Quadricuspid Aortic ValveCLINICAL PERSPECTIVE
Characteristics, Associated Structural Cardiovascular Abnormalities, and Clinical Outcomes
Background—Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect. This study sought to determine QAV frequency in a large echocardiography database, to characterize associated cardiovascular abnormalities, and to describe long-term outcomes.
Methods and Results—Fifty patients (mean±SD age, 43.5±21.8 years at the time of the index diagnosis; female sex, 52%) received a diagnosis of QAV between January 1, 1975, and March 14, 2014 (frequency, 0.006%). The QAV was type A in 32% and type B in 32% (Hurwitz and Roberts classification). Aortic dilatation was present in 29% of the patients, and 26% had moderate or severe aortic valve regurgitation at the index diagnosis. Stenosis affected only 8% of the valves and was mild. Other findings, including abnormalities of other cardiac valves, septal defects, persistent left superior vena cava, and patent ductus arteriosus, were present in 32% of patients. During a mean±SD follow-up of 4.8±5.6 years, 8 patients underwent aortic valve surgery, with severe aortic valve regurgitation being the surgical indication in 7 patients. One patient with mild to moderate aortic valve regurgitation underwent aortic valve repair for obstruction of the left coronary ostium by the accessory cusp of QAV. No infective endocarditis or aortic dissection was found. Overall survival was 91.5% and 87.7% at 5 and 10 years.
Conclusions—Aortic dilatation and other structural cardiac abnormalities were relatively common among patients with QAV. Aortic valve regurgitation was the predominant hemodynamic abnormality and the indication for aortic valve surgery in most patients who received surgery. Long-term survival was excellent.
Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect with an estimated frequency of <0.05%.1–4 In a previous study from the Mayo Clinic, in which the archived 2-dimensional echocardiography database between 1982 and 1988 was reviewed, 8 cases of QAV were identified from >60 000 individual patient examinations.2 Because of its rarity, the characteristics, natural history, and long-term outcomes of QAV are poorly defined.
Clinical Perspective on p 319
Most reports of QAV represent single-center experiences with small numbers of cases.2–6 These reports have shown that it is frequently associated with progressive aortic valve regurgitation (AR), whereas aortic valve stenosis and ascending aortic enlargement are uncommon.3,4 Nearly one-half of patients with QAV require a surgical procedure for their aortic valve disease.4 Options for QAV include aortic valve repair and aortic valve replacement,5,6 but data on long-term clinical and surgical outcomes are lacking. This investigation of patients with QAV sought to determine the characteristics of QAV in a large echocardiography database, including associated structural and hemodynamic cardiovascular abnormalities, and to describe the long-term outcomes.
This investigation was approved by the Mayo Clinic Institutional Review Board. We searched the echocardiography database of all patients seen between January 1, 1975, and March 14, 2014, for those with a QAV diagnosis through transthoracic or transesophageal procedures performed at any of the echocardiography laboratories of the Mayo Clinic. Echocardiographic images were reviewed, and the QAV diagnosis was confirmed in each case by 2 echocardiographers (including M.Y.C.T.) independently. Thirteen patients with a quadricuspid aortic or truncal valve in the presence of other conotruncal anomalies (eg, tetralogy of Fallot, pulmonary atresia, truncus arteriosus) were excluded.7–9 Pathological and cardiovascular surgical databases were searched to ensure that all patients with a QAV diagnosis were included in the study. Demographic information was obtained through medical record review.
From echocardiographic short-axis images or review of pathological specimens, QAVs were classified into 7 subtypes based on leaflet size and distribution, as described by Hurwitz and Roberts10 (Figures 1 and 2). This classification system was originally developed for differentiating various subtypes of quadricuspid pulmonary valve, which is more common than QAV.10 According to this classification system, type A contains 4 equal-sized cusps; type B, 3 equal cusps and 1 small cusp; type C, 2 equal large and 2 equal small cusps; type D, 1 large, 2 intermediate, and 1 small cusp; type E, 3 equal and 1 larger cusp; type F, 2 equal larger and 2 unequal smaller cusps; and type G, 4 unequal cusps.
