**6. Clinical course**

The clinical course of BAV patients is highly non-predictable. The factors determining the prognosis are older age, RN or RL BAV phenotype, flow dynamics (right-handed flow), male gender, elevated systolic blood pressure, smoking, presence of valvular and ventricular dysfunctions, aortic dilatation, endocarditis, high total cholesterol levels, valve degeneration score, and genetic predisposition [45, 69]. Aneurysm formation, aortic dissection, severe valvular dysfunction, and endocarditis are the most important causes of morbidity and mortality of BAV disease. AR is the most common complication in younger patients, more common in males, whereas AS is more common in elderly and females [45, 55]. In addition, RN BAV phenotype is strongly predictive of valve intervention when compared with RL BAV phenotype. RN BAV phenotype has a fourfold risk of time-related valve intervention compared with RL BAV phenotype during childhood [39, 66].

Some BAV cases may present with severe stenosis or regurgitation especially in infants or children. Children who present with AS in infancy have more severe disease and poor outcomes. Fortunately, balloon valvuloplasty is the successful treatment of choice for severe AS in this age group because of very little calcification [70].

With respect to the BAV manifestations, it is estimated that only 1 in 50 children would have a clinically significant valve disease by adolescence. The majorities of BAV patients have relatively normal valve function and remain undiagnosed until 40 years of age, when stenosis develops because of leaflet calcification. In total, 53% of the BAV patients with isolated AS undergo valve replacement [65, 70, 71]. In the elderly population, AS is the most common presentation which causes 75% of patients to undergo surgery, while AR was the reason for intervention in only 13–16% of BAV patients [45, 72]. Asymptomatic adults without significant valve dysfunction enjoy excellent long-term survival with a 10- and 20-year survival rate of 97 and 90%, respectively, identical to the expected survival of the population matched for age and sex [73]. Mean follow-up of 15 years showed a 6.7% death ratio, 1.4% of which were related with the aortic valve endocarditis, 0.47% with AS, and 0.47% with AR. In total, 18.3% of these patients underwent aortic valve surgery, most of which were due to severe AS [73]. The 10-year survival rate of the asymptomatic young adults with BAV was found to be 96%. Aortic valve and ascending aorta surgery were performed in 29% of these patients [46]. On the other hand, patients with BAV-AR and root aneurysm have shown a higher risk of aortic dissection and rupture [74].

Aortic dissection occurs 9 times more often and at an average of 1 decade earlier among patients with BAV than those with TAV [63]. The patients with BAV and aortic aneurysm >4.5 cm have been found eight times more likely to undergo an aortic dissection [75]. The patients with BAV-AR have a tenfold higher risk of post-AVR aortic dissection than the patients with BAV-AS [76]. The aortic dissection rate in BAVs has been found to be 0.77% and the frequency of aortic dissection is 0.1% per patient's year of follow-up [45].

The aortic diameter at the baseline is also an important predictor of aortic dilatation. In children under 18 years old, ascending aorta z score has been shown to progress with time and an initial z score > 2 with the presence of AS has been accepted as a clinical marker for higher z scores in early adulthood [48]. The z scores of 4 or above, present in 13% of the patients under 18 years old, have been considered to reveal significant aortic dilation which predicts the subsequent aneurysm development [75] Relevantly, it has been shown that an aortic diameter of 4 cm or more at the baseline evaluation independently predicts the subsequent development of aneurysm. The incidence of aortic dissection in these patients during 16 years of followup was 3.1%, significantly higher than the general population [75]. Dissection rates in the patients with the aortic diameters of above 3.5, 4.5, and 5.5 cm are 8.5, 57.1, and 10%, respectively [77]. The aortic size larger than 4.5 cm or aortic cross-sectional area/height > 8–10 should be considered for concurrent aortic valve and ascending aorta surgery [78, 79].

BAV types can predict the progression of aortic valve dysfunction or the development of aortic aneurysms [80]. The presence of a raphe has been associated with a higher prevalence of significant AS and AR, which increase the need for surgery. Despite the higher mortality in patients with BAV and raphe, raphe is not independently associated with increased all-cause mortality.
