**3. Clinic**

The clinical presentation of patients with BAV can vary from severe valve disease in infancy to asymptomatic valve disease in old age. It may be associated with abnormalities of the aortic wall such as coarctation of the aorta, aortic dissection, and aortic aneurysm. Most pa‐ tients with a BAV develop some complications during life [1,2].

Congenital coronary anomalies, coronary atherosclerosis, and calcification have been descri‐ bed in association with BAV[3].

The congenitally BAV may function normally throughout life, may develop progressive cal‐ cification and stenosis or may develop regurgitation with or without infection. Aortic root dilatation is common in BAV, even when the valve is haemodynamically normal, and conse‐ quently aortic dissection usually occurs in previously asymptomatic patients [4,5].

Sudden death may occur as a result of obstruction of the left ventricular outflow tract by a congenital BAV [54]. BAV are in most cases remain undetected until infection or calcification supervenes [55].

Aortic stenosis and regurgitation, infective endocarditis and aortic dissection are the most common complications. Left coronary artery dominance is more common in patients with a BAV (29-56.8%) and in 90% of cases, the left main coronary artery is less than 5 mm in length [7,8]. The ignorance of these associations may cause an inadequate myocardial pres‐ ervation and an increased risk of myocardial infarction[9,10].

Symptoms associated with aortic stenosis are angina pectoris, syncope, and congestive heart failure. The most common complication of aortic stenosis is congestive heart failure sympto‐ matically presented with dyspnea, which is a result of combined diastolic and systolic dys‐ function [56]. Angina pectoris occurs in patients with severe aortic stenosis and in those who do not have coronary artery disease; it may be a result of ventricular hypertrophy.

For BAV associated with stenosis, mean gradient and maximal flow velocity should be measured, but when regurgitation is present, the effective regurgitant area and Doppler jet size should be evaluated. For asymptomatic patients with aortic stenosis, echocardiography is recommended for evaluating disease progression. In asymptomatic patients, TTE recom‐ mended: every year for severe aortic stenosis, ever 1-2 years for moderate aortic stenosis and

In patients with poor acustic window, cardiac magnetic resonance (MRI) and multidetector computed tomography are useful for measuring the aortic valve area and is an alternative method to echocardiography in selected cases. MRI especially will enable views of the valve to be obtained without interference from calcification. It also allows for excellent assessment of the aorta. A recent study of 123 patients with confirmed BAV found that 10% of the pa‐ tients were misidentified as having a tricuspid valve using transthoracic echo and 28% had a nondiagnostic study, in comparison to 4% being misidentified as having a tricuspid valve

The current guidelines suggest that cardiac magnetic resonance imaging or cardiac comput‐ ed tomography is reasonable in patients with BAVs when aortic root dilatation is detected by echocardiography to further quantify severity of dilatation and involvement of theas‐

The clinical presentation of patients with BAV can vary from severe valve disease in infancy to asymptomatic valve disease in old age. It may be associated with abnormalities of the aortic wall such as coarctation of the aorta, aortic dissection, and aortic aneurysm. Most pa‐

Congenital coronary anomalies, coronary atherosclerosis, and calcification have been descri‐

The congenitally BAV may function normally throughout life, may develop progressive cal‐ cification and stenosis or may develop regurgitation with or without infection. Aortic root dilatation is common in BAV, even when the valve is haemodynamically normal, and conse‐

Sudden death may occur as a result of obstruction of the left ventricular outflow tract by a congenital BAV [54]. BAV are in most cases remain undetected until infection or calcification

Aortic stenosis and regurgitation, infective endocarditis and aortic dissection are the most common complications. Left coronary artery dominance is more common in patients with a BAV (29-56.8%) and in 90% of cases, the left main coronary artery is less than 5 mm in length [7,8]. The ignorance of these associations may cause an inadequate myocardial pres‐

quently aortic dissection usually occurs in previously asymptomatic patients [4,5].

every 3-5 years for mild aortic stenosis [51].

by MRI and 2% having a non-diagnostic study [52].

cending aorta (Clas IIa; Level of Evidence: B)[53].

tients with a BAV develop some complications during life [1,2].

ervation and an increased risk of myocardial infarction[9,10].

**3. Clinic**

340 Calcific Aortic Valve Disease

bed in association with BAV[3].

supervenes [55].

Syncope is another common symptom in patients with BAV. Syncope reflects the cerebral hypoperfusion caused by the inability to increase stroke volume during physical activity.

The clinical presentation in patients with BAV and presence of other cardiac congenital de‐ fects depends from structural complexity of the heart. In patients with interventricular sep‐ tal defects, the clinical presentation depends on the size of the defect area and the grade of aortic stenosis. If the interventricular defect is small, the patient may be asymptomatic, but when the interventricular defect is large, cardiac output will decrease and Eisenmenger syn‐ drome will develop.

Two large recent series reported that clinical course of unoperated patients with BAV de‐ pends on age, stenosis, and aortic incompetence. The severe aortic stenosis, and severe aortic incompetence in older patients increases the risk of primary cardiac events including cardiac death. Both these studies suggest that intervention on the basis of early symptoms or incipi‐ ent cardiac dysfunction may decreases the mortality of patients with BAV [57,58].

