬍.001
Left ventricular ejection fraction, mean (SD), % 60 (7) 62 (5) ⬍.001
Left ventricular ejection fraction⬍55% 15 (9) 13 (3) ⬍.001
Aortic sinus dimension
Mean (SD), mm 35 (6) 32 (6) ⬍.001
⬎35 mm 66 (41) 114 (24) ⬍.001
⬎40 mm 25 (16) 38 (8) .005
Abbreviation: m/s, meters per second.
aUnless otherwise indicated.
bCalculated as weight in kilograms divided by height in meters squared.
Table 2.Baseline Characteristics of Patients With and Without Baseline Aortic Valve Dysfunction No. (%) of Patientsa P Value Moderate or Severe Aortic Stenosis or Regurgitation (n = 236) Mild or Less Than Mild Aortic
Stenosis and Regurgitation (n = 406) Age, mean (SD), y 35 (16) 34 (15) .84 Male sex 185 (78) 252 (62) ⬍.001 Hypertension 67 (28) 103 (25) .40 Hyperlipidemia 17 (7) 20 (5) .23 Diabetes mellitus 5 (2) 7 (2) .72 Smoking 2 (0.8) 1 (0.2) .28
Family history of coronary artery disease (n = 225) 3 (1)
(n = 361) 20 (6)
.01
Body mass index, mean (SD)b (n = 218)
25 (4)
(n = 369) 25 (4)
.43
Prior diagnosis of aortic coarctation 25 (11) 134 (33) ⬍.001
Prior aortic valvuloplasty or valvotomy in childhood 39 (17) 11 (3) ⬍.001
Right-left leaflet orientation (n = 158)
49 (31)
(n = 352) 79 (22)
.04
Aortic root⬎35 mm 83 (35) 97 (24) .002
aUnless otherwise indicated.
bCalculated as weight in kilograms divided by height in meters squared.
was similar in both the bicuspid aortic valve group (mean [SD], 96% [1%]) and in the population estimates (mean [SD], 97% [1%]) (FIGURE2). The 157 pa-tients who experienced a nonfatal pri-mary cardiac event had a lower 10-year survival (mean [SD], 92% [2%]) than the 485 patients who did not (mean [SD], 99% [1%]).
Primary cardiac events, including in-tervention on aortic valve or ascend-ing aorta, cardiac death, hospital ad-mission for heart failure, or aortic complications, occurred in 161 pa-tients (mean [SD], 25% [2%]). The fre-quency and nature of outcome events are listed inTABLE3. Surgical or per-cutaneous intervention on the aortic valve or ascending aorta comprised the majority of primary cardiac events (142 patients; mean [SD], 22% [2%]). The indications for intervention were symp-tomatic aortic stenosis (84 patients), symptomatic aortic regurgitation or progressive left ventricular dysfunc-tion (37 patients), aortic sinus or as-cending aorta dilation (11 patients), and endocarditis (10 patients).
Eleven patients (mean [SD], 2% [1%]) had an aortic complication (dis-section or aneurysm), in whom 5 were dissections (3 ascending and 2 descend-ing). One patient with ascending aorta dissection died before surgery while an-other died postoperatively; both pa-tients had baseline dilatation of the aor-tic sinus and/or ascending aorta. In the third patient, who had surgery for a rap-idly dilating aorta, ascending aortic dis-section was diagnosed at time of the sur-gery. One patient with descending aortic dissection underwent aortic stent-ing while the other patient was treated medically. The frequency of aortic dis-section was 0.1% per patient-year of fol-low-up. Overall, 9 of 11 patients with aortic complications required opera-tive or catheter intervention.
Of the 16 patients (mean [SD], 2% [1%]) who required hospital admis-sion for congestive heart failure, it was precipitated by tachyarrhythmia in 3 pa-tients. Of the remainder, 9 patients sub-sequently underwent aortic surgery and the other 4 were treated medically.
