Novel assay for quantifying the cholesterol crystal dissolution capacity of serum predicts outcomes in patients with severe aortic stenosis undergoing TAVR

Abstract

Abstract Background Aortic stenosis (AS) is the most common valvular heart disease (VHD) in developed countries. The pathophysiology of calcific AS has several clinical and pathobiological findings in common with atherosclerosis including chronic inflammation and lipoprotein deposition. Histopathological examination has revealed atherosclerosis-like lesions, that mainly contain cholesterol crystals (CC) in resected calcific aortic valve 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. Purpose In this study, we sought to validate a novel assay for measuring the serum capacity to dissolve cholesterol crystals (CCDC) in patients with AS and to examine whether this biomarker may be associated with clinical outcomes. Methods Our study cohort included 348 patients with AS undergoing transcatheter aortic valve replacement. The CCDC was measured using flow cytometry to enumerate CC, that were added to a 50% 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 was 47.7% female and had a mean age of 80.9±6.2 years. The primary end point, a composite of one-year all-cause mortality and major vascular complication occurred less frequently in the high CCDC group (7.0%) as compared with the low CCDC group (15.3%, p=0.01). This was mainly driven by lower rates of one-year mortality in patients with a high CCDC (7.0% vs 13.6%, p=0.05), as presented in Figure 1. Furthermore, unplanned endovascular interventions were significantly less frequent in high CC dissolvers in contrast to low CC dissolvers (12.2% vs 20.5%, p=0.04). Although LDL cholesterol (101.8±37.3 mg/dL vs 97.9±37.6 mg/dL, p=0.35) and total cholesterol levels (158.1±43.8 mg/dL vs 154.1±40.2, p=0.41) were comparable in the high and low CCDC group, only patients with a low CCDC showed a benefit from statin treatment (Figure 2). In multivariate analysis, only low CCDC (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 all-cause mortality Conclusion The CCDC is a novel biomarker associated with clinical outcome in patients with AS undergoing TAVR. It may provide new insights into patient's preventative anti-inflammatory capacity and additional prognostic information to identify vulnerable patients beyond classic risk assessment. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).