All patients had undergone comprehensive 2-dimensional and Doppler echocardiography performed with commercially available ultrasonography equipment in accordance with the American Society of Echocardiography guidelines.11,12 Aortic stenosis was defined as 2-dimensional evidence of restricted aortic cusp motion and a peak aortic velocity >2.0 m/s. Aortic valve area was calculated by the continuity equation with the time-velocity integrals of the left ventricular outflow tract and aortic valve. Severity of AR was graded after integration of the available qualitative and quantitative parameters.13
Dimensions of the aortic root (aortic sinuses of Valsalva) and tubular ascending aorta were measured from the parasternal long-axis window at end diastole and compared with reference ranges for the patient’s age and body surface area.12,14 Aortic dilatation was classified as mild when its dimension was <5 mm above the upper limit of the reference range and as moderate when its dimension was 5 to 10 mm above the upper limit of the reference range or between 45 and 50 mm.15–17
Time 0 represented the time when the index diagnosis of QAV was made either through echocardiography or through surgical or pathological examination if not diagnosed preoperatively. To characterize the natural history of changes in AR and aortic dimensions, we identified the patients monitored through serial echocardiography at least 1 year after the index study. Subsequent need for aortic valve repair or replacement and the occurrence of cardiovascular events were obtained through review of the patient’s medical record.
Information on vital status was obtained from the US Social Security Death Index. For all-cause mortality, the records of patients not known to be deceased were censored at the time the US Social Security Death Index was interrogated. For survival free of cardiovascular events or aortic valve surgery, medical records of patients not known to have any of the listed characteristics were censored at the time of the last documented clinical follow-up.
Data were presented as mean±SD or number (percentage) of patients. The Pearson χ2 test was used to examine possible associations between various clinical characteristics. Overall survival was estimated with the Kaplan–Meier method and compared with the use of the log-rank test. Overall survival of patients with QAV was compared with an otherwise healthy population matched for age and sex on the basis of data from the Olmsted County, Minnesota, general population database. Statistical analyses were performed with SPSS version 20 (IBM Corp), and values of P<0.05 were considered significant.
Between January 1, 1975, and August 31, 2001, transthoracic echocardiography was performed on 357 228 patients at the Mayo Clinic, and 21 patients received the diagnosis of QAV (frequency, 0.0059%). From September 1, 2001, through March 14, 2014, a total of 431 505 patients underwent transthoracic echocardiography, of which 28 patients had a diagnosis of QAV (frequency, 0.0065%). Among these 49 patients with QAV diagnosed on the basis of echocardiographic findings, 7 had QAV first identified through transesophageal echocardiography.
For a 50th patient, severe regurgitation of a trileaflet aortic valve and mild aortic root dilatation had been diagnosed previously with echocardiography. At aortic valve surgery, the patient was found to have a QAV. Retrospective review of this patient’s preoperative echocardiographic images showed type F QAV.
The diagnosis of QAV was confirmed with transesophageal echocardiography or surgical or anatomic examination in 18 patients (36%). For the 50 patients, mean±SD age at diagnosis was 43.5±21.8 years (range, 2 days–84 years), and 52% were female (Table 1).
Classification according to subtypes of QAV is shown in Table 1 and the Table I in the online-only Data Supplement, and selected images from echocardiography or pathological specimens of various QAV subtypes are shown in Figures 1 and 2. Classification was not possible for 1 patient who did not have retrievable echocardiographic images; her diagnosis of QAV was confirmed with transesophageal echocardiography. A majority (64%) of our study cohort had type A (32%) or type B (32%) QAV.
Functional status of QAV in relation to valve subtypes is shown in Table 2. AR of any degree was present in 45 patients (90%), of whom 13 (26%) had moderate or severe AR, at the time of index diagnosis of QAV. Only 4 patients (8%) had aortic stenosis, which was mild in all 4.
Among 13 patients who underwent follow-up echocardiography without intervening aortic valve surgery, 3 (23%) were noted to have had progression of AR during a mean±SD follow-up of 5.5±3.7 years. The degree of AR increased from mild (grade I/IV) to moderate (grade II/IV) in 1 patient with type B QAV during 14 years of follow-up; the AR of 2 other patients (1 patient with type A and a 1 patient with type B QAV) worsened from moderate-severe (grade III/IV) to severe (grade IV/IV) during 2 and 5 years of follow-up, respectively. No significant association was found between changes in AR severity and QAV subtypes (P=0.34).