Predictors of Primary Outcomes The candidate variables examined by univariate analysis are shown in TABLE4. None of the variables with a level of significance of less than .05 on univariate analysis was highly corre-lated with each other. On multivariate analysis, the independent predictors of primary cardiac events were age older than 30 years (hazard ratio [HR], 3.01; 95% confidence interval [CI], 2.15-4.19;P⬍.001), moderate or severe
aor-tic stenosis (HR, 5.67; 95% CI, 4.16-7.80;P⬍.001), and moderate or severe aortic regurgitation (HR, 2.68; 95% CI, 1.93-3.76;P⬍.001). Age was not nor-mally distributed and was analyzed using its median value. The above pre-dictors were not time-dependent and the assumptions of the proportional hazard analysis were met. Risk esti-mates from bootstrapping were simi-lar to those of the original analysis. The 10-year rate for freedom from a pri-Figure 2.All-Cause Mortality of Adults With Bicuspid Aortic Valves
20 10 8 6 4 2 12 14 16 18 0 No. at risk Bicuspid aortic valve Comparison 642 642 2 4 6 8 10 641 576 476 373 258 642 642 622 622 622 Follow-up Duration, y Mortality , %
Bicuspid aortic valve Comparison Log-rank P = .71
The all-cause mortality in bicuspid aortic valve group (n=642) was 4% (SD, 1%). In the comparison group (n=642), which was a sex- and age-matched population with life expectancy estimates from Ontario, the all-cause mortality was 3% (SD, 1%).
Table 3.Cardiac Outcomes
Cardiac Outcomes
No. (%) of Patients (N = 642) Primarya
Intervention on aortic valve or ascending aorta 142 (22)
Bioprosthetic aortic valve replacement 47
Ascending aortic graft and aortic valve replacement 38
Pulmonary autograft (Ross procedure) 34
Mechanical aortic valve replacement 14
Valve sparing aortic root replacement 5
Aortic valve repair 3
Percutaneous aortic valvotomy 1
Cardiac death 17 (3)
Heart failure 12
Aortic dissection 2
Postoperative after cardiac surgery 3
Hospital admission for heart failure 16 (2)
Aortic complication 11 (2)
Aortic dissection 5
Descending thoracic or abdominal aortic aneurysm 6
Secondarya
Aortic valve endocarditis 13 (2)
Cardiac arrhythmias requiring treatment 30 (5)
mary cardiac event in patients with 0 predictors was a mean (SD) of 94% (2%); 1 predictor, mean (SD) of 82% (3%); and more than 1 predictor, mean (SD), 35% (5%) (FIGURE3). The at-tributable risk was 12% at 10 years for patients with 1 of the above-men-tioned risk factors compared with pa-tients without any risk factors. Coro-nary risk factors, prior pregnancy, and
bicuspid aortic valve leaflet orienta-tion were not independently predic-tive of primary cardiac events. Secondary Outcomes
Aortic valve endocarditis occurred in 13 patients (mean [SD], 2% [1%] or 0.3% per patient-year of follow-up), 3 of whom required urgent surgery, and 3 of whom developed endocarditis
fol-lowing aortic valve replacement. The re-maining 7 patients were initially treated medically but 5 patients eventually re-quired aortic valve replacement. Thirty patients (mean [SD], 5% [1%] or 0.6% per patient-year of follow-up) experi-enced cardiac arrhythmias requiring treatment (bradyarrhythmia in 6 pa-tients, supraventricular tachycardia in 22 patients, and ventricular tachycar-dia in 2 patients). The arrhythmias oc-curred during the postoperative pe-riod in 7 patients.
Outcomes in Patients With No Normal or Near Normal Baseline Aortic Valve Function
In the subset of 122 patients with aortic peak gradient of less than 25 mm Hg and no aortic regurgitation, 1 or more pri-mary cardiac events occurred in 4 pa-tients (mean [SD], 3% [2%]) consisting of cardiac death (aortic dissection in 1 patient with baseline dilatation of the aor-tic sinus, congestive heart failure, and ar-rhythmia in 1 patient with dilated car-diomyopathy attributed to alcohol abuse) and intervention on the aortic valve or aorta (2 patients). Aortic valve endocar-ditis affected 1 additional patient. The 5-and 10-year survival rate was a mean (SD) of 98% (1%) and 96% (3%), re-spectively. The 5- and 10-year rate for freedom from a primary cardiac event was a mean (SD) of 98% (1%) and 92% (5%), respectively.
