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.