Clinical manifestations and diagnosis of bicuspid aortic valve in adults

INTRODUCTION — The bicuspid aortic valve is one of the most common types of congenital heart disease, affecting approximately one percent of the population [1]. There is a strong genetic or heritable component to bicuspid aortic valve disease. Bicuspid aortic valve may occur sporadically or as an autosomal dominant inherited disorder with variable penetrance. It may occur as an isolated lesion or associated with other congenital cardiovascular defects or aortopathy syndromes. A bicuspid aortic valve may develop significant aortic stenosis and/or regurgitation and is at risk for infective endocarditis. The bicuspid aortic valve is often associated with aortic root and/or ascending aortic dilatation, and the prevalence of aortic enlargement increases with age [2]. Bicuspid aortic valve is a risk factor for aortic aneurysm and acute aortic dissection, which is related to underlying aortopathy, cystic medial degeneration, and hemodynamic factors.

This topic will discuss the clinical presentation and diagnosis of bicuspid aortic valve. Treatment of patients with bicuspid aortic valve disease is discussed separately. (See "Bicuspid aortic valve: General management in adults".)

VALVE ANATOMY — The anatomy of the bicuspid aortic valve includes unequal cusp size (generally due to fusion of two cusps producing the larger of two cusps), a raphe, and smooth cusp margins [1]. A raphe or fibrous ridge is the site of fusion of the two conjoined cusps and is identifiable in most cases. There is a wide spectrum of bicuspid aortic valves, including partial or complete leaflet fusion, the presence or absence of a raphe or multiple raphes, and different orientations of the true commissures [3]. The right and left coronary leaflets are the most commonly fused (70 to 86 percent) with the true commissures oriented in anterior-posterior position (typical pattern). Right and noncoronary leaflet fusion with right-left leaflet orientation (atypical pattern) occurs in 12 percent, while left and noncoronary leaflet fusion (3 percent) is the least common type of bicuspid aortic valve [4]. The coronary arteries usually arise in front of the cusps in which a raphe is present.

Leaflet orientation may affect valve function with fusion of the right and noncoronary leaflet associated with greater valvular dysfunction [5]. Leaflet orientation may also predict the pattern of aortopathy and is associated with differential regional aortic wall stress [6]. (See 'Aortic dilation and aortic dissection' below.)

Calcification of the bicuspid aortic valve increases with age and occurs more rapidly than that seen with tricuspid aortic valve. There is abnormal leaflet motion and turbulence during the cardiac cycle in bicuspid aortic valves and this may play a role in premature degeneration [7].

PREVALENCE — The prevalence of the bicuspid aortic valve has been estimated at approximately 1 percent of the population, with a 2 to 3:1 male to female ratio [1]. The Copenhagen Baby Heart Study reported the prevalence of bicuspid aortic valve in newborns to be 0.8 percent with a 2:1 male to female predominance [8]. A necropsy series of 21,417 cases reported 293 bicuspid valves (prevalence 1.37 percent) [9]. Of 20,946 military recruits, the prevalence of bicuspid aortic valve was 0.8 percent by echocardiographic survey [10]. There are groups with a higher prevalence of bicuspid aortic valves, including 30 to 50 percent of patients with coarctation of the aorta and 30 percent of Turner syndrome females [1].

GENETICS

Genetic syndromes — Large family studies have found a prevalence of a bicuspid aortic valve to be approximately 9 to 10 percent in first degree relatives of the individual with a bicuspid aortic valve [11,12]. Heritability estimates for the bicuspid aortic valve and other left ventricular (LV) outflow tract defects range from approximately 0.7 to 0.9, indicating a strong genetic component to the development of this congenital defect [13]. This is consistent with autosomal dominant inheritance with incomplete penetrance. Inheritance patterns for familial bicuspid aortic valve with ascending aortic aneurysm are also consistent with an autosomal dominant pattern with reduced penetrance and there is variable expressivity so some family members have an isolated bicuspid aortic valve, some have an ascending aortic aneurysm, some have both, and some obligate carriers have no manifest disease [14]. Thus, careful screening of the aortic valve and ascending aorta is necessary for first degree relatives of patients with bicuspid aortic valve or premature thoracic aortic aneurysm, as recommended below [1,14,15].

When faced with the patient with a bicuspid aortic valve and ascending aortic aneurysm, one must consider whether the aortic aneurysm is related to the bicuspid aortic valve alone (bicuspid aortic valve aortopathy) or whether it is related to another disease or aneurysm syndrome (such as bicuspid aortic valve with thoracic aortic aneurysm or other genetic syndrome) [14]. While bicuspid aortic valve has a strong genetic underpinning, the specific genetic cause or mutation is unknown for most individuals. Bicuspid aortic valve disease has been linked to a mutation on chromosome 9q [16] as well as to potential loci at 5q, 13q, 15q, and 18q in individuals with familial bicuspid aortic valve and aneurysm syndromes [14,17]. Mutations in NOTCH1 associate with familial and non-familial BAV, and may result in aortic aneurysms and early aortic calcification [1]. Mutations in other single genes such as GATA5, GATA6, and NKX2-5 have been associated with bicuspid aortic valve.

