Risk factors for progression of aortic valve stenosis

Aortic valve stenosis (AVS) is already the most common form of valvular heart
disease in the Western world affecting 25% of individuals over 65 years old. As
our population ages, the burden of AVS is expected to double within the next 50
years. To date, the only effective treatment for severe AVS is surgical or
percutaneous aortic valve replacement, both associated with considerable
perioperative morbidity and mortality, as well as substantial costs.
Importantly, the implanted aortic valve prosthesis and obligatory use of
anticoagulant therapy are also associated with additional long-term morbidity
and mortality. Understandably, a pharmacological intervention to prevent the
development and/or progression of AVS has been a holy grail in cardiovascular
medicine for decades. The feasibility of such an approach depends on the
identification of causal risk factors that can be used as therapeutic targets.
AVS shares many risk factors with atherosclerotic cardiovascular
diseases such as myocardial infarction and stroke. However, therapeutic
strategies that are successful in atherosclerosis including ACE-inhibitors and
LDL cholesterol lowering with statins have not been successful in AVS.
Interestingly, recent new insights have implicated lipoprotein(a), and not LDL
cholesterol, as a causal risk factor in the development of AVS. A large-scale
meta-analysis of genome-wide scans identified rs10455872 at the LPA locus as a
susceptibility single nucleotide polymorphism for aortic valvular calcium.
Because this variant defines a genetic predisposition to elevated
lipoprotein(a) plasma levels, these data support a causal role for
lipoprotein(a) in the development and/or progression of AVS. The associations
between rs10455872 as well as lipoprotein(a) levels, and clinically diagnosed
AVS were confirmed in two Danish population-based studies. In addition, we have
confirmed in the EPIC-Norfolk prospective population study that rs10455872, as
well as elevated lipoprotein(a) levels, were associated with an increased risk
of AVS. In summary, these data show that elevated lipoprotein(a) levels are
associated with severe end-stage calcified AVS, and suggest that lipoprotein(a)
is involved in development of aortic valve sclerosis and/or its slow
progression to severe calcified end-stage AVS over the years.
Interestingly, inhibition of proprotein convertase subtilisin/kexin
type 9 (PCSK9) by alirocumab or evolocumab as well as inhibition by an apo(a)
antisense oligonucleotide have recently been shown to be effective in lowering
lipoprotein(a) levels. This prompts the hypothesis that therapeutic
lipoprotein(a) lowering may reduce AVS development and/or progression. In order
to identify the potential for such an approach, this study aims to characterize
a cohort of patients with mild to moderate AVS, who are at risk of progressing
to severe, calcified end-stage AVS.

- To document the average progression of AVS in a large population of patients
with mild to moderate AVS.
- To assess the prevalence of elevated Lp(a) among patients with mild to
moderate AVS.
- To identify lipid and genetic risk factors for AVS.

This study is designed as a single center cross-sectional pilot study. We will
identify patients with mild to moderate AVS by screening the echocardiography
database of the Department of Cardiology, AMC. The study will require one visit
to the Academic Medical Center (AMC) hospital for questionnaire and blood
sampling. Prior to the visit, in- and exclusion criteria will be confirmed
using a questionnaire. The total duration of the visit will be approximately
one hour.

Considering that this is a study that requires only one blood drawing, we do
not expect any associated risk for participating patients other than the risk
of a small hematoma at the puncture site.