The Association of Remnant Cholesterol with Obstructive Sleep Apnea and Coronary Heart Disease: A Cross-Sectional Study

Introduction

Obstructive sleep apnea (OSA) is a prevalent disorder characterized by recurrent upper airway collapse during sleep, leading to intermittent hypoxia and sleep fragmentation. Substantial evidence has established OSA as an independent risk factor for coronary heart disease (CHD). A landmark long-term study demonstrated that severe, untreated OSA significantly increases the risk of cardiovascular mortality and non-fatal events.¹ It is widely accepted that OSA promotes the initiation and progression of atherosclerosis through multiple interconnected pathways, primarily driven by intermittent hypoxia, including oxidative stress, systemic inflammation, and sympathetic activation.²

Among modifiable cardiovascular risk factors, dyslipidemia plays a central role. In recent years, remnant cholesterol (RC), the cholesterol content of triglyceride-rich lipoproteins, has gained significant attention for its pathogenic role. Basic research indicates that RC particles can be directly taken up by macrophages in the arterial intima, promoting their transformation into foam cells, which is a crucial early step in atherosclerotic plaque formation.³ During this process, the degradation of triglycerides within the lipoproteins leads to the release of free fatty acids and monoacylglycerols, further triggering a local inflammatory cascade and accelerating plaque progression.⁴ A large prospective study involving over 73,000 participants from the Copenhagen General Population Study demonstrated that elevated remnant cholesterol levels, calculated from non-fasting lipid profiles, were significantly associated with an increased risk of ischemic heart disease; this association remained independent after multivariable adjustment, and Mendelian randomization analyses further supported a causal link between remnant cholesterol and ischemic heart disease.⁵ Concurrently, another large prospective cohort study based on the same community (the Copenhagen City Heart Study) found that non-fasting triglyceride levels, a major component of RC, were an independent and potent determinant of ischemic stroke risk in the general population.⁶ These clinical evidences, derived from the same high-caliber research platform, collectively confirm from both epidemiological and causal inference perspectives the central pathogenic role of RC and its related lipoproteins in atherosclerotic cardiovascular diseases.

Notably, a close association exists between OSA and an atherogenic lipid profile. The distinctive pathophysiological alterations in OSA—the recurrent pharyngeal collapse leading to cycles of intermittent hypoxia and reoxygenation during sleep—can trigger a cascade of interrelated pathological responses. These include hemodynamic stress due to sympathetic activation, dysregulation of stress hormone metabolism such as cortisol, enhanced oxidative stress, and systemic inflammatory activation.^7,8 These interconnected changes may interact and amplify each other, collectively disrupting normal lipid metabolism, for instance, by affecting hepatic very-low-density lipoprotein synthesis and secretion and reducing lipoprotein lipase activity, thereby specifically promoting the accumulation of triglyceride-rich lipoproteins and their remnants.⁹ However, existing evidence on the relationship between OSA and dyslipidemia remains inconsistent. While some studies have reported elevated triglyceride levels and decreased high-density lipoprotein cholesterol in OSA patients,¹⁰ others have suggested that the association may be largely confounded by obesity.⁹ The precise mechanisms underlying OSA-associated lipid disturbances are still not fully elucidated.¹⁰ This uncertainty underscores the need for a comprehensive evaluation of remnant cholesterol, a specific atherogenic remnant particle, in relation to both OSA severity and coronary atherosclerosis. Based on this, we propose a key scientific hypothesis: RC may play a significant mediating role in the pathological process leading to coronary artery lesions in OSA.

However, clinical studies that directly and simultaneously investigate the relationships among RC, OSA severity, and the anatomical severity of coronary atherosclerosis remain scarce, and existing findings are inconclusive. Therefore, this cross-sectional study aimed to systematically evaluate the associations of RC with the severity of both OSA and coronary artery lesions in a clinical cohort, intending to provide new epidemiological insights into the pathophysiology of OSA-associated cardiovascular risk.

Materials and Methods

Study Design and Settings

This was a single-center, cross-sectional study. A total of 368 consecutive patients with suspected coronary heart disease, who underwent both coronary angiography (or coronary CTA) and polysomnography between July 2017 and December 2024, were enrolled. Exclusion criteria were: 1) history of coronary artery bypass grafting; 2) severe hepatic or renal dysfunction; 3) active malignancy or autoimmune diseases; 4) recent acute infection or trauma; and 5) incomplete polysomnography data. The study was reviewed and approved by the Medical Ethics Committee of the General Hospital of Xinjiang Military Command (Approval No: 2026RR0101). All procedures were performed in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from all individual participants.