Progression of Aortic Valve Disease and Aortic Dimension Patients with moderate or severe aortic stenosis or regurgitation at baseline were more likely to be male, have right-left leaflet orientation, and aortic sinus di-lation than those without aortic valve dysfunction (Table 2). Follow-up echo-cardiograms were analyzed in 619 pa-tients (96%); parameters from the re-maining patients were not included because their follow-up studies were per-formed after aortic valve intervention. At a mean (SD) echocardiographic fol-low-up of 7 (4) years (median, 6 years; range, 1-23 years; IQR, 3-9 years), 50 pa-tients (mean [SD], 8% [1%]) with mild or less than mild aortic stenosis or re-Table 4.Predictors of Primary Cardiac Events
Candidate Variables
Univariate Analysis Multivariate Analysis HR (95% CI) P Value HR (95% CI) P Value Baseline age⬎30 y 2.11 (1.56-2.87) ⬍.001 3.01 (2.15-4.19) ⬍.001 Male sex 1.82 (1.27-2.62) .002 Hypertension 1.65 (1.24-2.20) .002 Hyperlipidemia 2.66 (1.70-4.18) ⬍.001 Diabetes mellitus 1.00 (0.35-2.84) .95 Smoking 5.36 (1.89-15.24) .004
Family history of coronary artery disease 0.52 (0.21-1.29) .20
Body mass indexa 1.00 (0.97-1.04) .91
Prior diagnosis of aortic coarctation 0.30 (0.19-0.48) ⬍.001 Prior aortic valvuloplasty or valvotomy 1.92 (1.29-2.85) .004
Prior pregnancy 0.38 (0.13-1.08) .10
Right-left leaflet orientation 1.57 (1.11-2.21) .02
Moderate or severe aortic stenosis 5.31 (3.98-7.09) ⬍.001 5.67 (4.16-7.80) ⬍.001 Moderate or severe aortic regurgitation 2.61 (1.96-3.48) ⬍.001 2.68 (1.93-3.76) ⬍.001 Left ventricular ejection fraction⬍55% 3.22 (1.98-5.24) ⬍.001
Aortic sinus⬎35 mm 1.93 (1.45-2.58) ⬍.001
Abbreviations: CI, confidence interval; HR, hazard ratio.
aCalculated as weight in kilograms divided by height in meters squared.
Figure 3.Cardiac Events in Adults With Bicuspid Aortic Valves 70 60 50 40 30 20 10 0 No. at risk 2 4 6 8 10 All participants 642 639 533 413 309 198 >1 142 141 95 66 51 36
By No. of risk factors
1 306 305 261 204 153 93 0 194 193 177 143 105 69 Follow-up Duration, y Primary Car diac Events, % All participants 0 By No. of risk factors
>1 1
The frequency of primary cardiac events in patients with more than 1 risk factor at baseline (n=142) was 65% (SD, 5%); in all participants (N=642), 25% (SD, 2%); in patients with 1 risk factor at baseline (n=306), 18% (SD, 3%); and in patients with no risk factors at baseline (n=194), 6% (SD, 2%). The risk factors for primary cardiac events were age older than 30 years, moderate or severe aortic regurgitation, and moderate or severe aortic stenosis.
gurgitation at baseline had progressed to moderate or severe aortic stenosis or re-gurgitation. The group that developed significant valvular dysfunction in-cluded 10 patients who were in the group of 122 patients with normal or near nor-mal aortic valve function at baseline. The remaining 352 patients (mean [SD], 57% [2%]) continue to have mild or less than mild aortic stenosis or regurgitation. The median increase in peak aortic valve gra-dient was 0.7 mm Hg per year (range, 0-35 mm Hg per year; IQR, 0-2 mm Hg per year) for the entire group.
