Cholesterol crystal dissolution rate of serum is associated with iliofemoral calcification and predicts outcomes in patients undergoing TAVR
Authors: Al-Kassou L , Al-Kassou B , Luetjohann D , Shamekhi J , Willemsen N , Niepmann S T , Baldus S , Kelm M , Nickenig G , Latz E , Zimmer S 
Published: November 2023

Abstract

Background
Calcific Aortic stenosis (AS) has several findings in common with atherosclerosis including inflammation and lipoprotein deposition. Histopathological examination has revealed atherosclerotic lesions, that mainly contain cholesterol crystals (CC) in resected AS cusps. Previous studies have demonstrated that CCs can activate the NLRP3 inflammasome, resulting in an IL-1 driven systemic inflammation, that leads to the development of atherosclerotic plaques.

Aims
Our aim was to quantify the endogenous cholesterol crystal dissolution rate (CCDR) in AS patients undergoing TAVR. We sought to examine whether CCDR may be associated with iliofemoral calcification and suitable for identifying patients at high risk for vascular complications and increased mortality.

Methods
The study included 348 AS patients undergoing TAVR. Pre-interventional computed tomography (CT) scans were analyzed to quantify iliofemoral calcification from the femoral artery bifurcation to the aortic bifurcation. The CCDR was measured using flow cytometry to enumerate CC, that were added to a serum solution, at baseline and after two hours of incubation. The dissolution capacity was indicated as percentage change in CC count at baseline and after incubation. The study cohort was stratified according to the median CCDC into high and low CC dissolvers.

Results
The study population had a mean age of 80.9±6.2 years. CT-based calcium assessment revealed significantly higher right as well as left iliofemoral calcification in low CC dissolvers as compared to high CC dissolvers (1280 vs 1083 mm3, p=0.03; 1292 vs 1043 mm3, p=0.04, respectively). Consistently, an unplanned endovascular intervention for access-related vascular injury was needed more frequently in patients with a low CCDR, as compared to patients with a high CCDR (20.5% vs 12.2%, p=0.04), Figure 1. However, the rate of major vascular complications tended to be higher in the low CCDR group (3.4%) as compared to the high CCDR group (0.6%) but was not significantly different (p=0.12). The one-year all-cause mortality was significantly higher in patients with a low CCDR (13.6%) as compared to patients with a high CCDR (7.0%, p=0.05). This difference was mainly driven by significantly increased cardiovascular death in low CC dissolvers (9.1% vs 1.7%, p=0.03), whereas non-cardiovascular mortality rates were similar between both groups (5.1% vs 5.2%, p=0.81). In multivariate analysis, only low CCDR (OR: 2.51 [95% CI: 1.02 – 6.15], p=0.05) and Albumin (OR: 0.88 [95% CI: 0.79 – 0.98], p=0.03) were independently associated with one-year mortality following TAVR.

Conclusion
The CCDR is a novel biomarker associated with outcomes in AS patients undergoing TAVR. We have demonstrated, that a low CCDR is associated with increased iliofemoral calcification and vascular injury as well as one-year mortality. Thus, CCDR may provide additional prognostic information to identify vulnerable patients beyond classic risk assessment.Figure 1