Valvular heart disease (VHD) remains to be a major burden worldwide. It was estimated that more than 42 million people worldwide suffered from VHD (1). In developing counties, due to the high incidence of rheumatic heart disease, as well as expanding of the aging population (age ≥ 60 years), hence, with the increase in the incidence of degenerative valvular disease (2, 3), more attention should be drawn to VHD. Valve replacement surgery (VRS) is the treatment of choice for VHD, however, the surgical mortality was high in the elderly population (4, 5). Early identification of these high-risk patients is essential for reducing mortality.

Low-density lipoprotein cholesterol (LDL-C) is recognized as the “bad cholesterol” for its biochemical role in carrying lipids to the periphery and pathogenesis of atherosclerosis (6, 7). Maintaining LDL-C at a lower level is the mainstay of cardiovascular therapeutic principles according to the current guideline, (8, 9) for the benefits of clinical outcome (10–12). However, several studies have demonstrated the role of LDL-C in preventing sepsis and worse clinical outcomes (13, 14) via clearing bacterial toxin (13, 15). The prognostic value of LDL-C in elderly patients undergoing VRS remains unclear. This study aimed to elucidate the relationship between the preoperative LDL-C and adverse outcomes in elderly patients undergoing VRS.

In this study, we explore the relationship between the preoperative LDL-C level and the rate of postoperative adverse events in elderly patients (≥ 60 years old) undergoing VRS. The univariate analysis showed that lower LDL-C level was associated with a higher risk of in-hospital and one-year mortality. However, this association disappeared after PS analysis and multivariate analysis, where potential confounding factors were matched or adjusted. Therefore, the negative relationship between LDL-C level and the clinical outcome might be confounded by clinical characteristics in the lower LDL-C group.

On one hand, as a carrier of cholesterol, the LDL-C has been well-accepted as a critical risk factor for developing atherosclerosis (19). Besides, elevated LDL-C was linearly correlated with the risk of unfavorable events (20), and the reduced amount of LDL-C was associated with a corresponding reduction in the risk of cardiovascular and cerebrovascular events (21, 22); consequently, lipid-lowering drugs, such as statins, were recommended by both European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines, indicating that LDL-C level should be as low as possible (8, 9).

On the other hand, LDL-C exhibited a protective effect in infectious diseases through its function of delivering toxic bacterial productions for hepatic elimination (23), thus patients with lower LDL-C levels were more likely to develop sepsis (13–15). Based on this theory, several studies have proved the link between lower LDL-C levels and higher mortality afterward, especially for elderly patients (24, 25). A similar result was found in our pre-matched analysis. However, no association between LDL-C level and mortality risk was found after matching the confounding factors. Although the exact mechanism is unclear, the following aspects from previous studies might account for our findings.

Firstly, the patients in the group with lower LDL-C were significantly older in our study. Aging is a complicated physiological process, where the function of all organ systems fades away (26). The antioxidative capacity declines with age, resulting in excessive oxidative stress in the cells (27). Reactive oxidative species (ROS) alters cholesterol metabolism by decreasing the acetyl-CoA acetyltransferase (ACAT) activity and the secretion rate of very low-density lipoprotein cholesterol, which could explain the decrease in LDL-C level as aging (28). Besides, older age was an independent risk factor for worse clinical outcomes. After matching the age and other variables between groups, LDL-C level was not associated with clinical outcomes in elderly patients undergoing VRS, which implied that LDL-C may not be able to influence the outcome independently and individual baseline characteristics should be considered as a whole during clinical evaluation.

Secondly, a significant positive correlation between PNI and LDL-C levels was found in our study. The PNI is a frequently used index in clinical practice to assess one's nutritional status and has been proven to be positively correlated with prognosis in multiple situations, such as surgical high-risk and elderly patients (29). As for VRS, a similar correlation was verified by Cho et al. (30) and Gürbak et al. (31). Thus, the significant relationship between LDL-C and mortality before matching in our study may be the result of the confounding effect of PNI.

In a summary, both older age and worse nutritional status were related to lower LDL-C levels, hence, could be the confounding factors in associating LDL-C level with clinical outcome after VRS. During clinical evaluation, LDL-C level should not be used independently to predict clinical outcome, instead, other clinically significant factors such as age and nutritional status should be integrated.

Yet, our current study had several limitations. First, due to the shortcomings inherent in the retrospective design, the underlying mechanism of low LDL-C level on admission was yet unknown; however, the primary aim of this study was to investigate the prognostic value of LDL-C in patients undergoing VRS. Second, the sample size was relatively small in the propensity score matching analysis. Finally, LDL-C was obtained once on admission, whether the change of LDL-C level during hospitalization would affect the clinical outcomes cannot be drawn from our findings.

The present study was the first to investigate the prognostic value of LDL-C level in elderly patients undergoing VRS. Low LDL-C level was associated with increased risk of in-hospital and one-year mortality. However, after PS analysis and multivariate analysis, the association disappeared. The prognostic effect of LDL-C needs to be further evaluated and confirmed by large sample, prospective, and randomized controlled studies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Guangdong Provincial People's Hospital. The Ethics Committee waived the requirement of written informed consent for participation.

S-hW, X-bW, and Z-hW were involved in the conception and design of this study. H-bL, B-qF, TT, and X-hL contributed to the data collection and statistical analysis. H-bL and B-qF constructed the manuscript, which was revised and approved by all the authors for publication. All authors contributed to the article and approved the submitted version.

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 82002014), Natural Science Foundation of Guangdong Province (Grant No. 2021A1515010107), Science and Technology Projects of Guangzhou (Grant No. 201903010097), and Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention (Grant No. 2017B030314041). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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