The natural history of BAV has been evaluated several cohort studies. It is known to be vari‐ able and of course somewhat dependent on associated abnormalities. It can range from se‐ vere aortic stenosis in childhood to asymptomatic disease until old age. There have indeed been incidental findings of a minimally calcified BAV in patients in their 70s.More common‐ ly however [in around 75% of patients] there is progressive fibrocalcific stenosis of the valve eventually requiring surgery. This usually leads to presentation in middle age only around 2% of children have clinically significant BAV disease [59].

The prevalence of fibrosis, cystic medial necrosis, elastic fragmentation, and inflammation has been shown to be significantly higher in patients with fusion of the left coronary and right coronary cusps. fusion of the left coronary and right coronary cusps was associated with a larger aortic root diameter and a smaller aortic arch,than was fusion of the right coro‐ nary and non-coronary cusps. Another study demonstraed that fusion of the right coronary and non-coronary cusps correlated with the more rapid growth of ascending aortic diameter in the pediatric population [60-63].

There have been a couple of studies looking at long-term followup of patients with unoper‐ ated BAV. A cohort of 212 asymptomatic patients with BAV were found to have the same 20-year survival rate as the normal population but an increased frequency of cardiac events including aortic valve surgery, ascending aorta surgery and any other cardiovascular sur‐ gery. Predictive factors for cardiovascular events were found to be age ≥50 years and valve degeneration at diagnosis while baseline ascending aorta ≥40 mm independently predicted surgery for aorta dilatation. Another study [64] 642 patients were followed up for a mean of 9 years, again with a 10-year survival rate similar to the normal population [96%]. One or more primary cardiac events occurred in 25% including cardiac death in 3, intervention on aortic valve or ascending aorta in 22%, aortic dissection or aneurysm in 2%, and congestive heart failure requiring hospital admission in 2%. Independent predictors of primary cardiac events were age older than 30 years, moderate or severe aortic stenosis, and moderate or se‐ vere aortic regurgitation [50].

disease after 30 years of follow-up. Age was the primary determinant of valvular disease

The Bicuspid Aortic Valve http://dx.doi.org/10.5772/52567 343

In adults, with BAV, stenosis occurs by similar methods to the process in patients with tri‐ cuspid aortic valves. It is felt to be due to calcification, endothelial dysfunction, inflamma‐ tion, lipoprotein deposition, and ossification of the aortic side of the valve leaflets. There has been a suggestion that leaflet orientation may be a predictive factor in the rate of valve stenosis. The folding and creasing of the valves and the turbulent flow are felt to contribute to development of fibrosis and calcification [59].more rapid progression in aortic valve gra‐ dients occurred in patients with anteroposteriorly located cusps[60]. However, not all stud‐ ies have found this association, and the 2 large studies in adults have not identified leaflet orientation as a risk factor for late adverse events. Olmsted County study identified a com‐ posite index of valve degeneration, which incorporated valve thickening, calcification, and mobility, that was an independent predictor of long-term cardiac events in a population of adults with no baseline valve dysfunction. The predictive role of both morphology and function in adults with BAV parallels that observed in series examining older adults with

Primary aortic regurgitation without infective endocarditis was uncommon, and 32% had an

One cohort of 118 BAV patients found that of 70 patients without aortic stenosis, 28 (40% had moderate to severe aortic regurgitation. The mechanisms of aortic incompetence in chil‐ dren are usually due to prolapsing cusps, myxoid degeneration, postvalve surgery and after balloon valvuloplasty or endocarditis, while as the patients age dilatation of the ascending aorta can lead to a functionally regurgitant valve[68,69]. With age, aortic incompetence may also develop secondary to dilation of the ascending aorta. In the Olmstead study of asymp‐ tomatic adults, 47% had some degree of aortic incompetence at baseline; however, interven‐ tions for severe aortic incompetence were relatively uncommon, occurring in only 3% of the cohort during follow-up. In the Toronto study 21% of the population had moderate or se‐ vere aortic incompetence at baseline; however, only 6% had an intervention for symptomat‐

BAV patients tend to develop vascular abnormalities of the aorta, such as dilation, coarcta‐ tion and dissection. Aortic dilation in BAV patients is thought to be caused by intrinsic aort‐ ic disease that is characterized by cystic medial necrosis and disruption of the extracellular matrix due to fibrillin deficiency. BAV is often associated with dilatation of the aortic root and the ascending aorta. This is otherwise known as aortopathy. This can lead to aneurysm and dissection. The dilatation has been reported during childhood, and it has also been sug‐ gested that increased aortic size at baseline is predictive for earlier dilatation and worse out‐ comes. Aortic size is larger generally in patients with BAV compared to those with normal

ic aortic incompetence or progressive left ventricular dysfunction [62,63].

progression [50,66].

**3.2. Aortic incompetence**

**3.3. Aortopathy/aortic dissection**

aortic stenosis mostly of acquired basis [50,62,63].

apparently normally functioning aortic valve [67].