The sample size was estimated a priori. The primary aim was to examine the correlation between OSA severity, quantified by the AHI, and the extent of coronary artery disease. Based on the landmark cross-sectional analysis from the Sleep Heart Health Study, which established a strong, graded association between sleep-disordered breathing and prevalent cardiovascular disease,¹¹ we anticipated a statistically significant and clinically relevant association in our cardiology-enriched cohort. We hypothesized a moderate correlation coefficient (ρ) of approximately 0.30 between AHI and the number of diseased vessels. Using G*Power 3.1 software (Heinrich Heine University Düsseldorf, Germany) for a two-tailed correlation test (Pearson), with an alpha error of 0.05 and a power (1-β) of 90%, the minimum required sample size was 112 participants. To ensure robust multivariable adjustment for potential confounders (eg., age, sex, BMI, diabetes) and to adequately power planned subgroup analyses (eg., by sex and OSA severity strata), we aimed to enroll at least 300 participants. The final consecutive cohort of 368 patients therefore provided sufficient statistical power for the primary and key secondary analyses.Given the non-normal distribution of key variables, nonparametric Spearman correlation was subsequently used for correlation analyses.

Data Collection

Baseline Characteristics

Baseline information, including age, sex, height, weight, body mass index (BMI), smoking history, alcohol consumption, history of hypertension, and diabetes mellitus, was collected by reviewing electronic medical records.

Serological Parameters

Fasting venous blood samples were drawn from all participants the morning after admission, following an overnight fast of at least 8 hours. All blood samples were collected before polysomnography. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and uric acid (UA) were measured using an automated biochemical analyzer. RC was calculated as: RC = TC - HDL-C - LDL-C.^5,12

Assessment of Coronary Artery Lesions

Coronary angiography or CTA results were independently assessed by two experienced cardiologists blinded to the sleep study results. The severity of coronary heart disease was quantified based on the number of diseased vessels, defined as: no disease, single-vessel disease, double-vessel disease, and multi-vessel (three or more) disease.¹³

All images were interpreted independently by two experienced cardiologists who were blinded to the sleep study results. The definition of a diseased vessel was a stenosis of ≥50% in any major epicardial coronary artery, and this threshold was applied uniformly for both coronary angiography and CTA. In cases of disagreement, a consensus was reached by discussion.

Assessment of OSA Severity

All participants underwent overnight polysomnography. According to the American Academy of Sleep Medicine guidelines, patients were categorized based on the apnea-hypopnea index (AHI) into two groups: a none/mild OSA group (AHI < 15 events/hour) and a moderate/severe OSA group (AHI ≥ 15 events/hour).¹⁴

Statistical Analysis

Statistical analyses were performed using SPSS software (version 26.0, IBM Corp). The normality of continuous variables was tested using the Shapiro–Wilk test. Normally distributed data were presented as mean ± standard deviation and compared using the independent samples t-test. Non-normally distributed data were presented as median (interquartile range) and compared using the Mann–Whitney U-test. Categorical variables were expressed as numbers (percentages) and compared using the Chi-square test.

Associations between variables were assessed using Spearman’s rank correlation analysis.To investigate independent associations, the following regression analyses were conducted:¹ Multiple Linear Regression models were constructed with AHI and the number of diseased vessels as dependent variables, respectively. Referring to previous population-based studies on sleep issues,^15,16 two models were built: Model 1 adjusted for age and sex; Model 2 further adjusted for BMI, hypertension, diabetes, smoking history, and LDL-C level.² Logistic regression analysis was performed with OSA severity (moderate/severe vs. none/mild) as the binary dependent variable. Additionally, subgroup analyses of the Spearman correlation between RC and the number of diseased vessels were conducted in different strata (eg., by sex, diabetes status). A two-sided P-value < 0.05 was considered statistically significant.

Ethical Considerations

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The study protocol received formal approval from the Medical Ethics Committee of the General Hospital of Xinjiang Military Command (Approval No: 2026RR0101). The ethics approval was obtained prior to the initiation of data analysis for this specific research project. It is important to clarify that the polysomnography and angiography procedures were part of the standard clinical evaluation for patients with suspected coronary heart disease. This study involved a retrospective analysis of de-identified clinical data and prospective collection of additional research variables under the approved protocol. Written informed consent was obtained from all individual participants included in the study, specifically covering the use of their clinical and polysomnographic data for research purposes.

Results

A total of 368 consecutive patients with suspected coronary heart disease were enrolled in this study. Based on AHI, 105 patients (28.5%) were categorized into the none/mild OSA group and 263 (71.5%) into the moderate/severe OSA group.

