Aortopathy in bicuspid aortic valve disease — genes or hemodynamics? or Scylla and Charybdis?

The bicuspid aortic valve (BAV) is a congenital malformation including a certain spectrum of different phenotypes that can be comprehensively classified into three types (Type 0, 1, and 2) according to the number of raphes [1]. In roughly 40–60%, the BAV is associated with a cluster of dilatation of the ascending aorta and aortic arch [2]. In the worst case, this aortopathy can result in rupture or dissection. There is still considerable controversy as to whether the BAV aortopathy is caused by genes or hemodynamics. This is of major clinical relevance because it will have an influence on the different surgical techniques of the valve and the ascending aorta [3,4]. If the cause is related to pathological valvular hemodynamics, the correction of the valvular disease would theoretically also ameliorate the aortopathy, rendering aortic replacement less necessary. If the cause is related to genes, the replacement of the dilated aorta will be performed more liberally to stop the hemodynamic independent process of dilatation and, thus, to reduce the risk for rupture or dissection. And this threat is real. In the past 14 years, we have operated on 413 patients with acute type A dissection, of whom 23 had BAV. With respect to the prevalence of BAV of 1% in the general population, the risk for acute type A dissection in our series is 6 times higher for BAV patients. There are an increasing number of hints on the genetic background of the aortopathy in BAV, which was reported to be present even in relatives of BAV patients [5]. On the other hand, there is significant evidence supporting an impact of hemodynamics on BAV aortopathy, which is thoroughly addressed by Girdauskas et al. [6, in this issue]. One main argument is the valve-pathology-related flow turbulence potentially leading to dilatation over time [7]. Up to now, there is no definite answer to the question whether genes or hemodynamics are the cause for BAV aortopathy. Probably, this question is not appropriate. It seems to be a characteristic for every living unit that a genetic code serves as a blueprint for determining and maintaining individual order of tissue structure, and interacts with external forces or stress over time, resulting in a certain phenotype and function at a certain point in time. And that probably holds also true for the BAV aortopathy. Many of us have seen the 70-year-old patient with a severe BAV stenosis and a normal-sized ascending aorta indicating ‘good’ genes for a strong aortic wall matrix. On the other hand, there is the young patient with normal valve hemodynamics and with the severest form of an aortopathy, an acute aortic dissection. This often occurs during hypertension due to physical or emotional stress [8], and is, in most but not all [9], cases associated with a somewhat dilated ascending aorta, indicating ‘bad’ genes for the wall structure. In between are many BAV patients with a severe stenosis and dilatation only at the convexity of the ascending aorta, the area of turbulence impact, whereas remote areas of the ascending aorta have normal size. the overall change of the probability(F) over time to get an aortopathy as a sum of 2 and 3; genes-related change of F; and influence of external impulse (hypertension, turbulence a.s.o.) on the change of F. In detail F is the probability of an aortopathy, t the time, the vector of parameters representing the individual health condition including: diameter of ascending aorta, age a.s.o., α and β the constant factors, can be positive or negative, and V is the potential of genes. Hypothetical interaction of genes and external impulse for risk prediction of BAV aortopathy. Eq. (1) is schematically shown, note that the constants α and β can be positive or negative. The X axis represents the potential of the genetic code and the Y axis the external stress The broken equipotential lines for an assumed probability to get an aortopathy (F = 0.5) demonstrate the different interrelationships, e.g.: ‘good’ genes and high stress (hypertension) (A) may have a similar risk (F) as virulent ‘bad’ genes and low stress (hypotension) (B). The risk for an aortopathy is increasing if the virulence of genes is increasing concomitantly with increasing external stress (C, or red area, Scylla and Charybdis) or vice versa (D, or green area). means average genetic predisposition. In general, the equations show that the subject of BAV aortopathy is an extremely complex interaction between genes and external stress factors, that this interaction is individual and time dependent, has an exponential course (e.g., if the diameter is increasing above 6 cm, the probability of aortopathy and the risk of dissection is increasing exponentially), and that the risk for developing an aortopathy can be approximated if we know the risk of a specific genetic predisposition (e.g., BAV, Marfan syndrome, a.s.o.) and if we know the risk of the different stress groups (e.g., BAV and hypertension, BAV and diameter at different levels a.s.o.) over time. These above considerations may also apply for decision making of surgery on the dilated aorta. As the equation shows, the risk of rupture or dissection is individual and general guidelines are difficult to be drawn. However, known risk factors could be included to specify or approximate more clearly the individual risk: family history of acute aortic events or aneurysm, reliable genetic pathways for BAV, syndrome-associated aortopathy gene mutations, especially fibrillin-1 gene mutations on chromosome 15 in Marfan syndrome (site of mutation) [10], younger age, diameter in relation to body size, progression of diameter, anatomic site of dilatation (cluster according to Fazel et al. [2]), hypertension, mechanical properties, biomarkers, physical and emotional stress, tissue characteristics (quick histology test during valve surgery), turbulence direction, a.s.o. In summary, there are some arguments that BAV aortopathy is not caused by genes or hemodynamics separately: it may rather be related to the individual interaction of both; in the worst case, it can be Scylla and Charybdis.