In the another study [61].the incidence of aortic dissection was found to be 1.5% in all pa‐ tients regardless of the progression of BAV; however this increased markedly in patients aged 50 or older at baseline to 17.4% and even more in those found to have aneurysm for‐ mation at baseline to [44.9%]. 25-year rate for aortic surgery was 25% and there was a signif‐ icant burden of progression of disease to cause aortic dissection with 49 of the 384 patients without baseline aneurysms developing them during followup [22].

Although the clinical presentation of patients with BAV can vary from severe valve disease in infancy to asymptomatic valve or thoracic aortic disease in old age, symptomstypically develop in adulthood. The clinical manifestations relate to the function of the aortic valve,the aortopathy/dissection, and acquired complications such as endocarditis. However in childhood, BAV disease is commonly asymptomatic [61]

Estimates of late cardiac events were approximately 25% at a mean age of 44 years in the study from Toronto and 40% at a mean age of 52 years in the Olmsted County study [62,63]. In the Olmsted County series, 27% of adults with BAV and no significant valve disease at baseline required cardiovascular surgery within 20 years of follow-up. Twenty-two percent of the patients in the Toronto cohort required intervention within 9 years of follow-up. In both studies, age was an important determinant of outcomes supporting the notion held by many that eventually most patients with BAV would require some form of intervention.

#### **3.1. Aortic stenosis**

A common complication of BAV disease is aortic stenosis. BAV is recognized as a frequent cause of aortic stenosis in adults. Aortic stenosis has been found in 72% of adults with BAV. In 388 patients with severe aortic valve disease alone, BAVs were found in 45% of the pa‐ tients with aortic stenosis and 24% of the patients with aortic regurgitation. In 110 patients with severe combined aortic and mitral valve disease, BAVs were found in only 12% [64].

Among the 600 patients analyzed, 213 (36%) had pure aortic stenosis, 265 (44%) had pure aortic regurgitation and 122 (20%) had combined stenosis and regurgitation. BAVs repre‐ sented 18%, as the third most important cause of aortic disorder following degenerative and rheumatic changes, followed by infective endocarditis (5%) [65].

The main symptoms are exertional dyspnea, syncope, and chest pain. These patients should be evaluated and managed similarly to patients with tricuspid aortic valve stenosis.

In the Joint Study of the Natural History of Congenital Heart Defects, one-third of the chil‐ dren in the cohort had increases in catheterization gradients during the 4- to 8-year followup period. In the follow-up study, children with baseline peak left ventricular to aortic gradients >50 mm Hg were at risk for serious cardiac events at a rate of 1.2% per year. In theUnited Kingdom cohort.20% of children with mild aortic stenosis at baselinehad mild disease after 30 years of follow-up. Age was the primary determinant of valvular disease progression [50,66].

In adults, with BAV, stenosis occurs by similar methods to the process in patients with tri‐ cuspid aortic valves. It is felt to be due to calcification, endothelial dysfunction, inflamma‐ tion, lipoprotein deposition, and ossification of the aortic side of the valve leaflets. There has been a suggestion that leaflet orientation may be a predictive factor in the rate of valve stenosis. The folding and creasing of the valves and the turbulent flow are felt to contribute to development of fibrosis and calcification [59].more rapid progression in aortic valve gra‐ dients occurred in patients with anteroposteriorly located cusps[60]. However, not all stud‐ ies have found this association, and the 2 large studies in adults have not identified leaflet orientation as a risk factor for late adverse events. Olmsted County study identified a com‐ posite index of valve degeneration, which incorporated valve thickening, calcification, and mobility, that was an independent predictor of long-term cardiac events in a population of adults with no baseline valve dysfunction. The predictive role of both morphology and function in adults with BAV parallels that observed in series examining older adults with aortic stenosis mostly of acquired basis [50,62,63].

#### **3.2. Aortic incompetence**

aortic valve or ascending aorta in 22%, aortic dissection or aneurysm in 2%, and congestive heart failure requiring hospital admission in 2%. Independent predictors of primary cardiac events were age older than 30 years, moderate or severe aortic stenosis, and moderate or se‐

In the another study [61].the incidence of aortic dissection was found to be 1.5% in all pa‐ tients regardless of the progression of BAV; however this increased markedly in patients aged 50 or older at baseline to 17.4% and even more in those found to have aneurysm for‐ mation at baseline to [44.9%]. 25-year rate for aortic surgery was 25% and there was a signif‐ icant burden of progression of disease to cause aortic dissection with 49 of the 384 patients

Although the clinical presentation of patients with BAV can vary from severe valve disease in infancy to asymptomatic valve or thoracic aortic disease in old age, symptomstypically develop in adulthood. The clinical manifestations relate to the function of the aortic valve,the aortopathy/dissection, and acquired complications such as endocarditis. However

Estimates of late cardiac events were approximately 25% at a mean age of 44 years in the study from Toronto and 40% at a mean age of 52 years in the Olmsted County study [62,63]. In the Olmsted County series, 27% of adults with BAV and no significant valve disease at baseline required cardiovascular surgery within 20 years of follow-up. Twenty-two percent of the patients in the Toronto cohort required intervention within 9 years of follow-up. In both studies, age was an important determinant of outcomes supporting the notion held by many that eventually most patients with BAV would require some form of intervention.