Other syndromes associated with bicuspid aortic valve and ascending aortic aneurysm include Turner syndrome (bicuspid valve present in approximately 30 percent), Loeys-Dietz syndrome (due to mutations in TGFBR1 and TGFBR2; bicuspid valve reported in 2.5 to 17 percent), and familial thoracic aortic aneurysm disease due to ACTA2 mutations (bicuspid aortic valve reported in 3 percent) and due to MAT2A, SMAD6, SMAD3, TGFB2, TGFB3, LOX and other genes (table 1) [18,19].

Screening — We suggest screening of first-degree relatives of patients with bicuspid (or unicuspid) aortic valve for bicuspid aortic valve (and aortic root and ascending aorta dilation) as suggested by the 2018 American College of Cardiology/American Heart Association (ACC/AHA) adult congenital heart disease guidelines [20]. Similarly, the 2010 guidelines for management of patients with thoracic aortic disease recommend evaluation of first-degree relative of patients with bicuspid aortic valve, premature onset of thoracic aortic disease with minimal risk factors, and/or a familial form of thoracic aortic aneurysm and dissection for the presence of a bicuspid aortic valve and asymptomatic thoracic aortic disease [15]. The 2020 ACC/AHA guidelines for the management of patients with valvular heart disease note that for first-degree relatives of patients with a known bicuspid aortic valve, a screening transthoracic echocardiogram might be considered to evaluate for a bicuspid aortic valve and/or dilation of the aortic sinuses and ascending aorta [21]. The ACC/AHA guidelines note that data are lacking on the impact of screening on outcomes and on the cost-effectiveness of this approach.

Screening is generally performed by echocardiography and should include assessment of the aortic root and ascending aorta. A study of echocardiography screening of 207 siblings (median age seven years) of 181 children with bicuspid valve found bicuspid aortic valve in 10 percent of siblings screened [22]. When performing screening, it is important to visualize the ascending aorta. If the ascending aorta is not well seen by echocardiogram, then computed tomography (CT) or cardiovascular magnetic resonance imaging (CMR) is recommended. (See 'Other imaging' below.)

ASSOCIATED CARDIOVASCULAR LESIONS — A bicuspid aortic valve may exist alone or associated with other congenital cardiovascular and aortic disorders. These include coarctation of the aorta, supravalvular aortic stenosis, subvalvular aortic stenosis, ventricular septal defect [23,24], patent ductus arteriosus, and sinus of Valsalva aneurysm (table 1).

Turner syndrome is due to complete or partial absence of one X chromosome and is commonly associated with bicuspid aortic valve (approximately 30 percent) and other cardiovascular defects (coarctation of the aorta, elongated aortic arch, partial anomalous pulmonary venous return) [18]. Individuals with Turner syndrome are at increased risk of aortic dissection and criteria for prophylactic surgery to replace the dilated aortic root are adjusted for the small body surface area of Turner women [25,26]. (See "Clinical manifestations and diagnosis of Turner syndrome" and "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

Coronary artery anomalies are associated with bicuspid aortic valves. Left coronary artery dominance is more common, and short left main coronary artery, separate ostia of the left coronary arteries, and anomalous origins of the coronary arteries have been described [1,27]. (See "Congenital and pediatric coronary artery abnormalities".)

A bicuspid aortic valve is present in approximately 15 to 20 percent of patients with sinus of Valsalva aneurysms. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm".)

The association between bicuspid aortic valve and aortic dilation, aortic dissection, and coarctation of the aorta is discussed below. (See 'Diseases of the aorta' below.)

CLINICAL MANIFESTATIONS — The clinical findings in the patient with bicuspid aortic valve depend upon the function of the valve and the presence of associated lesions.

The initial presentation of bicuspid aortic valve is variable with many patients presenting with asymptomatic auscultatory findings and others presenting with symptoms of valve dysfunction, bacterial endocarditis, with evidence of an aortic root or ascending aortic aneurysm, or after acute aortic dissection [1,28].

Patients with bicuspid aortic stenosis may remain asymptomatic for a prolonged period of time. Some with severe aortic stenosis may develop dyspnea, decreased exercise tolerance, exertional dizziness, angina, and syncope. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Symptoms'.)

Patients with bicuspid aortic regurgitation may also remain asymptomatic for a prolonged period of time. Some patients with severe aortic regurgitation may develop an uncomfortable awareness of the heartbeat, atypical chest pain, palpitations, or dyspnea. (See "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults", section on 'Symptoms'.)

A functionally normal bicuspid aortic valve produces an ejection sound or click. The ejection sound is heard at the cardiac apex or base (at the right second intercostal space) [29] and is often accompanied by a brief ejection murmur. (See "Auscultation of heart sounds", section on 'Aortic ejection sound'.)