At the time of index diagnosis of QAV, 48 of our 50 patients (96%) had an adequate assessment of the ascending aorta, with visualization of the sinus of Valsalva and the proximal to mid tubular ascending aorta. Aortic dilatation was present in 14 of the 48 patients (29%) and involved the aortic root in 5 (36%), the tubular ascending aorta in 5 (36%), and both the aortic root and tubular ascending aorta in 4 (29%). Eleven of these 14 patients (79%) had mild aortic dilatation; the other 3 had moderate dilatation. No significant association was detected between aortic dilatation at the index diagnosis and a documented history of hypertension (P=0.12). Among the 14 patients with aortic dilatation at the index diagnosis of QAV, 9 had moderate or greater AR. Only 4 of the 34 patients without aortic dilatation had moderate or greater AR, suggesting that aortic dilatation was associated with the presence of moderate or greater AR (P<0.001).
Changes in aortic dimensions were assessed by serial echocardiography in 20 patients (55% male), 7 of whom had undergone aortic valve surgery. Aortic dimensions (aortic root or tubular ascending aorta) increased over time in 10 patients (50%) by ≥2 mm during a mean±SD follow-up of 6.2±4.3 years, but 9 of these 10 patients had only a mild increase of ≤5 mm in aortic size. One patient’s ascending aortic diameter enlarged by 15 mm in the 17 years between the index diagnosis and the surgical aortic valve replacement and graft replacement of the ascending aorta. No significant association was found between changes in aortic dimension over time and QAV subtypes (P=0.64) or history of hypertension (P=0.64).
Associated Cardiac Disorders
Other structural cardiac abnormalities were present in 16 patients (32%; Table 3). No echocardiographic evidence of aortic coarctation was noted. Four of the 50 patients had undergone coronary artery assessment with invasive angiography or computed tomography, and no coronary anomalies were identified.
Family History of Congenital Heart Disease
Information on family history was available for 47 of the 50 patients (94%). One patient reported the diagnosis of a ventricular septal defect in his son; otherwise, no reported family history of QAV or other types of congenital heart disease was reported.
The mean±SD duration of clinical follow-up at our institution was 4.8±5.6 years (range, 0–23 years). Overall survival for the entire cohort was 91.5% and 87.7% at the 5- and 10-year follow-up, respectively (Figure 3A). Survival free of surgery or death was 73.9% at the 5-year follow-up (Figure 3B). No infective endocarditis or aortic dissection was documented.
During the follow-up period, 8 of the 50 patients (16%) underwent aortic valve surgery (6 replacements and 2 repairs). The mean±SD duration between the index diagnosis of QAV and aortic valve surgery was 4.3±6.2 years (range, 0–17 years). The indication for aortic valve surgery was severe AR for all but 1 patient (age, 16 years) with mild to moderate AR and occlusion of the left coronary ostium by the small fourth cusp of QAV and collateralization from the right coronary artery. Aortic valve repair for this patient consisted of surgical excision of the small fourth cusp and resuspension of the other cusps. Adequate perfusion of the left coronary system was documented postoperatively.
One of the 8 patients with aortic valve replacement underwent concurrent replacement of the ascending aorta 17 years after the initial diagnosis. Histopathological examination of the excised ascending aorta showed intimal thickening and focal medial degeneration but no evidence of tear or dissection. Among the 8 patients who underwent aortic valve surgery, 3 patients had type A QAV, 2 patients had type B, and 1 patient each had type C, type D, and type F. No other patient underwent concomitant repair of other structural cardiac lesions at the time of aortic valve surgery.
Among these 8 patients, no death occurred during a mean±SD postoperative follow-up of 12.4±7.2 years (Figure 4A). The patients were monitored at our institution for a mean±SD of 6.1±4.9 years after their operations. One patient had progressive AR and received a reoperation with a Ross procedure, consisting of replacement of the aortic valve and aortic root with a pulmonary autograft and a pulmonary valve replacement with a homograft at 4 years after the initial operation. Another patient had a transient ischemic attack 5 years after her surgery. One patient survived a cardiac arrest 7 years after his initial operation, but no specific cause of arrest was identified. No other patients had cardiovascular events requiring hospitalization at our institution.
Patients without aortic valve surgery (n=42) were monitored at our institution for a mean±SD period of 3.8±4.4 years (range, 0–16 years). Among the patients, QAV showed type A pattern in 13, type B in 14, and the other subtypes in 15. Development of atrial fibrillation in 2 patients was the only documented cardiovascular event during follow-up. Seven patients died during a mean±SD follow-up of 10.8±8.7 years. Overall survival was 89.9% and 84.9% at the 5- and 10-year follow-up, respectively (Figure I in the online-only Data Supplement). The cause of death was determined in 4 of the 7 patients who died and was unrelated to cardiovascular issues. No significant difference was found in overall survival between the postsurgical group and the nonsurgical group (P=0.15 by the log-rank test; Figure 4A). No significant difference occurred in overall survival of our patients with QAV versus an otherwise healthy population matched for age and sex (P=0.99 by the log-rank test; Figure 4B).