A common complication of BAV disease is aortic stenosis. BAV is recognized as a frequent cause of aortic stenosis in adults. Aortic stenosis has been found in 72% of adults with BAV. In 388 patients with severe aortic valve disease alone, BAVs were found in 45% of the pa‐ tients with aortic stenosis and 24% of the patients with aortic regurgitation. In 110 patients with severe combined aortic and mitral valve disease, BAVs were found in only 12% [64].

Among the 600 patients analyzed, 213 (36%) had pure aortic stenosis, 265 (44%) had pure aortic regurgitation and 122 (20%) had combined stenosis and regurgitation. BAVs repre‐ sented 18%, as the third most important cause of aortic disorder following degenerative and

The main symptoms are exertional dyspnea, syncope, and chest pain. These patients should

In the Joint Study of the Natural History of Congenital Heart Defects, one-third of the chil‐ dren in the cohort had increases in catheterization gradients during the 4- to 8-year followup period. In the follow-up study, children with baseline peak left ventricular to aortic gradients >50 mm Hg were at risk for serious cardiac events at a rate of 1.2% per year. In theUnited Kingdom cohort.20% of children with mild aortic stenosis at baselinehad mild

be evaluated and managed similarly to patients with tricuspid aortic valve stenosis.

without baseline aneurysms developing them during followup [22].

in childhood, BAV disease is commonly asymptomatic [61]

rheumatic changes, followed by infective endocarditis (5%) [65].

vere aortic regurgitation [50].

342 Calcific Aortic Valve Disease

**3.1. Aortic stenosis**

Primary aortic regurgitation without infective endocarditis was uncommon, and 32% had an apparently normally functioning aortic valve [67].

One cohort of 118 BAV patients found that of 70 patients without aortic stenosis, 28 (40% had moderate to severe aortic regurgitation. The mechanisms of aortic incompetence in chil‐ dren are usually due to prolapsing cusps, myxoid degeneration, postvalve surgery and after balloon valvuloplasty or endocarditis, while as the patients age dilatation of the ascending aorta can lead to a functionally regurgitant valve[68,69]. With age, aortic incompetence may also develop secondary to dilation of the ascending aorta. In the Olmstead study of asymp‐ tomatic adults, 47% had some degree of aortic incompetence at baseline; however, interven‐ tions for severe aortic incompetence were relatively uncommon, occurring in only 3% of the cohort during follow-up. In the Toronto study 21% of the population had moderate or se‐ vere aortic incompetence at baseline; however, only 6% had an intervention for symptomat‐ ic aortic incompetence or progressive left ventricular dysfunction [62,63].

#### **3.3. Aortopathy/aortic dissection**

BAV patients tend to develop vascular abnormalities of the aorta, such as dilation, coarcta‐ tion and dissection. Aortic dilation in BAV patients is thought to be caused by intrinsic aort‐ ic disease that is characterized by cystic medial necrosis and disruption of the extracellular matrix due to fibrillin deficiency. BAV is often associated with dilatation of the aortic root and the ascending aorta. This is otherwise known as aortopathy. This can lead to aneurysm and dissection. The dilatation has been reported during childhood, and it has also been sug‐ gested that increased aortic size at baseline is predictive for earlier dilatation and worse out‐ comes. Aortic size is larger generally in patients with BAV compared to those with normal valves. The most likely risk factor for progression is felt to be age. Aortic root size itself is related to valve morphology and the presence of significant disease [22,6]; however, a recent study did suggest that while most patients with BAV and ascending aortic aneurysm had severe valve dysfunction, there was a small proportion of patients (5%) who did have aneur‐ ysm formation without any aortic valve dysfunction [50].

muscle cell (VSMC) apoptosis and extracellular matrix degeneration in the absence of a sig‐

The Bicuspid Aortic Valve http://dx.doi.org/10.5772/52567 345

Abnormalities in the ascending aorta of the patients with BAV, specifically premature medi‐ al layer VSMC apoptosis, have been described, explaining the higherthan-expected preva‐

In patient with BAV there are fibrillin, fibronectin, and tenascin abnormality. Additionally Bonderman et al suggested that a primary role for VMSC apoptosis in the development of

The FBN1 gene encodes fibrillin-1, a large glycoprotein that is secreted from cells and depos‐ ited in the extracellular matrix in structures called microfibrils. Microfibrils are found at the periphery of elastic fibers, including the elastic fibers in the medial layer of the ascending

The histopathological appearance of thoracic aortic aneurysm in Marfan and BAV is similar, and includes evidence of VSMC apoptosis and extracellular matrix degeneration in the ab‐ sence of a significant inflammatory response. Abnormalities in the ascending aorta of the patients with BAV, specifically premature medial layer smooth muscle cell apoptosis, have been described, explaining the higherthan-expected prevalance of aortic dissection in these