Baseline aortic sinus dilation was pre-sent in 180 patients (28%). This group had a higher proportion of patients who were older than 30 years (75% vs 42% of nondilated group;P⬍.001), were male (87% vs 61% of nondilated group;
P⬍.001), had hypertension (40% vs 21% of nondilated group;P⬍.001), or had moderate or severe aortic stenosis or regurgitation (46% vs 33% of non-dilated group;P=.002). In 63 of the 180 patients (10% of total), the aortic si-nus dimension was higher than 40 mm, a clinically important threshold.9 Base-line ascending aortic dimension was not analyzed due to the limited number of patients with available data. The ab-sence of baseline ascending aorta di-mension data in most patients pre-cluded a systematic examination of whether bicuspid aortic valve orienta-tion is related to aortic dilataorienta-tion.
At follow-up, 222 patients (mean [SD], 38% [2%]) had aortic sinus dilation. In the 245 patients in whom the ascending aortic dimension could also be assessed, 143patientshadadilatedascendingaorta. Dilatedaorticsinusand/orascendingaorta was present in 280 patients (mean [SD], 45% [2%]) at follow-up. Dilated ascend-ing aorta with normal aortic sinus dimen-sion was present in 58 patients at follow- up.Theaorticsinusand/orascendingaor-tic dimension exceeded 40 mm in 124 patients(mean[SD],20%[2%])atfollow-up. The median increase in aortic sinus dimension was 0.2 mm per year (range, 0-9.0 mm per year; IQR, 0-0.7 mm per year) for the entire group. Changes in aor-tic peak gradient and aoraor-tic sinus dimen-sion are displayed inFIGURE4.
A total of 139 patients (mean [SD], 22% [2%] of the group with follow-up echocardiography) also underwent either CMR (129 patients) or CT (10 pa-tients) during the median follow-up pe-riod of 8 years (range, 1-22 years; IQR, 4-11 years) as part of the recently imple-mented follow-up template for assess-ment of coarctation repair (96 patients) and/or to screen for aortopathy in tients with bicuspid aortic valve (43 pa-tients). This more contemporary group was generally younger (mean [SD] age, 27 [11] years) with a lower proportion of moderate or severe aortic stenosis or regurgitation (26%) at baseline com-pared with the 480 patients who did not undergo CMR or CT (mean [SD] age, 37 [16] years with significant valve dys-function in 40%;P⬍.001 for both com-parisons of mean age and proportion with significant valve dysfunction). The frequency of dilated aortic sinus and/or ascending aorta was similar to that de-termined by echocardiography (n=59; mean [SD], 42% [4%]). Thirty-two pa-tients with dilated ascending aorta had normal aortic sinus dimension. In 35 of the 59 patients with dilated ascending aorta or aortic sinus (mean [SD], 25% [4%]), 1 or more of these aortic dimen-sions exceeded 40 mm. In the 37 pa-tients who underwent at least 2 CMR or CT studies separated by a median
inter-val of 5 years, the median rate of change in ascending aortic dimension was 0.30 mm per year (range, 0-2 mm per year; IQR, 0-0.7 mm per year).
COMMENT
In this study examining the largest con-secutive series of adults with bicuspid aortic valve to date, 25% of patients ex-perienced a primary cardiac event dur-ing a mean follow-up of 9 years. Inter-vention on the aortic valve and aorta comprised the vast majority of the pri-mary cardiac events. Reassuringly, the overall mortality rate of this ambula-tory cohort was not significantly dif-ferent from population estimates. Older age, moderate or severe aortic steno-sis, and moderate or severe aortic re-gurgitation independently predicted the occurrence of a primary cardiac event. At follow-up, almost half of the study population had dilation of either the aortic root or ascending aorta.
