Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy

Eur Heart J. 2022 Feb 12;43(7):683-697. doi: 10.1093/eurheartj/ehab757.


Calcific aortic valve disease (CAVD) is a highly prevalent condition that comprises a disease continuum, ranging from microscopic changes to profound fibro-calcific leaflet remodelling, culminating in aortic stenosis, heart failure, and ultimately premature death. Traditional risk factors, such as hypercholesterolaemia and (systolic) hypertension, are shared among atherosclerotic cardiovascular disease and CAVD, yet the molecular and cellular mechanisms differ markedly. Statin-induced low-density lipoprotein cholesterol lowering, a remedy highly effective for secondary prevention of atherosclerotic cardiovascular disease, consistently failed to impact CAVD progression or to improve patient outcomes. However, recently completed phase II trials provide hope that pharmaceutical tactics directed at other targets implicated in CAVD pathogenesis offer an avenue to alter the course of the disease non-invasively. Herein, we delineate key players of CAVD pathobiology, outline mechanisms that entail compromised endothelial barrier function, and promote lipid homing, immune-cell infiltration, and deranged phospho-calcium metabolism that collectively perpetuate a pro-inflammatory/pro-osteogenic milieu in which valvular interstitial cells increasingly adopt myofibro-/osteoblast-like properties, thereby fostering fibro-calcific leaflet remodelling and eventually resulting in left ventricular outflow obstruction. We provide a glimpse into the most promising targets on the horizon, including lipoprotein(a), mineral-binding matrix Gla protein, soluble guanylate cyclase, dipeptidyl peptidase-4 as well as candidates involved in regulating phospho-calcium metabolism and valvular angiotensin II synthesis and ultimately discuss their potential for a future therapy of this insidious disease.

Keywords: Ageing; Calcific aortic valve disease; Lipoprotein(a); Medical therapy; Nitric oxide; Notch1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aortic Valve / pathology
  • Aortic Valve Stenosis* / complications
  • Calcinosis* / complications
  • Cells, Cultured
  • Humans
  • Osteogenesis