Aortic valve stenosis (AVS) is one of the most common cardiovascular diseases with considerable impact on morbidity and mortality. AVS is progressive with age and present in 2%–5% of patients aged over 65 years (1–3). Still, recent data indicate that chronic inflammation and lipid metabolism disorders play pivotal roles in fibrosis formation and leaflet thickening, which results in severe AVS (4–7).

Over the past decades, close interaction of inflammation and immune system-related cells such as neutrophils, platelets and lymphocyte with the pathogenesis of AVS has attracted great attention (8–12). Accordingly, various inflammation hematological ratios have been developed from the count of these cells in diverse combinations in order to predict the progression and prognosis of AVS (8, 10, 11, 13). Among them, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR) were well-defined inflammation biomarkers that were found to be associated with the severity of AVS in previous studies (10, 11, 14). Systemic inflammation index (SII) was also a novel marker that brought together these peripheral cell counts of neutrophils, lymphocytes, and platelets, and was demonstrated to predict severe calcific AVS (9). In a recent study, monocyte/high density lipoprotein ratio (MHR) was determined as a significant independent predictor for the speed of progression and diagnosis of severe bicuspid AVS (15). However, there is debate about which of the above inflammatory hematological ratios has the best predictive performance for AVS risk.

This study sought to investigate the association between various inflammatory hematological ratios and AVS.

In this retrospective cross-sectional study, we demonstrated that MHR level was significantly increased in AVS patients compared to patients without AVS, indicating MHR was significantly associated with the presence of AVS. Furthermore, multivariable analysis revealed a stronger independent association between MHR and the presence of AVS compared to established inflammatory ratios such as SII, NLR, PLR, and LMR. To our knowledge, this is one of the few studies to comprehensively compare multiple inflammatory hematological ratios, including MHR, SII, NLR, PLR, and LMR, in relation to AVS using PSM to control for confounding factors. Our findings highlight the superior association of MHR with AVS compared to other established ratios.

AVS is a progressive valvular disease in the population that resembles atherosclerosis with activation of calcification, lipoprotein deposition and chronic inflammation (17–20). The endothelial damage resulting from increased mechanical stress and reduced shear stress may allow lipids to penetrate the valvular endothelium, and subsequently, lipid deposition and oxidation occur in valvular endothelium. Afterward, complex inflammatory pathways are activated with the contribution of inflammatory and immune system-related cells such as monocytes, macrophages, and lymphocytes (21, 22). Biomarkers derived from the counts of the cell types have been widely investigated in recent years due to the fact that they are affordable and available. Among them, PLR, NLR and LMR were shown to possess predictive and prognostic roles in AVS (8, 10, 14). A previous study demonstrated that NLR was related to the severity of calcific AVS and LV systolic dysfunction in patients with severe calcific AVS (23–25). Likewise, PLR was shown to been independently associated with the presence of AVS (11, 25). Other studies have also proven that increased PLR was linked with the severity of degenerative AVS, and PLR should be used to monitor patients' inflammatory responses and the efficacy of treatment (25, 26). SII, which include the peripheral counts of neutrophils, lymphocytes, and platelets, was recently found to be better than NLR and PLR in predicting severe calcific AVS (9, 27). However, it is not clear which indicator has the most excellent correlation with AVS. In our study, we included MHR, a novel inflammatory marker, and focused on the comparison on AVS association ability among diverse inflammatory hematological ratios. The results highlighted that MHR emerged stronger associational strength with AVS compared to other inflammatory hematological ratios such as SII, NLR, PLR and LMR. More importantly, compared to previous studies, we used propensity score matching analysis to balance the baseline confounding factors that may affect the incidence of AVS, including age, gender, hypertension, diabetes, Cr and γ-GT, partly minimizing the impact of selection bias on the results.