Murmurs of aortic stenosis or regurgitation may be present, depending upon the valve function. (See "Auscultation of cardiac murmurs in adults", section on 'Aortic outflow obstruction'.) With progressive aortic stenosis, the ejection murmur becomes harsher and later peaking and the ejection sound diminishes or becomes inaudible. When aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border. When the aortic regurgitation murmur is loudest at the right midsternal border, a dilated ascending aorta may be present. (See "Auscultation of cardiac murmurs in adults", section on 'Aortic regurgitation'.)

Physical examination should include a careful arterial pulse examination, including evaluation for coexistent disease, such as coarctation of the aorta. When aortic aneurysm is present, especially involving the aortic root, it is important to evaluate the patient for features of an underlying syndromic aortopathy [30]. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Carotid pulse' and "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults", section on 'Physical examination' and "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Clinical manifestations'.)

The chest radiography may demonstrate aortic valve calcification or an enlarged aortic shadow (if aneurysm is present) or rib notching (if coarctation is present), but usually is unremarkable.

DIAGNOSIS

Approach to diagnosis — The diagnosis of bicuspid aortic valve is usually made by transthoracic echocardiography. Findings of a bicuspid aortic valve include: systolic doming, eccentric valve closure, leaflet redundancy, leaflet prolapse, presence of a raphe, elliptical orifice of valve during systole, distinct opening pattern, and a dilated aortic root and/or ascending aorta [1]. Unexplained eccentric aortic regurgitation jets may also suggest a bicuspid aortic valve. One must evaluate the valve carefully in systole, as a raphe may simulate a trileaflet appearance during diastole. The finding of eccentric valve closure has limited sensitivity and specificity since up to 25 percent of bicuspid aortic valves do not demonstrate eccentric valve closure and some tricuspid aortic valves show eccentric closure. Incomplete bicuspid aortic valves with very small raphes or partial leaflet fusion patterns should also be sought out, especially in the setting of aortic dilation [31].

When unexplained aortic dilatation is discovered and bicuspid aortic valve disease is not completely excluded by transthoracic echocardiogram, transesophageal echocardiogram, cardiac CT or CMR may be very useful in diagnosing or excluding an underlying bicuspid aortic valve, especially in the setting of partial aortic valve leaflet fusion [32].

Echocardiography — Transthoracic echocardiogram has a sensitivity of 78 to 92 percent and specificity of 96 percent for detecting bicuspid aortic valve [33,34]. However, the accuracy depends upon image quality, valve calcification, the presence of aneurysm disease, and the experience of the interpreter. Three-dimensional transthoracic echocardiography may enhance detection. When significant calcification and stenosis complicate the bicuspid valve, it may be difficult to discern the valve leaflet number accurately. By the time aortic valve replacement for aortic stenosis is required, the accuracy of the transthoracic echocardiogram for discerning leaflet number is substantially less. In a study of 100 patients (mean age 70 years) with aortic stenosis undergoing aortic valve replacement, the echocardiogram was considered interpretable in 86 cases [33]. Congenitally malformed valves were present in 44 patients and tricuspid valves in 42 patients. Valve structure was concordant by echocardiogram in 57 of 86 cases (66 percent).

Echocardiography generally establishes the diagnosis of bicuspid aortic valve and also provides an evaluation of aortic valve dysfunction and associated lesions. Patients with bicuspid aortic valve should undergo primary imaging by Doppler echocardiography, including assessment of any aortic stenosis or aortic regurgitation, measurement of aortic root and ascending aorta diameters, and to assess for the presence of aortic coarctation [20,21,35,36]. The echocardiogram should also assess any coexistent lesions such as dilation of the aortic root and ascending aorta, septal defects, and coarctation of the aorta.

Transesophageal echocardiogram is not generally required to diagnose bicuspid aortic valve but when performed has a high sensitivity of detecting the bicuspid aortic valve (approaching 100 percent) unless significant valvular calcification is present, which lowers the accuracy.

Other imaging — CT or CMR are recommended for evaluating the size and anatomy of the aortic root and ascending aorta when these cannot be adequately assessed by echocardiography or when coexisting lesions require further evaluation [21,36].

Since echocardiography is generally diagnostic, other imaging modalities are not usually needed to examine the bicuspid aortic valve itself. However, when echocardiography is suboptimal, such as in the patient with unexplained aortic sinus or ascending aortic dilation or eccentric aortic valve regurgitation, especially if calcification interferes with accurate leaflet evaluation, other imaging may be diagnostic. Multidetector CT (MDCT) and CMR have high accuracy for diagnosis of bicuspid aortic valve (sensitivity and specificity of 94 and 100 percent for MDCT and 100 and 95 percent for CMR) [37,38]. CT and CMR are also important in the assessment of bicuspid aortic valve morphology and calcification patterns before transcatheter aortic valve implantation [39,40].

CMR can also be helpful for assessment of the regurgitant volume when quantification of aortic regurgitation by echocardiography is uncertain [36]. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Regurgitant valve disease'.)

