Understanding the driving mechanisms of bioprosthetic valve degeneration

Over the last decade, it has become increasingly clear that different mechanisms drive the development of native aortic stenosis. Most patients who develop native aortic stenosis have hypertension, and some have increased cholesterol. However, male sex, body mass index, smoking, metabolic syndrome, renal failure and genetic factors (eg, bicuspid aortic valve) have been identified in epidemiological studies as risk factors for developing native aortic stenosis. These studies have led to a series of clinical variables, which provide the foundation for understanding the mechanisms. The lowdensity lipoprotein (LDL) radius theory gives a framework for understanding the development of native aortic stenosis. In native aortic stenosis, LDLcholesterol insudates into endothelial cells, resulting in an inflammatory reaction forming increased oxidised phospholipids, leading to osteogenesis. This process is further propagated by high blood pressure; in patients with asymptomatic mildtomoderate aortic stenosis, blood pressure levels around 130–139 mm Hg/70–90 mm Hg have improved outcomes compared with higher blood pressure levels. Although the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study did not show a benefit for reducing LDLcholesterol on the progression of native aortic stenosis, a following subanalysis reported by Greve et al discovered that a reduction of LDLcholesterol in patients with LDLcholesterol above the median did reduce the progression of aortic stenosis. The lesson from this subanalysis suggested that interventional pharmacological treatment must focus on the mechanisms driving the development of aortic stenosis. That is, lowering LDLcholesterol does not prevent the progression of native aortic stenosis in patients with normal LDLcholesterol and other mechanisms that drive aortic stenosis progression. A decade ago, Thanassoulis et al discovered that the role of genetic variation in the lipoprotein(a) locus was associated with the development of native aortic stenosis, and it has since been well established that elevated levels of serum lipoprotein(a) are associated with increased incidence of calcification of the native aortic valve. Data from the Effect of Lipid Lowering with Rosuvastatin on Progression of Aortic Stenosis: Results of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial showed that patients with mildtomoderate aortic stenosis and elevated lipoprotein(a) had a faster aortic stenosis progression rate and more need for aortic valve replacement. Since transcatheter aortic valve implantation procedures emerged, most implanted valves are bioprosthetic. More than 200 000 heart valve replacements are performed annually, with a predicted four to fivefold increase over the next 25 years. There have been early reports of bioprosthetic valve degeneration due to cholesterol deposition. However, the pathogenesis of bioprosthetic valve degeneration is still not well understood. Farina et al evaluated 210 patients undergoing bioprosthetic aortic valve replacement and the risk of bioprosthetic aortic valve degeneration in a retrospective analysis of collected data from the Mayo Clinic in Minnesota, Arizona, and Florida from 2010 through 2020. The report showed that 33 patients had the end point ‘bioprosthetic aortic valve degeneration’, and those patients had significantly higher lipoprotein(a) than those without bioprosthetic aortic valve degeneration. In addition, in multivariate analysis, only lipoprotein(a) and smoking were independently associated with bioprosthetic aortic valve degeneration. Because of the small number of end points and the retrospective nature of the study, the authors did not have the full ability to access other candidate variables to explain the mechanisms that drive bioprosthetic valve degeneration as measurements of lipid insudation (eg, urine albumintocreatinine ratio), and continuous measurements of blood pressure seen as risk factors for promoting native aortic stenosis. As noted, the mechanisms underlying bioprosthetic aortic valve degeneration are incompletely understood. Recent studies suggest the host immune response as a major modality of bioprosthetic valve disease pathogenesis, manifested by a combination of processes phenocopying the longterm transplant rejection, atherosclerosis and calcification of native aortic valves. Surprisingly, similar mechanisms involve bioprosthetic valve degeneration compared with native aortic stenosis (table 1). The mechanisms involve mechanical stress, calcification and trigger an immune response against xenografts (patients with aortic stenosis have an immune response against the native valve). However, bioprosthetic valve degeneration does share some risk factors with atherosclerosis and calcific native aortic stenosis, like hypertension, metabolic syndrome, smoking and hyperlipidemia. The molecular basis of bioprosthetic valve degeneration involves chronic inflammation due to xenogenic glycans and thrombi adhering to bioprosthetic valves that recruit monocytes that enter the bioprosthetic tissue with subsequent differentiation into macrophages and multinuclear giant cells. Immune cells internalise disintegrated fragments of collagen fibres and release reactive oxygen species, proteolytic enzymes and calciumbinding extracellular vesicles, altogether promoting degeneration and calcification of the extracellular matrix. In addition, immune cells produce proteoglycans, which bind LDLcholesterol and lipoprotein(a) from plasma. Macrophages engulf LDLcholesterol and lipoprotein(a) that are then transformed into foam cells like the pathophysiological processes observed in atherosclerotic plaques and calcific