Aortic root dilation has been documented in childhood, suggesting that this process begins early in life. Furthermore, children with BAV have greater increases in aortic dimensions than do children with trileaflet valves. In both children and adults, progressive dilation of the aorta is more common in patients with larger aortas at baseline. In BAV disease, the aort‐ ic annulus, sinus, and proximal ascending aorta are larger than those found in adults with

In the Olmsted County study, the prevalence of ascending aorta dilation (>40 mm) was 15% and in the subset of patients with repeat measurements, the prevalence increased to 39% at study completion. Dilation of the ascending aorta was an independent risk factor for ascend‐ ing aorta surgery. Although there are a number of risk factors associated with dilation of the ascending aorta including increased systolic blood pressure, male sex, and significant valve disease, the most important variable is likely age [50,63,64]. Aortic root size is shown to be re‐ lated to valve morphology and the presence of significant valve disease. In the Toronto series, the prevalence of dissection was 0.1% per patient-year of follow-up, and in the Olmsted Coun‐ ty study, there were no cases of dissection. Despite the low rates of dissection, the increased‐ prevalence of BAV disease relative to Marfan syndrome make dissections due to BAV equal to or more common than dissections due to Marfan syndrome [86]. Dissection in BAV, when it oc‐ curs, typically involves the ascending aorta, but involvement of the descending aorta has been reported in older patients. Although dissection is more common in patients with dilated aor‐ tas, there are reports of dissection in normal-sized aortic roots and after valve replacement. Risk factors for dissection have included aortic size, aortic stiffness, male sex, family history, and the presence of other lesions such as coarctation of the aorta or Turner syndrome [50].

Also recently studies show less elastic tissue in the aortas of BAV patients [83,84].

nificant inflammatory response [81].

aneurysm these patients [85].

patients [82,83].

trileaflet valves [50].

lance of aortic dissection in these patients [82].

aorta, and in tissues not associated with elastic fibers.

In the ascending aorta as well as the pulmonary trunk, the severity of cystic medial necrosis, elastic fragmentation and changes in the smooth muscle cell orientation have been found to be significantly more severe in patients with bicuspid valves than in those with tricuspid valves.

Factors leading to aortic dissection four years after the Bentall operation have been considered to be an impact of congenital BAV or proximal anastomosis of venous grafts, or both [70].

Studies have suggested that patients with BAV have an intrinsic defect in the aortic wall that results in aortic disease, regardless of aortic valve function. BAV was associated with signifi‐ cantly less intimal change, and less fragmentation and loss of elastic tissue, compared with patients with a tricuspid aortic valve. Type I and III collagens were significantly decreased in dilated aortas of BAV patients, compared with controls, particularly at the convexity. Ex‐ pression of messenger RNA [ribonucleic acid] for collagens was lower than normal only in the regurgitant subgroup. Fewer smooth muscle cells and greater severity of elastic fiber fragmentation were observed at the convexity than at the concavity [71-73].

Among 119 cases of fatal dissecting aneurysm of the aorta, 11 cases of congenital BAV (9%) were observed. Among the latter, three had coarctation of the aorta and one had Turner's syndrome without coarctation. In each case, cystic medial necrosis of the aorta was present. Hypertension was either established or inferred from cardiac weight in 73% of the cases. The high incidence among subjects with dissecting aneurysm suggested a causative relation‐ ship between BAV and aortic dissecting aneurysm [74].

Many theories have been postulated for the mechanism of BAV aortopathy. For a long time there has been felt to be a genetic component; however there is increasing evidence for a haemodynamic mechanism. It is felt that it is due to defects in the aortic media, such as elas‐ tin fragmentation, loss of smooth muscle cells, and an increase in collagen [6,22]. Systemic features have also been noted in BAV patients which may predispose to aneurysm forma‐ tion including systemic endothelial dysfunction and higher plasma levels of matrix metallo‐ proteinases [75].

Pathological examination of surgical specimens from the aortic wall of patients with aortic dissection associated with BAV showed cystic medial necrosis or mucoid degeneration [76].

Matrix metalloproteinases (endogenous enzymes that degrade matrix components) have been implicated in atherosclerotic aortic aneurysm formation and appear to be elevated in the aorta of patients with BAVs [77].

The histological findings of BAV are nonspecific, and had been described by several authors in patients with Marfan syndrome [78-80]. The histopathological appearance of thoracic aortic aneurysm in Marfan and BAV is similar, and includes evidence of vascular smooth muscle cell (VSMC) apoptosis and extracellular matrix degeneration in the absence of a sig‐ nificant inflammatory response [81].

Abnormalities in the ascending aorta of the patients with BAV, specifically premature medi‐ al layer VSMC apoptosis, have been described, explaining the higherthan-expected preva‐ lance of aortic dissection in these patients [82].