Criteria for thoracic aortic aneurysm — The thoracic aorta is considered dilated when the diameter is greater than two standard deviations above the mean (or a z-score >2), based on aortic segment-specific (aortic root at the sinus of Valsalva or ascending aorta) age-, sex-, and body size-adjusted nomograms, based upon echocardiographic, CT, or CMR data (figure 1 and figure 2) [35,41-46]. There are different definitions of what degree of aortic enlargement is necessary to be considered an aneurysm, one being an enlargement of the aorta segment at least 50 percent greater than that expected for an unaffected individual of the same age and sex. Women have smaller aortic diameters than men and it is important to consider age, sex, and body surface area in determining the significance of the aortic size [44]. A true aneurysm involves all three layers of the arterial wall. It is important to obtain an accurate measurement of the aorta perpendicular to the long axis of blood flow or using double oblique techniques [46]. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm", section on 'Definition of TAA'.)

Since varying criteria have been used to identify thoracic aortic aneurysm, recommendations for monitoring and treatment of aortic disease generally include specific numeric thresholds for aortic diameter. The 2016 ACC/AHA statement of clarification from the Task Force on Clinical Practice Guidelines regarding surgery for aortic dilatation in patients with bicuspid aortic valves noted that some evidence supports adjusting absolute aortic dimensions for body size [47]. Indexing aortic size to body size to assist with determining surgical threshold is especially important in Turner syndrome [26]. Thus, consideration of body size may affect decision making about timing of aorta aneurysm surgery in certain populations [48,49]. (See "Bicuspid aortic valve: Intervention for valve disease or aortopathy in adults", section on 'For the ascending aorta'.)

VALVE DISEASE

Natural history — The natural history of bicuspid aortic valve is defined by the occurrence of specific complications, including aortic stenosis, aortic regurgitation, infective endocarditis, aortic aneurysm, aortic dissection, and sequelae of coexisting congenital heart defects. In some individuals, the bicuspid aortic valve remains clinically silent and functions nearly normally for a lifetime, whereas in others, the valve lesion or aortic complication leads to significant morbidity (or mortality) at a relatively young age. It has been estimated that at least a third, and likely a majority, of bicuspid aortic valve patients will develop a complication during their lifetime [50-52]. However, asymptomatic or minimally symptomatic patients with bicuspid aortic valve disease treated in large referral centers have a life expectancy no different than the general population [51,52].  

In one series, 218 patients with congenitally malformed aortic valves were studied at autopsy: 28 (13 percent) had a unicuspid valve and 190 (87 percent) had a bicuspid valve [53]. Ages at death ranged from 21 to 89 years (mean ages: 55 years) and 80 percent were men. Of the 218 patients, the aortic valve functioned normally during life in 54 (25 percent) and abnormally in 164 (75 percent): aortic stenosis was present in 142 (65 percent), pure aortic regurgitation without superimposed infective endocarditis in two (1 percent), and infective endocarditis superimposed on a previously normally functioning aortic valve in 20 (9 percent). Endocarditis occurred in a total of 31 (14 percent) of the 218 patients: involving a previously normally functioning valve in 20 (65 percent) and a previously stenotic valve in 11 (35 percent). Of the 218 patients, at least 141 (65 percent) died as a consequence of aortic valve disease (124 patients) or ascending aortic tears with or without dissection (17 patients). Data from this study suggest that approximately 75 percent of patients with bicuspid aortic valve (who have not undergone aortic valve or aneurysm surgery) will develop a major complication. Conversely, about 25 percent will go through life without a complication.

Aortic stenosis — In autopsy series, aortic stenosis was present in 15 to 75 percent of bicuspid aortic valves [1,53].

In surgical series, about 50 percent of aortic stenosis leading to aortic valve replacement in adults is due to bicuspid aortic valve stenosis [54]. The prevalence of bicuspid aortic valves among patients undergoing aortic valve replacement for aortic stenosis varies with patient age, as illustrated by the following studies. In a series of 932 adults with isolated nonrheumatic aortic stenosis who underwent aortic valve replacement, among patients <50 years old, approximately two-thirds had a bicuspid aortic valve and one-third had a unicuspid aortic valve. Among the 40 percent of patients undergoing aortic valve replacement between 50 and 70 years old, two-thirds had a bicuspid aortic valve and one-third had a tricuspid aortic valve. Among the 53 percent of patients over 70 years old, 40 percent had a bicuspid aortic valve and 60 percent had a tricuspid aortic valve. In a series of 347 octogenarians and 17 nonagenarians who underwent aortic valve replacement for aortic stenosis, 78 (22 percent) and 3 (18 percent) had a congenital bicuspid aortic valve [55].

Histopathology of bicuspid aortic valve stenosis is similar to that in tricuspid aortic valve stenosis with lipid deposition, neoangiogenesis, and inflammatory cell infiltration [56]. Pathologic changes, including fibrosis, lipid accumulation, and inflammatory cell infiltration, begin at variable ages but may be seen in the second decade and progress to calcification by the fourth decade [57,58]. Leaflet morphology and atherosclerotic risk factors play a role in progression of aortic stenosis. In children, right and noncoronary leaflet fusion is associated with stenosis, while in adults, fusion of the right and left coronary cusps is associated with more rapid aortic stenosis [50,59]. Two population studies in adults did not demonstrate any effect on valve leaflet orientation and valve degeneration [51,52].