Frequency of QAV
Previous studies have found the frequency of QAV to be 0.01% to 0.04% on the basis of echocardiographic or autopsy data.1–3,10,18 In the present study, QAV occurred in 0.006% of patients undergoing a comprehensive echocardiographic study at the Mayo Clinic. Only patients with unequivocal evidence of QAV were included in our study, and these patients were identified from a larger population than in previous studies. Consequently, we consider our results representative of a more accurate estimate.
In our study population, 52% were female (male-to-female ratio, 1:1.08), but 75% of the patients who subsequently underwent aortic valve surgery were male. We speculate that the male preponderance reported in previous literature3 might be a result of the inclusion of only patients who had undergone aortic valve surgery.
Aortic Valve Characteristics
Previous studies have demonstrated that the 3 commonest QAV subtypes are types A, B, and C.5,19 In addition, AR is the predominant hemodynamic abnormality observed in patients with a QAV.3,4 The distribution of QAV subtypes and the associated hemodynamic abnormalities identified in our cohort were similar to other clinical and autopsy series.
Progressive cusp fibrosis with subsequent failure of cusp coaptation over time has been suggested as the key mechanism in regurgitation.3 An association between QAV morphological characteristics and severity of AR was not observed in our 50 patients. Rather, various QAV subtypes were found in patients who initially presented with moderate or severe AR and among those who subsequently underwent aortic valve surgery.
To the best of our knowledge, the natural history of changes in AR and aortic dimensions over time has not been specifically examined among patients with QAV. In the present study, among the 13 patients monitored through serial echocardiography who did not receive an aortic valve surgery, 23% had progression of their AR.
In the present study, AR was the predominant hemodynamic abnormality observed in patients with QAV, whereas evidence of aortic stenosis was noted in only 8% of our patients. This observation is similar to findings reported by previous studies.3,4
Ascending Aortic Characteristics
Ascending aortic dilatation, common in patients with congenital bicuspid aortic valve,23 has been reported rarely in patients with QAV in the past.19,24–26 However, in our study cohort, echocardiography showed that 29% of patients had dilatation of the aortic root, tubular ascending aorta, or both at the time of the index diagnosis of QAV. In addition, this aortic dilatation was associated with poorer survival free of aortic valve surgery or death, although the enlargement was only mild in 79% of these patients. Interestingly, a recent report of outcomes in patients who underwent surgery for a dysfunctional QAV also suggests that 13 of 31 patients (42%) had an ascending aortic diameter of ≥4 cm, and 7 patients underwent concomitant repair of ascending aorta.27 The discrepancy in the reported frequency of aortic dilatation may have arisen from the use of different cutoff values for abnormal ascending aortic dimensions or from inadequate examination of the ascending aorta by echocardiography.
Aortic dimensions were found to have increased over time in 10 of our 20 patients monitored with serial echocardiography, but 9 of these 10 patients showed a mild increase of only ≤5 mm in their aortic diameters. Whereas aortic dilatation was not uncommon at the time of index diagnosis of QAV, only 1 of 8 patients who subsequently underwent aortic valve surgery received concomitant ascending aortic repair or replacement. Overall, our data indicate that the severity of AR and aortic dimensions stayed stable or progressed relatively slowly in most patients.
The current evidence is inadequate to determine whether the aortic dilatation observed in patients with a QAV represents a genetically mediated aortopathy or is simply the result of hemodynamic factors related to valvular dysfunction.26 QAV was not associated with ascending aortic dissection or rupture in our series.
Types of Associated Cardiac Disorders
QAV is generally an isolated anomaly, although a few coexistent cardiac disorders have been reported in some patients. These disorders include anomalies of the origin and epicardial distribution of coronary arteries, atrial septal defect, ventricular septal defect, patent ductus arteriosus, discrete subaortic stenosis, congenital pulmonary valve stenosis, mitral valve prolapse, and hypertrophic cardiomyopathy.3,19,28,29 In our study, coexisting structural cardiac anomalies were present in 32% of the 50 patients.