Also recently studies show less elastic tissue in the aortas of BAV patients [83,84].

valves. The most likely risk factor for progression is felt to be age. Aortic root size itself is related to valve morphology and the presence of significant disease [22,6]; however, a recent study did suggest that while most patients with BAV and ascending aortic aneurysm had severe valve dysfunction, there was a small proportion of patients (5%) who did have aneur‐

In the ascending aorta as well as the pulmonary trunk, the severity of cystic medial necrosis, elastic fragmentation and changes in the smooth muscle cell orientation have been found to be significantly more severe in patients with bicuspid valves than in those with tricuspid

Factors leading to aortic dissection four years after the Bentall operation have been considered to be an impact of congenital BAV or proximal anastomosis of venous grafts, or both [70].

Studies have suggested that patients with BAV have an intrinsic defect in the aortic wall that results in aortic disease, regardless of aortic valve function. BAV was associated with signifi‐ cantly less intimal change, and less fragmentation and loss of elastic tissue, compared with patients with a tricuspid aortic valve. Type I and III collagens were significantly decreased in dilated aortas of BAV patients, compared with controls, particularly at the convexity. Ex‐ pression of messenger RNA [ribonucleic acid] for collagens was lower than normal only in the regurgitant subgroup. Fewer smooth muscle cells and greater severity of elastic fiber

Among 119 cases of fatal dissecting aneurysm of the aorta, 11 cases of congenital BAV (9%) were observed. Among the latter, three had coarctation of the aorta and one had Turner's syndrome without coarctation. In each case, cystic medial necrosis of the aorta was present. Hypertension was either established or inferred from cardiac weight in 73% of the cases. The high incidence among subjects with dissecting aneurysm suggested a causative relation‐

Many theories have been postulated for the mechanism of BAV aortopathy. For a long time there has been felt to be a genetic component; however there is increasing evidence for a haemodynamic mechanism. It is felt that it is due to defects in the aortic media, such as elas‐ tin fragmentation, loss of smooth muscle cells, and an increase in collagen [6,22]. Systemic features have also been noted in BAV patients which may predispose to aneurysm forma‐ tion including systemic endothelial dysfunction and higher plasma levels of matrix metallo‐

Pathological examination of surgical specimens from the aortic wall of patients with aortic dissection associated with BAV showed cystic medial necrosis or mucoid degeneration [76]. Matrix metalloproteinases (endogenous enzymes that degrade matrix components) have been implicated in atherosclerotic aortic aneurysm formation and appear to be elevated in

The histological findings of BAV are nonspecific, and had been described by several authors in patients with Marfan syndrome [78-80]. The histopathological appearance of thoracic aortic aneurysm in Marfan and BAV is similar, and includes evidence of vascular smooth

fragmentation were observed at the convexity than at the concavity [71-73].

ship between BAV and aortic dissecting aneurysm [74].

ysm formation without any aortic valve dysfunction [50].

valves.

344 Calcific Aortic Valve Disease

proteinases [75].

the aorta of patients with BAVs [77].

In patient with BAV there are fibrillin, fibronectin, and tenascin abnormality. Additionally Bonderman et al suggested that a primary role for VMSC apoptosis in the development of aneurysm these patients [85].

The FBN1 gene encodes fibrillin-1, a large glycoprotein that is secreted from cells and depos‐ ited in the extracellular matrix in structures called microfibrils. Microfibrils are found at the periphery of elastic fibers, including the elastic fibers in the medial layer of the ascending aorta, and in tissues not associated with elastic fibers.

The histopathological appearance of thoracic aortic aneurysm in Marfan and BAV is similar, and includes evidence of VSMC apoptosis and extracellular matrix degeneration in the ab‐ sence of a significant inflammatory response. Abnormalities in the ascending aorta of the patients with BAV, specifically premature medial layer smooth muscle cell apoptosis, have been described, explaining the higherthan-expected prevalance of aortic dissection in these patients [82,83].

Aortic root dilation has been documented in childhood, suggesting that this process begins early in life. Furthermore, children with BAV have greater increases in aortic dimensions than do children with trileaflet valves. In both children and adults, progressive dilation of the aorta is more common in patients with larger aortas at baseline. In BAV disease, the aort‐ ic annulus, sinus, and proximal ascending aorta are larger than those found in adults with trileaflet valves [50].

In the Olmsted County study, the prevalence of ascending aorta dilation (>40 mm) was 15% and in the subset of patients with repeat measurements, the prevalence increased to 39% at study completion. Dilation of the ascending aorta was an independent risk factor for ascend‐ ing aorta surgery. Although there are a number of risk factors associated with dilation of the ascending aorta including increased systolic blood pressure, male sex, and significant valve disease, the most important variable is likely age [50,63,64]. Aortic root size is shown to be re‐ lated to valve morphology and the presence of significant valve disease. In the Toronto series, the prevalence of dissection was 0.1% per patient-year of follow-up, and in the Olmsted Coun‐ ty study, there were no cases of dissection. Despite the low rates of dissection, the increased‐ prevalence of BAV disease relative to Marfan syndrome make dissections due to BAV equal to or more common than dissections due to Marfan syndrome [86]. Dissection in BAV, when it oc‐ curs, typically involves the ascending aorta, but involvement of the descending aorta has been reported in older patients. Although dissection is more common in patients with dilated aor‐ tas, there are reports of dissection in normal-sized aortic roots and after valve replacement. Risk factors for dissection have included aortic size, aortic stiffness, male sex, family history, and the presence of other lesions such as coarctation of the aorta or Turner syndrome [50].