Bicuspid aortic valve stenosis requires surgery on average 5 to 10 years earlier than expected for tricuspid aortic valve stenosis [54]. In a population study from Toronto of 642 patients with bicuspid aortic valve with baseline age 35±16 years, 22 percent had at least moderate aortic stenosis at study entry [52]. Over a 9±5-year follow-up period, 21 percent required valve surgery. Most of the patients undergoing valve surgery had either symptomatic aortic stenosis (63 percent) or progressive LV dysfunction (28 percent).

Aortic regurgitation — Some degree of aortic regurgitation is common in patients with bicuspid aortic valve, but isolated moderate to severe aortic regurgitation complicating the bicuspid aortic valve is less common, affecting approximately 2 to 10 percent of patients [60]. Mixed aortic stenosis and regurgitation are often present. Population studies have reported that approximate 2 to 6 percent of patients with bicuspid aortic valve undergo aortic valve replacement for severe aortic regurgitation during long-term follow-up [51,52].

Pure aortic regurgitation is more commonly seen in younger patients, as some degree of aortic stenosis coexists in older patients. Bicuspid aortic valve is considered to be the most common cause of primary aortic regurgitation in the developed world [50]. Mechanisms for bicuspid aortic valve regurgitation include: leaflet abnormalities (redundancy, prolapse, unequal leaflet size); leaflet thickening and immobility; endocarditis; aortic root and annular dilatation with loss of valve support; aortic dissection; and postvalvuloplasty (for congenital aortic stenosis). The aortic root phenotype (dilatation of the aortic root) occurs in approximately 10 percent of bicuspid valve aortopathy and is often associated with aortic regurgitation [61].

Clinical manifestations from bicuspid aortic regurgitation occur earlier than for aortic stenosis and on average, aortic valve replacement is performed at an age 10 years younger than for aortic stenosis [4].

Infective endocarditis — The bicuspid aortic valve is at risk for infective endocarditis, whether related to abnormal leaflet structure or turbulent flow. Older pathologic studies reported more than one-third of aortic valve specimens with endocarditis were bicuspid valves [1]. Population studies report an incidence of 2 to 5 percent (over 5 to 25 years) among bicuspid aortic valve patients [51,52,62]. In a population study from Mayo Clinic, the incidence of infective endocarditis (definite and possible) in patients with bicuspid aortic valves was 9.9 per 10,000 patient years, resulting in an age-adjusted relative risk of endocarditis for those with bicuspid aortic valves of 16.9 compared with the general population, and a 25-year risk of endocarditis of 5±2 percent [62]. In an autopsy study, infective endocarditis occurred in 14 percent of bicuspid aortic valve patients [53]. Between 25 and 30 percent of aortic valve endocarditis is due to bicuspid aortic valve, and in children, the bicuspid aortic valve is one of the most common underlying lesions associated with endocarditis [63]. A previously unrecognized bicuspid aortic valve may be first recognized in the course of evaluating an episode of endocarditis. Up to 60 percent of severe aortic regurgitation in bicuspid aortic valve (often related to leaflet perforation) is a result of infective endocarditis [50].

It has also been reported that bicuspid aortic valve endocarditis requires surgery more often than trileaflet aortic valve endocarditis [64]. Individuals with bicuspid aortic valve endocarditis require cardiac surgery in 54 to 85 percent of cases and have a higher rate of perivalvular abscess compared with tricuspid aortic valve endocarditis [65-67].

Bicuspid aortic valve is not included among the high risk lesions that require antibiotic prophylaxis in the current guidelines for antibiotic prophylaxis (see "Prevention of endocarditis: Antibiotic prophylaxis and other measures"). However, some clinicians have suggested that given to the risk of infective endocarditis and a higher risk of serious complications, that bicuspid aortic valve patients may be considered for shared decision-making for antibiotic prophylaxis [67,68]. Appropriate dental hygiene should be emphasized. Individuals with bicuspid aortic valve should be educated about signs and symptoms of endocarditis and to report such symptoms to their health care providers.

Other complications of valve disease — Patients with aortic stenosis, including those with a congenital bicuspid aortic valve, are at risk for sudden death with higher risk in patients with symptomatic aortic stenosis versus those with asymptomatic disease [21]. Patients with chronic aortic regurgitation with markedly increased LV end-diastolic dimension (>80 mm) are also at risk for sudden death. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Sudden cardiac death'.)

DISEASES OF THE AORTA — Bicuspid aortic valve is a well-recognized risk factor for aortic dilation and aortic dissection and it is also associated with coarctation of the aorta [18].