Other investigators have reported coronary anomalies, including malformation and displacement of coronary ostia, in up to 10% of patients with a QAV.4,27 In contrast, the frequency of a clinically significant abnormality of coronary ostia was only 2% in our study and involved a patient whose left coronary ostium was occluded by a small accessory aortic valve cusp. It is generally difficult to assess the coronary ostia with echocardiography in adults, which may explain the lower frequency of such anomalies in our study.
To the best of our knowledge, our study is the first to investigate the long-term outcomes of patients with QAV. Only 8 of our 50 patients (16%) received aortic valve surgery during follow-up. Five of these 8 patients had type A or B QAV. Similar findings have been reported by other investigators.30,31 It is unclear whether these specific subtypes of QAV predispose patients to more severe AR or whether this is simply a reflection of the predominance of types A and B in patients with QAV.
All 8 surgical patients had regular postoperative follow-up visits at our institution for a mean±SD period of 6.1±4.9 years. During this time, 1 patient who had initially undergone an aortic valve repair later had aortic valve replacement for progressive worsening of AR.
Complete heart block has been reported as a potential complication for patients undergoing aortic valve surgery.32 None of the patients in the present study had this complication.
Long-term outcome was favorable not only for patients without aortic valve surgery but also for those who underwent aortic valve repair or replacement. There was no significant difference in long-term survival between patients who had aortic valve surgery and those who did not. Importantly, despite a structurally abnormal aortic valve and the presence of an enlarged ascending aorta in 29% of our patients, no instances of infective endocarditis or aortic dissection were documented. This outcome contrasts with the behavior of bicuspid aortic valve, which is associated with an 8-fold increase in the age-adjusted risk of aortic dissection compared with that of the general population.23
Our analysis was limited by the relatively small size of our study cohort and by its retrospective design, although it reflects the analysis of a large database. QAV is a rare congenital anomaly, and it may not be easily identified on transthoracic echocardiography. The reported frequency of QAV in our study may therefore represent an underestimation. In addition, anatomic confirmation through surgical or pathological examination was available in only the 8 patients who had undergone an aortic valve surgery. Comparison of individual cusp size for the purpose of classifying the aortic valve into different subtypes can be challenging and may not correlate well with surgical or pathological findings. In our study, however, the distribution of various subtypes of QAV was consistent with that reported in previous studies.
In addition, the mean duration of clinical follow-up at our center was 4.8 years, and it is possible that some patients might have undergone aortic valve surgeries at another institution at a later time. Still, our study represents the first attempt in the literature to examine the natural history and long-term outcomes of patients with QAV.
QAV is a rare congenital cardiac anomaly, and our study provides important insights into its frequency, echocardiographic characteristics, natural history, and long-term outcomes. AR was the predominant hemodynamic abnormality, whereas aortic stenosis was rare. Aortic dilatation was more prevalent than has been reported previously. Nevertheless, a majority of our patients had no or only mild progression of AR and aortic dilatation over time, and only 16% underwent aortic valve surgery during a mean follow-up of almost 5 years. Long-term survival was excellent both without and with aortic valve surgery.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.017743/-/DC1.
- Received May 29, 2015.
- Accepted November 25, 2015.
- © 2015 American Heart Association, Inc.
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Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect in which an aortic valve is made up of 4 aortic valve cusps instead of 3 semilunar cusps as observed in a normal aortic valve. Given its low estimated frequency (<0.05%), QAV characteristics, natural history, and long-term outcomes have remained poorly defined. The present study sought to provide insights into these domains by analyzing 50 patients with QAV (frequency, 0.006%) from a large echocardiography database. In contrast to the male preponderance of QAV reported by other investigators, the sex distribution was relatively equal in our study. When QAVs were classified into 7 subtypes according to criteria proposed by Hurwitz and Roberts, type A (4 equal-sized cusps) and type B (3 equal and 1 smaller cusp) were the most common subtypes. Aortic regurgitation was the predominant hemodynamic abnormality associated with QAV, and aortic stenosis was rare. Aortic dilatation (found in 29% of our patients) and other structural cardiac abnormalities (documented in 32% of our cohort) were relatively common among patients with QAV. A majority of our patients had no or only mild progression of aortic regurgitation and aortic dilatation over time. During a follow-up of almost 5 years, only 16% of our patients had aortic valve surgery, with severe aortic regurgitation being the surgical indication in all but 1 patient. No infective endocarditis or aortic dissection was documented in our cohort. Long-term outcome was favorable not only for patients who did not receive aortic valve surgery but also for those who underwent aortic valve surgery.