### **3.4. Endocarditis**

Endocarditis is more common in BAV. The estimated incidence is 0.16% per year in unoper‐ ated children and adolescents [87]. In adults the case series by Michelena give an incidence of 2% per year [56].

with BAV and may be associated with hand anomalies. BAV is reported to be present in up to 30 % of adult patients with small ventricular septal defects. However, BAV may also be associated with large ventricular septal defects and poor clinical outcome. There is signifi‐ cantly higher incidence of aortic arch obstruction (51.1%). The frequency of BAV in speci‐

The Bicuspid Aortic Valve http://dx.doi.org/10.5772/52567 347

Hypoplastic left heart syndrome, complete atrioventricular canal defect, Ebstein's anomaly, partial or total anomalous pulmonary venous return, tetralogy of Fallot, double-outlet right ventricle, septal left ventricular diverticulum,Williams syndrome,Down syndrome and an‐ nuloaortic ectasia are occasionally associated with BAV. Shone's complex, which is defined by four cardiovascular defects including supravalvular mitral membrane, valvular mitral stenosis with a parachute mitral valve, subaortic stenosis and aortic coarctation, is a rare en‐

It has been reported that BAV is presented in > 50 % of patients with coarctation of the aorta [COA]. Patients with COA and BAV are reported to have more severe disease associated with aortic stenosis, aortic regurgitation, and aortic aneurysm. The risk of dissection of the

Turner syndrome characterized by a defect in or the absence of one X chromosome. Except for gonadal dysgenesis, cardiovascular defects are commonly present in this group of patients. Clinical research on patients with Turner Syndrome reports that BAV is present in 30% of cas‐ es, that over 95% of BAV s result from fusion of the right and left coronary leaflets, and that

Thrombus formation in a native BAV is a rare complicaton. Pathological studies have indi‐ cated that post-inflammatory changes ocur in the resected BAV, which is prone to develop

Microthrombus formation and valve thickening with incompetence could result in emboli‐

Embolization from calcific BAVs may lead to stroke and myocardial infarction. Conservative management with anticoagulation, to treat associated post-stagnation thrombosis, or aortic

Medical therapies are to try and alleviate symptoms and slow progression. It is generally felt that blood pressure should be aggressively controlled to try and slow the progression of

aortic ascending diameters are significantly greater in this group of patients [13].

mens with complete transposition of great arteries has been found to be 1% [13,50].

tity and forms another association in BAV cases [94].

**3.7. Thromboembolism**

**4. Management**

**4.1. Medical**

aortopathy [51].

aorta and death is greater when COA and BAV are comorbid.

thrombosis on the valve surface or in the calcification area [95].

zation, and subsequent cerebrovascular events [96].

valve replacement as the treatment, is debatable [97].

Outcomes in BAV patients with infective endocarditis tend to be worse than in those with normal valves. A recent study of 310 patients with infective endocarditis found that the 50 patients with BAV were younger at presentation and had a higher incidence of aortic peri‐ valvular abscess. In-hospital mortality and 5-year survival were also comparable to patients with normal valves [22].

Most patients are unaware of their condition until the onset of infective endocarditis

Patients with BAV endocarditis are young, and there is strong male predominance. Staphy‐ lococci and viridans streptococci account for nearly three-quarters of the cases affecting BAVs. Endocarditis can lead to severe acute aortic incompetence, heart failure and it is poor‐ ly tolerated [88].

Endocarditis risk was estimated to range between 2% or 0.3%/year. Because the risk of endo‐ carditis is felt to be low, the ACC/AHA practice guidelines no longer suggest bacterial endo‐ carditis prophylaxis in patients with straightforward BAV disease, except in patients with a prior history ofendocarditis [50,89].

#### **3.5. Coronary artery disorders**

Some reports have also suggested that the involvement of coronary arteries, including con‐ genital coronary artery anomalies, coronary artery fistulas, spontaneous coronary artery dis‐ section, immediate bifurcation and a shorter length of the left main coronary artery [6,13]. The incidence of left dominance in BAVs has been found to be unusually high (24.4-56.8%), compared with the incidence in tricuspid valves [9.5%]. Patients with BAVs have higher in‐ cidence of immediate bifurcation of the left main coronary artery, and higher incidence of left main coronary length less than 10 mm. The mean length of the left main coronary artery is significantly shorter in BAV patients [90].

Anomalous origins of the right 20,21 and left 22 coronary arteries, association with annu‐ loaortic ectasia, and anomalous origins of the left circumflex coronary artery 23 and single left coronary artery,24 have been noted in patients with BAVs. Spontaneous coronary artery dissection may occur in BAV patients [91]

There have also been some case reports describing patients with BAVdisease associated with coronary heart disease [92] and even with acute myocardial infarction[10].

Also Recently studies[93]Yuan et al. suggested that the prevalence rate of angiographic cor‐ onary heart disease was higher among the patients with BAVdisease.

