Unlocking the phenotype of aneurysm disease: Are women the key?

Despite major advances in the treatment and diagnosis of aneurysm disease in the last 20 years, our appreciation of the phenotypic manifestations is only just being understood. In modern clinical practice, the genetic basis of the disease can be discovered as clinicians have access to rapid and in-depth genetic analysis for patients with aneurysms. The keys to our understanding of all aneurysm disease, not just in the subset of patients with obvious syndromic characteristics, are being unexpectedly revealed. In this issue of Vascular Medicine, van de Luijtgaarden and colleagues have taken an even more basic approach, and reviewed the family history of patients presenting with aneurysms in their practice. ¹ They report that 22.5% of patients with aortic aneurysms have a first degree relative with aneurysm disease. Further analysis in the affected families determined that the risk of presenting with aneurysm disease among individuals with an affected relative was higher than expected in the general population in both sexes, but relatively higher for female relatives (2.8-fold risk in women versus 1.7-fold risk in men). Furthermore, they report that first degree relatives of female aneurysm patients are at higher risk than their male counterparts to have aneurysm disease.

The familial link of aneurysm disease has long been suspected, and clinicians are now beginning to understand that the aggressiveness of a patient’s disease can be deciphered by taking a detailed family history. For example, is there a family history of aortic dissection or rupture? At what age did this occur? Of course, the most pronounced and aggressive aneurysm syndromes are inherited, and in some, genetic mutations have been identified that follow Mendelian inheritance patterns, although variable penetrance seems to be more common as details are revealed. For non-syndromic aneurysms, early reports linking anatomic aggressiveness with disease in a first or second degree relative provided hints that family history was an important aspect of the surgical risk stratification process. ² These beliefs are further reinforced in recent reports suggesting that family history is linked to increased likelihood of endovascular complications. ³ The paper by van de Luijtgaarden and colleagues subdivides this familial risk even further, suggesting a sex-related bias among aneurysm patients with a family history. This may provide insight into a subclassification of aggressive aneurysm phenotype that will make sense of the heterogenous pattern of disease we currently observe. Although the predictive value of family history is still not clear, these authors have added another brick to the foundation of a theory that not all aneurysms behave the same, and inheritance patterns may be a clue to their ‘behaviour’.

By finding a sex-related bias, as well as a strong link to family history, this paper casts further light on another mystery: the behaviour of aneurysm disease in women. Women are underrepresented in large trials of aneurysm disease. The prevalence of disease is most often quoted from the large randomized controlled trials of abdominal aortic aneurysm (AAA) screening from the UK, Australia and Sweden ⁴ ; however, only one of these four trials included women, meaning that the most frequently quoted statistics about the prevalence of AAA disease in women is based on a cohort of 9348 women, representing only 6.8% (9348/137,233) of the total population studied. Using this as the basis for ‘population norms’ may be flawed. The pattern of underrepresenting women in trials of aneurysm disease is repeated throughout the literature and is often misinterpreted as a simple reflection of the lower prevalence among women, but this pattern likely represents a combination of both lower prevalence in study populations and ascertainment bias. Women constituted only 188/1090 (17%) of patients in the UK Small Aneurysm Trial, ⁵ and 128 of the 1433 (8.9%) of patients in the two RCTs (DREAM ⁶ and EVAR-1 ⁷ ) comparing open and endovascular surgery for AAA, which are three of the modern citations considered ‘gold standard evidence’ commonly relied on as a basis to guide care. In comparison, a large observational trial revealed that 21% (13,105/61,598) of patients actually undergoing aneurysm repair in the United States between 2001 and 2004 were women, suggesting a much higher baseline prevalence. ⁸ By finding that women with aneurysms carry a more aggressive form of disease, in that their first degree relatives are more likely to carry the disease, van de Luijtgaarden and colleagues argue that they may have uncovered a variation in presentation based on ‘genetic burden’. However, it is also possible that this new finding will renew interest in screening women for aneurysms (as we do not yet know the true prevalence in the female population), and their discovery will uncover not just individual patients, but entire families with a potentially lethal and treatable disease.