Genetics of Calcific Aortic Stenosis: A Systematic Review

Abstract

Background: Calcific aortic stenosis is the most prevalent valvular abnormality in the Western world. Factors commonly associated with calcific aortic stenosis include advanced age, male sex, hypertension, diabetes and impaired renal function. This review synthesises the existing literature on genetic associations with calcific aortic stenosis. Methods: A systematic search was conducted in the PubMed, Ovid and Cochrane libraries from inception to 21 July 2024 to identify human studies investigating the genetic factors involved in calcific aortic stenosis. From an initial pool of 1392 articles, 78 were selected for full-text review and 31 were included in the final qualitative synthesis. The risk of bias in these studies was assessed using the Newcastle Ottawa Scale. Results: Multiple genes have been associated with calcific aortic stenosis. These genes are involved in different biological pathways, including the lipid metabolism pathway (PLA, LDL, APO, PCSK9, Lp-PLA2, PONS1), the inflammatory pathway (IL-6, IL-10), the calcification pathway (PALMD, TEX41) and the endocrine pathway (PTH, VIT D, RUNX2, CACNA1C, ALPL). Additional genes such as NOTCH1, NAV1 and FADS1/2 influence different pathways. Mechanistically, these genes may promote a pro-inflammatory and pro-calcific environment in the aortic valve itself, leading to increased osteoblastic activity and subsequent calcific degeneration of the valve. Conclusions: Numerous genetic associations contribute to calcific aortic stenosis. Recognition of these associations can enhance risk stratification for individuals and their first-degree relatives, facilitate family screening, and importantly, pave the way for targeted therapeutic interventions focusing on the identified genetic factors. Understanding these genetic factors can also lead to gene therapy to prevent calcific aortic stenosis in the future.

Keywords: aortic stenosis; calcific.

Figure 1

A simplified illustration of the human aortic valve is shown. Panel (A) depicts the anatomical structure of the aortic valve in relation to aorta and ventricle. Reproduced with permission from Henderson et al. [2] under a creative commons attribution 4.0 international license. Panel (B) focuses on the aortic valve leaflet. The left side presents a schematic cross-section of the non-coronary leaflet of the aortic valve. The enlarged section on the right highlights the three-layered structure of the extracellular matrix, indicating the locations of the aortic valve endothelial cells (VECs) and valvular interstitial cells (VICs). Reproduced with permission from Rutkovskiy et al. [1] under a creative commons attribution 4.0 international license.

Figure 2

PRISMA flow diagram summarising study selection.

Figure 3

Schematic representation of Lp(a). Lp(a) consists of apolipoprotein B100 covalently linked to apo(a), and high levels enable a pro-inflammatory and pro-calcific environment. Variants with smaller kringle IV type 2 repeats are associated with higher blood Lp(a) levels; hence, the plasma concentration of Lp(a) is genetically determined. Reproduced with permission from Telyuk et al. [46] under a creative commons attribution 4.0 international license.

Figure 4

Mechanism of action of PCSK9 inhibitors. PCSK9 identifies and marks the LDL receptor for phagocytosis (number 1), thereby allowing more LDL to circulate in the bloodstream. PCSK9 inhibitors bind to LDL receptors (2), and thus allow the LDL receptors to clear more LDL particles (shown in 3). Reproduced from Beltran et al. [68] under a creative commons attribution 4.0 international license.