Descriptive Statistics

As shown in Table 1, compared to the none/mild OSA group, patients with moderate/severe OSA had a higher proportion of males, were older, had greater body weight and BMI, and exhibited a significantly higher prevalence of diabetes and coronary heart disease (all p < 0.05). No significant differences were found in hypertension, hyperlipidemia, and other baseline characteristics between the two groups.

Table 1 Comparison of Baseline Characteristics Between Patients with None/Mild and Moderate/Severe Obstructive Sleep Apnea [n (%)/M (P25, P75)]

Regarding serological parameters (Table 2), the moderate/severe OSA group had higher fasting blood glucose but significantly lower levels of HDL-C and LDL-C (all p < 0.05). However, no statistical difference was observed in remnant cholesterol levels between the two groups (p = 0.871).

Table 2 Comparison of Serological Parameters Between Patients with None/Mild and Moderate/Severe Obstructive Sleep Apnea [Mean ± SD/M (P25, P75)]

Regarding the severity of coronary artery lesions (Table 3), the moderate/severe OSA group had a significantly higher proportion of multi-vessel disease (16.7% vs. 4.8%) and a lower proportion of no disease (28.1% vs. 83.8%), with the difference being highly statistically significant (p < 0.001).

Table 3 Comparison of Coronary Heart Disease Severity Between Patients with None/Mild and Moderate/Severe Obstructive Sleep Apnea [n (%)]

Correlation Analysis

Spearman correlation analysis (Table 4) revealed that in the overall population, AHI was strongly positively correlated with the number of diseased vessels (r = 0.612, p < 0.001), and also positively correlated with BMI and history of diabetes (all p < 0.01), but showed no significant correlation with RC (r = −0.051, p = 0.327). Conversely, the number of diseased vessels was strongly correlated with AHI and positively correlated with age and history of diabetes, but only showed a weak negative correlation with RC (r = −0.107, p = 0.040, Table 4).

Table 4 Spearman Correlation Analysis of Various Indicators with the Number of Diseased Coronary Vessels

Regression Analysis

To control for potential confounders, logistic regression analysis were performed. Multiple Linear Regression (Table 5) showed that after adjusting for age, OSA severity, various sleep parameters, and diabetes, AHI remained a strong independent determinant of the number of diseased vessels (β = 0.804, p < 0.001). Furthermore,logistic regression analysis confirmed that the number of diseased vessels was an independent risk factor for moderate/severe OSA (OR = 3.575, 95% CI: 2.506–5.099, p < 0.001).

Table 5 Multiple Linear Regression Analysis of Factors Associated with the Number of Diseased Coronary Vessels

Subgroup Analysis

We explored the relationship between RC and the number of diseased vessels across different subgroups (Table 6). The results indicated that RC had a statistically significant, albeit weak, negative correlation with the number of diseased vessels in males (r = −0.120, p = 0.036) and in patients with moderate/severe OSA (r = −0.130, p = 0.035). No significant association was observed in females or in the none/mild OSA group.

Table 6 Correlation of Remnant Cholesterol and Apnea-Hypopnea Index with the Number of Diseased Coronary Vessels in Different Subgroups

Discussion

This cross-sectional study examined the interrelationships among RC, OSA severity, and the extent of CHD. We confirmed a strong and significant independent association between OSA severity and CHD severity. Contrary to our initial hypothesis, RC was not a primary mediator of this link at the population level, although a weak inverse correlation was observed in male patients and those with moderate/severe OSA. While the individual associations linking OSA, CHD, and dyslipidemia are well-established, studies that directly integrate all three components remain scarce. Our study addresses this gap by simultaneously assessing polysomnography-defined OSA severity, angiography-quantified coronary atherosclerosis burden, and RC levels within the same cross-sectional sample.

The strong association between OSA and CHD identified in this study is highly consistent with the existing body of epidemiological and clinical evidence.¹ For instance, a large prospective cohort study based on the Sleep Heart Health Study, which followed 6,441 community-dwelling middle-aged and older adults for an average of 8.7 years, found that the presence of moderate/severe OSA (AHI ≥ 15 events/hour) at baseline was significantly associated with an increased risk of incident coronary heart disease and heart failure after adjusting for multiple potential confounders.¹⁷ This key finding—that OSA is an independent predictor of cardiovascular events—provides robust longitudinal support for our current cross-sectional observation of an association between OSA severity and CHD. Furthermore, a systematic review and meta-analysis by Xie et al, which synthesized data from multiple observational studies involving patients with cardiovascular or cerebrovascular diseases, confirmed that OSA is an independent predictor of major adverse cardiovascular events in patients with acute coronary syndrome¹⁸ This finding is highly consistent with the conclusion drawn in our study that “OSA severity is an independent determinant of coronary artery lesion severity.”Our multiple regression models further confirmed that AHI remained an independent determinant of coronary lesion severity even after thorough adjustment for traditional cardiovascular risk factors. This strongly suggests that, beyond mechanisms mediated by traditional risk pathways, OSA may directly be associated with the progression of atherosclerosis through its unique pathophysiological mechanisms, such as intermittent hypoxia.²