Coarctation of the aorta — A bicuspid aortic valve occurs in approximately 30 to 50 percent of cases of coarctation of the aorta, while coarctation of the aorta has been found in 6 percent of patients with bicuspid aortic valve [69]. In the presurgical era, the combination of bicuspid aortic valve and coarctation was associated with a greater risk of aortic complications (including aneurysm and aortic dissection) than coarctation alone, as was first observed by Abbott in 1928 and discussed below [1,70-72]. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and 'Aortic dilation and aortic dissection' below.)

Aortic dilation and aortic dissection

Prevalence of aortic dilation and aneurysm — The aortic dilatation in bicuspid aortic valve disease may affect the aortic root and/or the ascending aorta, and is usually largest in the mid-ascending aorta [1,73]. The rate of aortic dilation increases in older adults with bicuspid aortic valve [74,75]. (See "Bicuspid aortic valve: General management in adults", section on 'Surveillance'.)

Distinct aortic phenotypes associated with bicuspid aortic valve disease have been identified [2,76,77]:

Type I: Dilatation of the tubular ascending aorta primarily along its convexity with mild to moderate root dilatation (most common type; associated with right-left cusp fusion and aortic stenosis).

Type II: Isolated tubular ascending aorta dilatation (with relative sparing of the aortic root), which may extend into the arch (associated with right-noncoronary cusp fusion).

Type III: Isolated aortic root dilatation (also known as the root phenotype) with normal tubular ascending aorta and arch dimensions (rarer [approximately 10 percent]; associated with young age at diagnosis; may be the form most likely to have a genetic cause) [61].

The reported prevalence of aortic dilation in patients with bicuspid aortic valve disease has ranged from 20 to 84 percent [2]. The frequency of aortic dilation in patients with bicuspid aortic valve depends upon the definition used (including site of measurement, method of measurement, and aortic diameter threshold) and the characteristics of the population studied (including age and valve disease), as illustrated by the following studies:

●In a population-based study of 25,556 newborns in Denmark, 196 (0.8 percent) had a bicuspid aortic valve, and in these patients aortic dilation (aortic z-score >3) was present in 33 percent [8].

●In a population of 280 adults with isolated bicuspid aortic valve, mid-ascending aortic dilation (defined here as >1.1 times the expected value) was observed in 56 percent of patients <30 years old and 88 percent of those >60 years old [78].

●In an Olmstead County cohort of 416 adults (aged 55 ±17 years) with bicuspid aortic valve, 32 (7.7) percent had an ascending aortic aneurysm (defined as aortic diameter >45 mm; mean diameter 48 ±6 mm) at baseline [75]. In these 32 patients with an initial aortic aneurysm, the 15-year risk of surgery was 46 percent and of aortic dissection was 7 percent. In 384 patients without an aneurysm at time of initial study, 49 developed an aortic aneurysm at 14±6 years after diagnosis. The 25-year risk of developing an aneurysm was 26 percent.

●In a study from Toronto of 642 adults (aged 36±16 years) with bicuspid aortic valve, aortic sinus dilation >35 mm was identified in 28 percent and aortic sinus dilation >40 mm was present in 9.8 percent [52].

The rate of aortic enlargement in bicuspid aortic valve disease is variable with reported rates ranging from 0.2 to 2.3 mm/year, [1,2,79]. Most aortas demonstrate slow growth with aneurysmal aortas growing more rapidly. Periodic imaging of the aorta by transthoracic echo, CMR, or CT is recommended, with the interval determined by the degree and rate of progression of aortic dilation and family history. After aortic valve replacement for bicuspid aortic valve, continued lifelong serial imaging of the aorta is reasonable if the aortic sinuses or ascending aorta are >4.0 cm [21]. (See "Bicuspid aortic valve: General management in adults".)

Risk of aortic dissection — The risk of aortic dissection in bicuspid valve disease increases with greater degrees of aortic dilatation. In autopsy series of aortic dissection, 5 to 7 percent of patients are found to have bicuspid aortic valves [9,50]. In series of patients under 40 years old with acute dissection, 9 to 28 percent had a bicuspid aortic valve [1,80]. It has been estimated that aortic dissection occurs 5 to 10 times more commonly in patients with bicuspid aortic valve, as compared to patients with tricuspid aortic valve [1,18]. Aortic dissection occurs in patients with bicuspid aortic valve at an age approximately one decade earlier (54 versus 62 years) than in patients with tricuspid aortic valves [81]. (See "Clinical features and diagnosis of acute aortic dissection".)

The lifetime risk of aortic dissection for the bicuspid aortic valve patient followed longitudinally is relatively low, and is highly dependent upon the degree of aortic dilation and the patient's age, as illustrated by the following studies [51,52,75]. These data do not necessarily reflect the natural history of aortic disease since patients were longitudinally followed with patients referred for elective surgery as deemed clinically appropriate.

●In a report from Toronto of 642 patients with bicuspid aortic valve (mean age at baseline 34 years), five suffered an aortic dissection during 9±5 years of follow-up [52]. Eleven patients underwent surgery for aortic root or ascending aorta dilation.