Prior series examining outcomes in patients with bicuspid aortic valve re-ported high rates of mortality and se-rious complications relating to endo-carditis, cardiac surgery, heart failure, and dissection.1,2,4,5,23Although a high frequency of cardiac events was ob-served in our cohort, serious cardiac morbidity and mortality was infre-quent. Outcome differences between Figure 4.Changes in Aortic Velocity and Aortic Sinus Dimension
6 2 3 4 5 1 m/s Baseline Follow-up
Peak Aortic Velocity
60 20 30 40 50 10 mm Baseline Follow-up
Aortic Sinus Dimension
Aortic peak velocity and aortic sinus diameter at baseline and follow-up in 619 patients with serial echocar-diographic parameters. Horizontal lines inside boxes denote medians. Lower and upper limits in boxes denote 25th and 75th percentiles. Lower and upper limits of vertical bars denote the lowest and highest value within 1.5 interquartile range beyond the 25th and 75th percentile, respectively. The circles represent outliers. The peak aortic velocity increased from a mean at baseline of 2.3 (SD, 0.8) meters per second (m/s) to 2.6 (SD, 1.0) m/s at follow-up (P⬍.001 by pairedttests). The aortic sinus dimension increased from a mean at base-line of 32 (SD, 6) mm to 34 (SD, 6) mm at follow-up (P⬍.001 by pairedttests).
present and prior studies can be attrib-uted to differences in the era that pa-tients were examined, the population that was examined, the frequency of cardiac events associated with high mortality (aortic dissection and endo-carditis), and advances in periopera-tive management.1,2,4,5,23
The Olmsted County study24 of asymptomatic patients with normally functioning bicuspid aortic valve also reported similar mortality as the gen-eral population in Minnesota. Both the Olmsted County study and our study reported a significant and incremental rate of nonfatal cardiac events with in-creasing age, with intervention on the aortic valve being a frequent outcome. Intervention on the basis of early symp-toms or deterioration in cardiac func-tion may contribute to the low mortal-ity observed in both studies. The generalizability of our study results is reinforced by the similarity in the find-ings (low mortality and high rate of nonfatal cardiac outcomes) reported in the Olmsted County study, despite dif-ferences in the era from which the study population was identified (1980-1999 for Olmsted vs 1996-2001 in our study), duration of follow-up, and origin of the patient population (community-based vs hospital-(community-based).
Our results extended the findings of prior studies25,26to younger adults with bicuspid aortic valve by our reporting of age-dependent progression of aortic valve disease. If we apply our study results together with those of 2 recently pub-lished studies examining community and surgical populations, one can cau-tiously project that many young adults with bicuspid aortic valve will eventu-ally need intervention for aortic valve dis-ease or aortic dilatation.24,25Several stud-ies examining mostly older asymptomatic patients with degenerative aortic valve disease have established the prognostic role of moderate or severe aortic steno-sis even in the absence of symp-toms.27-29The predictive role of moder-ate or severe aortic regurgitation has not been previously identified in a large sample of adults with bicuspid aortic valve. In contrast, the frequency of
pri-mary cardiac events, including cardiac death, was the lowest in the subset of adults with normal or near normal aor-tic valve function at baseline.
The association between orientation of bicuspid aortic valve leaflets, aortic valve dysfunction, and subsequent in-tervention has been reported in chil-dren and adolesents.11,30This associa-tion may be mediated by the influence of bicuspid aortic valve leaflet spatial ori-entation on aortic elastic properties.12In the present study, bicuspid aortic valve leaflet orientation did not indepen-dently predict cardiac events. It is likely that the relationship between bicuspid aortic valve leaflet orientation and sub-sequent outcomes, identified in chil-dren and adolescents, may have been modified by the process of aging and other acquired factors. Indeed, valve de-generation at diagnosis, rather than bi-cuspid aortic valve leaflet orientation, predicted future cardiovascular events in the Olmsted County study.24
Dilated aortic sinus and ascending aorta in patients with bicuspid aortic valve have been attributed to acceler-ated smooth muscle apoptosis in the aor-tic media.31-35This propensity for aor-tic dilatation begins early in life because children with bicuspid aortic valve gen-erally have larger aortic sinus dimen-sions than normal controls.36In the pre-sent study, almost half of the patients had dilation of the aortic root or ascending aorta at follow-up, similar to that re-ported in the Olmsted County study.24 Although echocardiography has an es-tablished role in the assessment of aor-tic valvular function and aoraor-tic dimen-sion, CMR or CT imaging provided complementary data by its ability to im-age the entire aorta. The importance of aortic assessment in adults with bicus-pid aortic valve was highlighted by our findings that 29% of the patients who underwent aortic valve surgery also re-quired replacement of their dilated as-cending aorta. The association be-tween moderate or severe aortic stenosis or regurgitation and larger aortic sinus dimension underscores the additional in-fluences of aortic valve disease on aor-tic dilatation.32,34Aortic dissection in