#### **3.6. Congenıtal heart defects**

Patent ductus arteriosus and ventricular septal defect are the most frequent congenital heart defects associated with BAV. Patent ductus arteriosus is usually present in pediatric patients with BAV and may be associated with hand anomalies. BAV is reported to be present in up to 30 % of adult patients with small ventricular septal defects. However, BAV may also be associated with large ventricular septal defects and poor clinical outcome. There is signifi‐ cantly higher incidence of aortic arch obstruction (51.1%). The frequency of BAV in speci‐ mens with complete transposition of great arteries has been found to be 1% [13,50].

Hypoplastic left heart syndrome, complete atrioventricular canal defect, Ebstein's anomaly, partial or total anomalous pulmonary venous return, tetralogy of Fallot, double-outlet right ventricle, septal left ventricular diverticulum,Williams syndrome,Down syndrome and an‐ nuloaortic ectasia are occasionally associated with BAV. Shone's complex, which is defined by four cardiovascular defects including supravalvular mitral membrane, valvular mitral stenosis with a parachute mitral valve, subaortic stenosis and aortic coarctation, is a rare en‐ tity and forms another association in BAV cases [94].

It has been reported that BAV is presented in > 50 % of patients with coarctation of the aorta [COA]. Patients with COA and BAV are reported to have more severe disease associated with aortic stenosis, aortic regurgitation, and aortic aneurysm. The risk of dissection of the aorta and death is greater when COA and BAV are comorbid.

Turner syndrome characterized by a defect in or the absence of one X chromosome. Except for gonadal dysgenesis, cardiovascular defects are commonly present in this group of patients. Clinical research on patients with Turner Syndrome reports that BAV is present in 30% of cas‐ es, that over 95% of BAV s result from fusion of the right and left coronary leaflets, and that aortic ascending diameters are significantly greater in this group of patients [13].

#### **3.7. Thromboembolism**

**3.4. Endocarditis**

346 Calcific Aortic Valve Disease

of 2% per year [56].

with normal valves [22].

prior history ofendocarditis [50,89].

is significantly shorter in BAV patients [90].

dissection may occur in BAV patients [91]

**3.6. Congenıtal heart defects**

**3.5. Coronary artery disorders**

ly tolerated [88].

Endocarditis is more common in BAV. The estimated incidence is 0.16% per year in unoper‐ ated children and adolescents [87]. In adults the case series by Michelena give an incidence

Outcomes in BAV patients with infective endocarditis tend to be worse than in those with normal valves. A recent study of 310 patients with infective endocarditis found that the 50 patients with BAV were younger at presentation and had a higher incidence of aortic peri‐ valvular abscess. In-hospital mortality and 5-year survival were also comparable to patients

Patients with BAV endocarditis are young, and there is strong male predominance. Staphy‐ lococci and viridans streptococci account for nearly three-quarters of the cases affecting BAVs. Endocarditis can lead to severe acute aortic incompetence, heart failure and it is poor‐

Endocarditis risk was estimated to range between 2% or 0.3%/year. Because the risk of endo‐ carditis is felt to be low, the ACC/AHA practice guidelines no longer suggest bacterial endo‐ carditis prophylaxis in patients with straightforward BAV disease, except in patients with a

Some reports have also suggested that the involvement of coronary arteries, including con‐ genital coronary artery anomalies, coronary artery fistulas, spontaneous coronary artery dis‐ section, immediate bifurcation and a shorter length of the left main coronary artery [6,13]. The incidence of left dominance in BAVs has been found to be unusually high (24.4-56.8%), compared with the incidence in tricuspid valves [9.5%]. Patients with BAVs have higher in‐ cidence of immediate bifurcation of the left main coronary artery, and higher incidence of left main coronary length less than 10 mm. The mean length of the left main coronary artery

Anomalous origins of the right 20,21 and left 22 coronary arteries, association with annu‐ loaortic ectasia, and anomalous origins of the left circumflex coronary artery 23 and single left coronary artery,24 have been noted in patients with BAVs. Spontaneous coronary artery

There have also been some case reports describing patients with BAVdisease associated

Also Recently studies[93]Yuan et al. suggested that the prevalence rate of angiographic cor‐

Patent ductus arteriosus and ventricular septal defect are the most frequent congenital heart defects associated with BAV. Patent ductus arteriosus is usually present in pediatric patients

with coronary heart disease [92] and even with acute myocardial infarction[10].

onary heart disease was higher among the patients with BAVdisease.

Most patients are unaware of their condition until the onset of infective endocarditis

Thrombus formation in a native BAV is a rare complicaton. Pathological studies have indi‐ cated that post-inflammatory changes ocur in the resected BAV, which is prone to develop thrombosis on the valve surface or in the calcification area [95].

Microthrombus formation and valve thickening with incompetence could result in emboli‐ zation, and subsequent cerebrovascular events [96].

Embolization from calcific BAVs may lead to stroke and myocardial infarction. Conservative management with anticoagulation, to treat associated post-stagnation thrombosis, or aortic valve replacement as the treatment, is debatable [97].
