Thesis supervisor: Anikó Ilona Nagy
Location of studies (in Hungarian): Semmelweis Egyetem Abbreviation of location of studies: SE
Description of the research topic:
The diagnostic and prognostic value of aortic valve calcium load in discordant grading aortic stenosis
Calcified aortic valve stenosis (AS) is the most common valvular heart disease in developed countries
affecting over 3% of people aged ≥ 75 in Europe. In the symptomatic stage, if untreated, the yearly mortality
of severe AS reaches 50%. Understanding the molecular pathophysiology leading to aortic valve
calcification forms a field of intensive research, however to date, the underlying mechanisms remain poorly
understood, leaving aortic valve replacement the sole therapeutic option. Transcatheter aortic valve
implantation (TAVI) has revolutionized the treatment of AS by offering a less invasive treatment strategy
compared to open heart surgery. With technical developments and accumulating operator experience the
complication rate of TAVI has decreased significantly. However, despite its less invasive nature it still carries
a non-negligible risk of potentially devastating complications, including stroke, cardiac tamponade, vascular
complications, infections, or need for a permanent pacemaker. Moreover, some patients who have
undergone a successful TAVI procedure fail to experience the expected clinical improvement in terms of
both symptoms and survival. Thus, optimal patient selection, i.e. identifying those patients who are really
in the need of aortic valve replacement and who are going to benefit from the procedure is of major
importance, in order to avoid unnecessary and potentially risky interventions as well as to allocate limited
resources in the best possible way. The diagnosis of AS relies on echocardiography. Criteria for severe AS
include a mean transvalvular pressure gradient ≥ 40 mmHg and a valve opening area ≤ 1 cm2. However, in
up to 40% of the cases echocardiography provides discordant results, i.e. the valve opening area is ≤ 1 cm2
despite a low (≥ 40 mmHg) mean transvalvular pressure gradient. Low gradient (LG) AS is a challenging
group from both diagnostic and therapeutic points of view. Sometimes the low mean transvalvular pressure
gradient can be explained by reduced flow through the stenotic valve (low flow = LF), due to obvious (e.g.
depressed myocardial contractility, concomitant other valve disease, atrial fibrillation, impaired diastolic
filling) or less obvious reasons, whereas in other patients, the transvalvular flow appears preserved and the
cause of LG remains elusive. Cardiac computed tomography (CT) has emerged as the primary diagnostic
tool to corroborate the severity of AS in LGAS where echocardiography is inconclusive. Aortic valve calcium
score (AVCS) quantified by CT provides a robust, reproducible objective measure of aortic valve calcification
load. Among patients with concordant echocardiography results, the AVCS strongly correlates with the
transvalvular gradient and AS severity. AVCS as a binary threshold differentiates moderate from severe AS
with good diagnostic accuracy and carries important prognostic value. These results led to the
recommendation to apply AVCS in discordant grading AS. However, the prevalence of low AVCS is much
higher among LGAS patients compared to high gradient AS, and its diagnostic as well as prognostic power
appears weaker in this this cohort. Thus, we hypothesize that despite the established and generally valid
association between aortic valve calcium load and AS severity, in selected cases, presumably, when the
underlying mechanism of AS is predominantly fibrosis rather than mineralisation, AVCS might
underestimate AS severity and low AVCS in these patients is not necessarily a marker of benign prognosis.
Our aim is to identify determinants of low AVCS in patients with severe AS, especially those with LGAS and
to determine the prognostic significance of low AVCS among patients with discordant echocardiographic
measures.
The potential role of pyrophosphate homeostasis in the pathomechanism of aortic valve calcification
Despite the high prevalence and severe consequences of calcific aortic valve disease, its etiology remains
poorly understood. An intriguing characteristic of aortic valve calcification is that for the same aortic
stenosis severity, women present significantly lower calcification loads than men. The cause of this sexrelated
difference is unknown. Inorganic pyrophosphate (PPi) is an established inhibitor of calcification.
Low systemic PPi levels have been associated with inappropriate connective tissue mineralization in several
rare hereditary diseases, like pseudoxanthoma elasticum (PXE) and generalized arterial calcification of
infancy (GACI), that affect PPi homeostasis. More importantly, it was recently shown that orally
administered PPi can efficiently rescue calcification in GACI and PXE mouse models. A previous study
looking at the role of PPi in peripheral vascular calcification in PXE patients demonstrated significantly
higher levels of PPi in females along with less arterial calcification, as compared to males. PPi has also been
implicated in the pathomechanism of aortic valve calcification in ex vivo models. However, because the
methodology of PPi measurement from biological samples has only been recently established, whether
there is association between plasma PPi levels and the degree of aortic valve calcification in vivo, has not
yet been investigated. We hypothesized that circulating plasma PPi might play a role in the
pathomechanism of aortic valve calcification. Proving this concept could provide a potential target for
medical treatment of AS by oral PPi supplementation.
Our aim is to investigate the potential role of PPi in aortic valve calcification by correlating circulating
plasma PPi levels to the aortic valve calcium load.
Deadline for application: 2024-05-31
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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