Unloading the Stenotic Path to Identifying Medical Therapy for Calcific Aortic Valve Disease

alcific aortic valve disease (CAVD) represents an enormous public health problem in terms of adverse health consequences and economic burden. Approximately 5% to 10% of older adults have aortic stenosis (AS) and more than 25% have aortic sclerosis, the precursor to AS; clinically significant valve disease is anticipated to double by 2050. 1,2 To date, there are no drugs approved to slow the progression of CAVD. Anticipation about statins turned into disappointment after several trials showed no benefit, which may have dampened enthusiasm for CAVD therapy. Although CAVD attracts comparatively less attention and is less mature than mechanistic research in atherosclerosis, numerous studies have elucidated the molecular biology underlying CAVD and point to several potentially promising drug targets (reviewed previously 3,4 ). For example, a causal role for lipoprotein(a) has been demonstrated, which, along with oxidized phospholipids, provides a potential link between atherosclerotic disease and CAVD and offers a rationale for testing drugs that lower lipoprotein(a) (eg, antisense oligonucleotides, PCSK9 inhibitors). 5 However, despite numerous promising targets and drugs available directed at those targets, as of December 2, 2020, on clinicaltrials.gov, there are currently no actively enrolling clinical trials testing medical therapy to slow progression of CAVD; 1 trial testing both denosumab and bisphosphonates is completed and undergoing analysis. This dearth of active trials is sobering. We offer several potential reasons for this along with suggestions for addressing barriers (Figure).