●In a series from Olmstead County of 416 patients with known bicuspid aortic valve (age at diagnosis 35±12 years) followed for a mean of 16 years, aortic dissection occurred in two patients for an incidence of 3.1 cases per 10,000 patient-years and an age-adjusted relative risk of 8.4 (95% CI 2.1-33.5) compared with the general population [75]. Higher rates were observed in patients aged ≥50 years at baseline (17.4 cases per 10,000 patient-years) and in patients with ascending aortic aneurysm (defined as a diameter >4.5 cm) at baseline (44.9 cases per 10,000 patient-years, compared with an age matched population risk of 0.31 per 10,000 person-years). A total of 49 patients underwent surgery of the thoracic aorta, including 36 for elective aneurysm repair.

●In a series from the Cleveland Clinic, outcomes of 1181 bicuspid aortic valve patients with an aortic diameter >4.7 cm at the sinus of Valsalva or ascending aorta were reported [82]. Eight hundred and one patients underwent aortic surgery (68 percent with valve surgery). The 380 patients who did not undergo immediate surgery were followed for a median of three (range 0 to 17) years; 175 of 380 underwent aortic surgery during follow-up. Ten of 380 (2.6 percent) suffered acute type A aortic dissection. The risk-adjusted probability of acute aortic dissection increased at an aortic diameter >5 cm in the sinuses of Valsalva or >5.3 cm in the ascending aorta. The risk of dissection was 3.8 percent at an ascending aortic diameter of 5.3 cm and was nearly 10 percent at an ascending aortic diameter of 6.0 cm. In this study, aortic cross-sectional area-to-height ratio was a better predictor of aortic dissection than aortic diameter.

Pathophysiology of aortic disease — Aortic dilation and aortic dissection in patients with bicuspid aortic valve is related to an underlying aortopathy with cystic medial degeneration. The relative contribution of hemodynamic effects of the bicuspid aortic valve and underlying genetic defects to the aortopathy of bicuspid aortic valve disease is debated [2].

Supporting an underlying aortic defect is that aortic dilatation is present in newborns and children with bicuspid aortic valve without primary valve stenosis or regurgitation and that aortic dilatation may occur late after aortic valve replacement.

A primary defect in the aortic wall with cystic medial degeneration related to genetic factors may underlie the aortic complications, including aortic aneurysm and aortic dissection associated with bicuspid aortic valve [1,2,73]. Patients with bicuspid aortic valve have aortic root and ascending aortic size greater than control patients, controlling for age, valvular lesions, and hypertension [83]. Echocardiogram surveys have demonstrated aortic dilation in the sinuses and ascending aorta compared to controls, and when underlying valve regurgitation is severe, the ascending aorta is generally larger [1,78].

Regardless of the relative contributions of hemodynamic alternations or genetic underpinnings, histopathologic sampling of the aortic media in bicuspid aortic valve patients without aortic dilation has demonstrated cystic medial degeneration [1,73]. Compared with aortic aneurysms associated with a tricuspid aortic valve, the bicuspid aortic valve aortic aneurysm demonstrates increased levels of apoptosis, more intense elastic fragmentation, and higher levels of matrix metalloproteinase inhibitors [73,84]. Decreased fibrillin-1 content and increased collagen-related stiffness has been described [85]. Abnormalities in protein kinase C-signaling pathways [86] and upregulation of transforming growth factor-beta signaling may play a role in pathogenesis [87]. The type of valve dysfunction associated with aortic dilatation may be important in predicting cystic medial degeneration. The aortic histology was examined for cystic medial degeneration from operatively excised dilated aortas (>4.5 cm) in patients undergoing aortic valve replacement for aortic stenosis (from unicuspid or bicuspid valves) or pure aortic regurgitation (from bicuspid valves) [88]. In the 58 patients with aortic stenosis, the aortic media was normal or nearly normal in 87 percent of bicuspid aortic valve patients. Of the 38 patients with pure aortic regurgitation, the aortic media was normal in 53 percent and abnormal in 47 percent.

Alterations in mechanical properties of the aorta have been observed in bicuspid aortic valve patients. Patients with bicuspid aortic valve have reduced aortic elasticity and distensibility, as demonstrated by magnetic resonance imaging [89]. First degree relatives of the patient with bicuspid aortic valve and aortic aneurysm may also have abnormal aortic elastic properties [90].

There is increasing evidence in support of abnormal hemodynamic effects and associated regional aortic wall shear stress from bicuspid aortic valve flow patterns as an underlying cause for bicuspid aortic valve aortopathy and possibly related to various aortic phenotypes [91].