Consistent with the results of our study, a significant association between MHR levels and inflammation was demonstrated by the study of Acikgoz et al. (28). Monocytes are pivotal immune cells and molecules that associate with endothelial cells, attending to aggravation of inflammatory pathways. Since macrophages originate from circulating monocytes, the number of circulating monocytes and monocyte subsets with different properties has attracted attention in both atherosclerosis lesions and valvular disease studies (15, 29, 30). Moreover, HDL-cholesterol is well-known as an anti-inflammatory indicator. HDL protects endothelial cells from inflammation and oxidative stress by preventing the displacement of macrophages and oxidation of low-density lipoprotein molecules, and also by controlling monocyte progenitor cell proliferation and monocyte activation (31–33). Therefore, it is reasonable to use MHR as a single marker by integrating monocyte and HDL-C. The advantage of MHR is that it provides more reliable information than either monocyte or lipoprotein alone for predicting inflammatory and cholesterol burden. Recently, MHR has been reported to be a novel marker for valvular heart disease (34–38). Ozcan et al. reported that MHR is strongly associated with mitral valve prolapse (MVP) and might be a prognostic factor for patients with MVP (34). In our study, ROC analysis and further DeLong tests showed that MHR indicated AVS with a higher sensitivity than LMR and NLR. Most notably, among the five inflammation hematological ratios evaluated, only MHR was positively associated with AVS after adjusting for the confounding factors. Furthermore, in comparison to previous studies, a nonlinear and S-shaped association was firstly revealed between MHR and AVS using RCS analysis while no nonlinear association were shown between other inflammation hematological ratios and AVS, providing more meaningful evidence for the close relationship between MHR and AVS. RCS analysis showed risk accelerated once MHR exceeded 0.33 and plateaus after 0.83, supporting 0.33 as an early-intervention threshold and 0.83 as a high-risk ceiling in clinical practice.

The precise role of the MHR in the pathogenesis of AVS has yet to be fully elucidated. Monocytes and their differentiated descendants, macrophages, play a central role in the initiation and progression of aortic valve calcification (39). In the early stages of AVS, mechanical stress and endothelial dysfunction facilitate the infiltration of lipids and circulating monocytes into the valvular subendothelium. Once localized, monocytes differentiate into macrophages, which phagocytose oxidized lipids and transform into foam cells—a key feature of early valve lesions. These activated macrophages secrete pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and promote the expression of osteogenic mediators such as bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase, thereby driving the transition from inflammation to active calcification (40, 41). HDL cholesterol exerts atheroprotective and anti-inflammatory effects that counter these processes. Functionally intact HDL facilitates reverse cholesterol transport from macrophage foam cells, reduces lipid peroxidation, and inhibits the expression of adhesion molecules on endothelial cells, thereby limiting further monocyte recruitment (42). Moreover, HDL-associated enzymes like paraoxonase-1 attenuate oxidative stress, while HDL modulates monocyte activation and macrophage polarization toward anti-inflammatory phenotypes (43). In AVS, however, HDL may become dysfunctional—losing its protective capacity—due to oxidative modification or systemic inflammation, thereby exacerbating valvular injury and calcification (15). The MHR thus integrates both the pro-inflammatory burden (monocyte activation) and the anti-inflammatory capacity (HDL function), offering a composite biomarker that reflects the net inflammatory–lipid imbalance driving valvular calcification.

TG and LDL are also identified as associated factors of AVS in addition to MHR in multivariate logistic regression analysis. The pathophysiology of AVS was consisted of both an initiation phase including lipid infiltration, oxidation and inflammation, and a propagation phase characterized by fibrosis and calcification. Emerging studies revealed lifelong exposure to high cholesterol increases the risk of symptomatic AVS (19, 44, 45). Additionally, the prevalence of AF in patients with AVS is high and AF is associated with poor prognosis in AVS (46–48). Age-related changes in heart structure (left atrial dilation, left ventricular hypertrophy and increased fibrosis) in conjunction with chronic pressure or volume overload induced by the valvular obstacle may explain this over-representation of AF in AVS.

Our study has important clinical relevance. In this study, we confirmed a statistically significant correlation between increased MHR and AVS. These results are consistent with the previous evidence that inflammation and cholesterol play essential roles in the pathology of AVS. Accordingly, modulation of inflammation with the anti-inflammatory therapies combined with statin may slow the progression of AVS. Furthermore, MHR can be calculated easily from the routine blood parameters, and also MHR should be considered as an early associated factor of patients who have a high inflammatory risk and a high rate of progression to severe AVS.

The present study suggested that elevated MHR level was significantly associated with the presence of AVS for the first time in the literature. MHR showed the best associational strength in AVS than other inflammation hematological ratios such as SII, NLR, PLR and LMR.