Disease drivers in aortic stenosis vs atherosclerosis

Aortic stenosis (AS) due to fibrosis and calcification of the aortic valve is a hazardous component of cardiovascular disease burden—after developing symptomatic AS, patients survive for an average of less than 2 years without treatment. Alongside the shared presence of many traditional cardiometabolic risk factors, the earliest comparisons of AS and atherosclerotic lesions suggested gross morphological and histological similarities (eg, basement membrane disruption, lipid deposition, immune cell infiltration, and mineralization) and led to the belief that AS might be an atherosclerosislike disease of the aortic valve. However, the preponderance of basic, clinical, and translational research over the 30 years that followed has shown that this is not entirely true. Fewer than half of patients with valvular calcification also develop vascular calcification, suggesting differential modes of pathogenesis. Furthermore, prospective clinical trials of statin-mediated lipid lowering have repeatedly failed to provide any benefit in AS outcomes. Indeed, there remain no approved pharmaceutical therapies for AS; aortic valve replacement by surgical or transcatheter approaches is the only option for patients with AS. This unmet clinical need for pharmacotherapeutic strategies tailored specifically to AS has spurred contemporary efforts to unravel the development of this disease from atherosclerosis. Trenkwalder and colleagues take an important step in this direction with the first genome-wide association study (GWAS) of AS that is fully adjusted for comorbid coronary artery disease (CAD).