• Bicuspid Aortic Valve
• Aortic Aneurysm

Not all patients with bicuspid aortic valves behave similarly. Some patients have early valve dysfunction and require intervention in infancy or childhood. More commonly, bicuspid valves degenerate gradually throughout adulthood and valve failure does not occur until the fifth decade or later. Some patients have primarily aortic stenosis while others have aortic regurgitation. Others have mixed valve dysfunction. The aorta dilates in some, but not all patients with bicuspid aortic valves. Furthermore, dilation can occur at the sinuses, in the mid-ascending aorta, or in both regions. Numerous authors have attempted to explain this heterogeneity in valve dysfunction and aortic morphology. However, to date, the reason for the variability in presentation remains incompletely explained.

The most common way to categorise bicuspid aortic valves is according to the morphology of leaflet fusion, since most valves are trileaflet with a fused commissure. Fusion of the right and left coronary cusps (RL fusion) is most common, followed by fusion of the right and non-coronary cusps (RN fusion). Fusion of the left and non-coronary cusps is quite rare. Some valves have no identifiable raphe and are described as ‘true’ or ‘pure’ bicuspid aortic valves.

Because the morphology of bicuspid aortic valves is usually easy to define by echocardiography, it is tempting to ascribe the clinical heterogeneity to valve phenotype, and some correlations frequently observed: RN fusion is more commonly associated with aortic stenosis in some, but not all, studies.1 2 The pattern of aortic dilation also varies depending on aortic valve morphology: mid-ascending aortic dilation is common in patients with RN fusion but dilation at the aortic sinuses is rare.3 4

Within this context, Evangelista presents a multicentre study to define correlations between aortic valve morphology, aortic valve function and patterns of aortic dilation.4 The authors included 852 patients, making it the largest study of this type. The methodology is excellent: images were obtained according to a prespecified protocol and a core-lab adjudicated review of all images to define valve morphology, function and aortic dilation.

Overall, the results of the study are consistent with prior publications.1–3 5 Patients with RN fusion are most likely to have aortic stenosis. Those with pure bicuspid aortic valves (no raphe) are more likely to have normally functioning valves. While most (76%) patients have aortic dilation, the location of maximal dilation varied by valve type: aortic sinus dilation was least common in those with RN fusion. Patients with normally functioning aortic valves have smaller aortas than patients with dysfunctional aortic valves. Overall, the findings support the position that there are both haemodynamic and demographic variables which contribute to degeneration of the valve and the aorta. The demographic features which lead to valve deterioration in patients with bicuspid aortic valves are the same ones associated with valve calcification in patients with trileaflet aortic valves—older age, dyslipidaemia and smoking.

Can the associations described here and elsewhere help clinicians better manage patients? Unfortunately, it is unlikely. Despite the statistically significant associations between demographics, valve morphology, valve dysfunction and aortic dilation, there remains too much overlap to tailor therapy to valve type. For example, in the current paper, patients with RN fusion are more likely to have valve calcification and aortic stenosis (approximately 30% with RN fusion had calcification and/or aortic stenosis compared with approximately 20% with RL fusion). However, this difference does not provide enough discrimination to offer different surveillance strategies to patients based on valve morphology. Similarly, even though patients with RL fusion are statistically more likely to have aortic dilation, nearly as many patients with RN fusion had dilated aortas (83% vs 74%). So all patients with bicuspid aortic valves require similar follow-up for aortopathy.

Valve morphology and demographics only partially explain the clinical heterogeneity seen in patients with bicuspid aortic valve. The current paper is among the largest and highest quality studies to describe these associations. Nevertheless, even with a large sample size and a core lab to minimise misclassification bias, only relatively small (although significant) differences are seen between bicuspid valve types. Much of the remaining heterogeneity is likely genetic.

A number of different genetic loci are associated with bicuspid aortic valve, including NOTCH1, TGFBR1, TGFBR2, ACTA2, KCNJ2 and others.6 Several of these genetic variations have been separately associated with pathology frequently seen in patients with bicuspid aortic valves. For example, NOTCH1 mutations are associated with valve calcification and ACTA2 mutations are associated with thoracic aortic aneurysms.6 7 It seems likely that there is an interaction between the genetics and the valve morphology which further accounts for the diversity seen in patients with bicuspid aortic valves. Genetic variations may further explain why studies in different populations have sometimes been inconsistent when correlating valve morphology to aortic phenotype.3–5 8

The relative contributions of genes and flow become even more difficult to establish because while the aortopathy of bicuspid aortic valve is inherited,9 the gene mutation does not necessarily define the pattern of leaflet fusion. In one study of first-degree relatives of patients with bicuspid valves, only half of families who had bicuspid valves had consistent bicuspid valve type across the family.10 This disconnect between valve morphology and genetics means that ascribing the diversity seen with bicuspid valves to either flow or genetics alone is unlikely to be inadequate.

Finally, the authors describe how traditional cardiovascular risk factors may accelerate valve calcification and stenosis, and suggest that early aggressive intervention may prevent or delay valve deterioration. Unfortunately, clinical trials performed in patients with advanced disease have not supported this hypothesis. It is possible that early intervention, prior to advanced calcification, will be more effective. This question is being investigated by the authors in an ongoing randomised placebo controlled trial of atorvastatin in patients with non-calcified aortic valves (NCT02679261).

The Bicuspid Aortic Valve Consortium is investigating the relationship between phenotype and genetics using a very large number (>4000) of patients with well-characterised bicuspid aortic valve to allow for genome-wide association studies.6 This type of research, simultaneously examining the genetics and haemodynamics of bicuspid valves, has promise for identifying the high-risk patient and offering tailored surveillance or therapy.