bi-cuspid aortic valve patients, although infrequent in our study and not ob-served in the Olmsted County study, was associated with a case-fatality rate of 40% in patients. An international study also reported that acute aortic association is associated with a high mortality rate in both young (⬍40 years; 22%) and older (ⱖ40 years; 24%) patients, irrespective of the site of dissections.37The impor-tance of the aorta in patients with bi-cuspid aortic valve is further under-scored by the 1 dissection death in a patient with a normal or near normal aortic valve function at baseline. Limitations
Our study has several limitations. Risk estimates were derived from a retrospec-tively identified population and the base-line extent of ascending aortic dilation could not be defined in most patients. However, aortic root dilation tended to parallel ascending aorta dilation, thus the frequency of aortic root dilation pro-vided an indirect estimate of ascending aortic involvement.34It is unlikely that echocardiography has significantly un-derestimated the frequency of aortopa-thy because the frequency of aortic root or ascending aortic dilation was simi-lar in those who also underwent CMR or CT imaging. The selection bias asso-ciated with the University Health Net-work being a major regional center for the care of adults with congenital heart disease is reduced by the role of the Toronto Congenital Cardiac Centre for Adults as the primary adult continuity clinic for the cardiac program of the Toronto Hospital for Sick Children. Our study results are applicable only to adults with bicuspid aortic valve, who are re-ferred for cardiac assessment, because cardiac assessment of the general popu-lation is not feasible.24This is likely not a major limitation because echocardi-ography is widely available and used in Ontario, as was the case in Olmsted County.24 The provision of universal health insurance coverage for all resi-dents of Ontario further reduces the bar-rier to referral. Intermediate outcome data was not available in the present study, precluding analysis of progress of 1324 JAMA,September 17, 2008—Vol 300, No. 11(Reprinted) ©2008 American Medical Association. All rights reserved.
the various stages of the disease. Fi-nally, it is not possible to adjust for pos-sible differences in risk profiles (such as smoking, socioeconomic status, or eth-nicity) when comparing mortality be-tween the study patients and the gen-eral population, although almost one-third of our study group had at least 1 coronary risk factor.
CONCLUSIONS
In this study population of young adults with bicuspid aortic valve, age, sever-ity of aortic stenosis, and seversever-ity of aor-tic regurgitation were independently as-sociated with primary cardiac events. During the mean follow-up duration of 9 years, survival rates were not lower than for the general population. Young adults with bicuspid aortic valve have a high likelihood of eventually requir-ing interventions on the aortic valve and/or aorta and will need serial sur-veillance of aortic valve and aortic di-mensions.
Author Contributions:Drs Tzemos and Siu had full ac-cess to all of the data in the study and take respon-sibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design:Tzemos, Therrien, Yip, Webb, Siu.
Acquisition of data:Tzemos, Yip, Thanassoulis, Tremblay, Jamorski, Siu.
Analysis and interpretation of data:Tzemos, Therrien, Yip, Webb, Siu.
Drafting of the manuscript:Tzemos, Siu.
Critical revision of the manuscript for important in-tellectual content:Tzemos, Therrien, Yip, Thanassoulis, Tremblay, Jamorski, Webb, Siu.
Statistical analysis:Siu. Obtained funding:Siu.
Administrative, technical, or material support: Tzemos, Therrien, Yip, Thanassoulis, Tremblay, Jamorski, Webb, Siu.
Study supervision:Therrien, Webb, Siu. Financial Disclosures:None reported.
Funding/Support:Dr Tzemos was partially sup-ported by a fellowship grant from the University of Toronto Department of Medicine. Dr Thanassoulis was supported by a research fellowship from the Fonds de Recherche en Sante´ du Que´bec. The study was sup-ported by operating grants from the Canadian Insti-tutes of Health Research (grant 53130) and the Heart and Stroke Foundation of Canada (grant NA5662). Role of the Sponsor:The funding organizations had no role in the design and conduct of the study; col-lection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
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