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BACKGROUND AND AIMS: Leukocytosis, the expansion of white blood cells, is associated with increased cardiovascular risk. Studies in animal models have shown that high-density lipoprotein cholesterol (HDL-c) suppresses leukocytosis by mediating cholesterol efflux from hematopoietic stem and progenitor cells. HDL-c showed a moderate negative association with leukocyte numbers in the UK Biobank and Multi-Ethnic Study of Atherosclerosis. Cholesterol efflux capacity of HDL (HDL-CEC) or HDL particle (HDL-P) number has been proposed as improved inverse predictor of CVD compared to plasma HDL-c. In the LifeLines DEEP (LLD) cohort (n = 962), a sub-cohort representing the prospective population-based LL cohort from the North of The Netherlands, we tested the hypothesis that HDL-CEC and HDL-P were associated with lower leukocyte counts.METHODS: We carried out multivariable regression and causal mediation analyses (CMA) to test associations between HDL-c, HDL-CEC, or HDL-P and leukocyte counts. We measured HDL-CEC in THP-1 macrophages and HDL-P and composition using nuclear magnetic resonance.RESULTS: HDL-c associated negatively with leukocyte counts, as did extra-large and large HDL-P, while HDL-CEC showed no association. Each one-standard deviation (SD) increase in extra-large HDL-P was associated with 3.0% and 4.8% lower leukocytes and neutrophils, respectively (q < 0.001). In contrast, plasma concentration of small HDL-P associated positively with leukocyte and neutrophil counts, as did small HDL-P triglycerides (TG) and total plasma TG. CMA showed that the association between S-HDL-P and leukocytes was mediated by S-HDL-TG.CONCLUSIONS: The association between HDL-P and leukocyte counts in the general population is dependent on HDL-P size and composition, but not HDL-CEC.

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T-cells accumulate cholesterol, which could lead to a pro-inflammatory phenotype. However, the role of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) in T-cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generated mice with T-cell-specificAbca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T-cellAbca1/Abcg1-deficiency decreased blood, lymph node, and splenic T-cells, and increased T-cell activation and apoptosis. T-cellAbca1/Abcg1-deficiency induced a premature T-cell aging phenotype in middle-aged (12-13 months)Ldlr-/-mice, reflected by upregulation of senescence markers. Despite T-cell senescence and enhanced T-cell activation, T-cellAbca1/Abcg1-deficiency decreased atherosclerosis and aortic inflammation in middle-agedLdlr-/-mice, accompanied by decreased T-cells in atherosclerotic plaques. We attribute these effects to T-cell apoptosis downstream of T-cell activation. Collectively, T-cell cholesterol efflux pathways are critical for maintaining T-cell numbers, suppress senescence, and induce atherosclerosis in middle-agedLdlr-/-mice.

Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future.