The bicuspid aortic valve exhibits abnormal leaflet folding, wrinkling, and increased leaflet doming, which can result in turbulence even in the absence of a stenotic lesion [1]. The aortic curvature and regions of turbulent flow may also play a role. Markedly abnormal helical flow patterns in the ascending aorta of patients with bicuspid aortic valve with and without aortic aneurysms have been demonstrated, and this abnormal helical flow correlates with abnormal wall shear stress [1,2,77]. Partial leaflet fusion bicuspid aortic valve is also associated with abnormal regional aortic wall hemodynamics and wall stress [32]. Regional variation in aortic wall shear stress may also be related to the type of bicuspid valve leaflet fusion phenotype [92]. Further studies examining aneurysmal aortic tissue from sites of increased wall shear stress document a strong correlation between elevated regional wall shear stress and greater degrees of cystic medial degeneration, increased matrix metalloproteinase activity, and increased TGF-beta expression [6].

Impact of coarctation — Different series have reported variable relationships or contributions of aortic coarctation to the aortic event rates among patients with bicuspid aortic valve.

●Some studies have reported an increased rate of aortic events when aortic coarctation accompanies a bicuspid aortic valve [70,71]. Among patients with aortic coarctation, the presence of a coexistent bicuspid aortic valve was strongly associated with aortic dilation [93]. In a series of 622 adult patients with bicuspid aortic valve (mean age 32 years) followed during the period 1989 to 2006, the prevalence of ascending aortic complications (aneurysm >55 mm aortic dissection or rupture) was 8 percent in patients with bicuspid aortic valve plus coarctation versus 4 percent in patients with bicuspid aortic valve alone [70]. Among the 341 patients with a bicuspid aortic valve and no baseline aortic complications who were followed for a median of seven years, the incidence of developing complications was significantly higher in the group with coarctation of the aorta (130 versus 20 per 10,000 patient-years; hazard ratio 7.5, 95% CI 2.0-28).

●A later study of patients with bicuspid aortic valve found no increase in aortic events associated with history of corrected aortic coarctation. Among 499 patients with a bicuspid aortic valve (mean age 40±16 years) followed from 2003 to 2019, 121 (24 percent) had coexisting aortic coarctation [72]. All patients with hemodynamically significant coarctation underwent surgical or interventional correction. An adverse aortic event (aortic dissection or prophylactic aneurysm surgery) occurred in 7.6 percent of patients at a mean age of 49±14 years. There was no significant difference in the occurrence of aortic dissection or a markedly dilated ascending aorta (>50 mm) between patients with or without aortic coarctation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bicuspid aortic valve" and "Society guideline links: Cardiac valve disease" and "Society guideline links: Aortic dissection and other acute aortic syndromes" and "Society guideline links: Congenital heart disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Bicuspid aortic valve is one of the most common types of congenital heart defects, affecting approximately 1 percent of the population. There is a 2 to 3:1 male predominance. (See 'Prevalence' above.)

●The diagnosis of bicuspid aortic valve is generally established by transthoracic echocardiography. Echocardiographic features include systolic doming, eccentric valve closure, presence of a raphe, elliptical opening, and a dilated ascending aorta. It is important to determine leaflet number and appearance in systole since a raphe can simulate a trileaflet appearance in diastole. (See 'Diagnosis' above.)

●The bicuspid aortic valve is usually isolated, but may coexist with other congenital heart defects or genetic syndromes, and may be inherited as an autosomal dominant condition with incomplete penetrance or be a component of an underlying familial thoracic aortic aneurysm syndrome. (See 'Genetics' above.)

●The ascending aorta in bicuspid aortic valve disease should be completely visualized by echocardiogram (and cardiovascular magnetic resonance imaging [CMR] or computed tomography [CT] if necessary) to evaluate for associated aortopathy.

●Echocardiographic screening of first-degree relatives of the patient with a bicuspid valve may be considered, especially if the patient with bicuspid valve has associated aortopathy or a family history of valvular heart disease or aortopathy. (See 'Screening' above.)

●Patients with bicuspid aortic valve develop significant aortic stenosis much more frequently than significant aortic regurgitation and are at risk for infective endocarditis. (See 'Valve disease' above.)

●Patients with bicuspid aortic valve are at risk for aortic dilation (most commonly involving the ascending aorta) and aortic dissection when the aorta is dilated. These aortic complications are caused by an underlying aortopathy with cystic medial degeneration, which may relate to hemodynamic factors and abnormal aortic wall shear stress and may have a genetic contribution. (See 'Aortic dilation and aortic dissection' above and 'Pathophysiology of aortic disease' above.)

●A bicuspid aortic valve is frequently associated with other congenital cardiovascular defects, including coarctation of the aorta, supravalvular aortic stenosis, subvalvular aortic stenosis, ventricular septal defect, and sinus of Valsalva aneurysm. The combination of bicuspid aortic valve and coarctation of the aorta has been associated with a higher risk of aortic complications in some studies, but later studies have questioned this relationship. (See 'Associated cardiovascular lesions' above.)

ACKNOWLEDGMENTS

The editorial staff at UpToDate acknowledges Martin G Keane, MD, FACC, FAHA, FASE, Thomas P Graham, MD, and Catherine M Otto, MD, who contributed to earlier versions of this topic review.

The editorial staff would also like to acknowledge Martin St. John Sutton, MD (deceased), who contributed to earlier versions of this topic.