Regarding remnant cholesterol, our findings differ from some previous studies. In the overall population analysis, we did not find a positive independent association between RC and AHI or the number of coronary lesions. However, several influential prospective studies, such as the work by Varbo et al, have indeed confirmed that RC is an independent and potentially causal risk factor for myocardial infarction.⁵ Furthermore, a community-based cohort study by Joshi et al also indicated that RC is significantly associated with the risk of incident coronary heart disease.¹² However, studies specifically examining the direct link between RC and OSA are scarce and inconsistent. The lack of a positive independent association between RC and AHI or the number of diseased vessels in our overall analysis may indicate that RC is not a primary factor in the complex network of OSA-related CHD. The mechanism might be that OSA inflicts vascular damage through more immediate pathways like intense sympathetic activation, oxidative stress, and systemic inflammation, whose impacts on RC metabolism might be overshadowed by stronger metabolic compensatory mechanisms or exhibit non-linear relationships.

Nevertheless, the weak inverse correlation between RC and coronary disease observed in the subgroups of males and patients with moderate/severe OSA is a finding worthy of further exploration. Several plausible biological explanations may account for this counterintuitive phenomenon. Firstly, confounding by statin therapy is a primary consideration. Patients at high risk for CHD, such as males with moderate/severe OSA in our cohort, have a higher prevalence of statin use. Statins not only potently lower LDL-C but also moderately reduce triglycerides and consequently RC levels.¹⁹ Therefore, patients with more severe disease might exhibit lower RC levels due to more intensive lipid-lowering therapy, potentially creating a reverse false association. Secondly, systemic inflammation and metabolic consumption might play a role. Severe OSA coupled with extensive coronary disease represents a state of heightened systemic inflammation, characterized by elevated levels of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α).²⁰ This chronic inflammatory state might accelerate the turnover and clearance of triglyceride-rich lipoproteins, leading to relatively lower circulating RC levels.²¹ Finally, the hypothesis of residual risk redistribution should be considered. In patients with a very high OSA burden, the effects of more direct pathways of vascular injury, such as intermittent hypoxia, oxidative stress, and inflammation, might be so dominant that they overshadow the independent contribution of traditional lipid risk factors like RC, causing it to appear as a weak or even inverse correlate in statistical analyses.⁷ Furthermore, sex-specific differences in lipid metabolism, such as the influence of estrogen on lipid profiles, may partly explain why the inverse correlation was observed only in male patients, although this hypothesis requires further investigation.

Several limitations should be considered when interpreting our findings. First, the cross-sectional design precludes definitive causal inferences regarding the relationships among RC, OSA, and CHD, particularly for mediation analyses which require temporal precedence. While our regression models adjusted for key confounders, the temporal sequence cannot be established. Second, as a single-center study conducted in a cardiology setting, the generalizability of our findings to the general population or other ethnic groups may be limited. Third, we lacked detailed information on lipid-lowering medications (particularly statins and fibrates), which could significantly influence RC levels. This unmeasured confounding may partly explain the unexpected inverse correlation observed in some subgroups. Furthermore, while the sample size was adequately powered to detect the primary association between OSA and CHD severity, we did not perform a post-hoc power analysis for the mediation analysis. The null finding regarding RC should therefore be interpreted with caution, acknowledging that insufficient power could not be entirely ruled out. Additionally, the study period spanned from 2017 to 2024, during which clinical practices regarding lipid-lowering therapy and imaging modalities may have evolved. However, all patients were consecutively enrolled, minimizing selection bias. Finally, RC was calculated indirectly rather than measured directly via advanced lipoprotein profiling, which might introduce measurement error. Future prospective, multi-center studies with serial measurements of directly quantified RC and detailed medication records are warranted to confirm and extend our observations.

Conclusion

In this cross-sectional study, we identified a strong and significant independent association between OSA severity and the extent of coronary atherosclerosis, reinforcing OSA as a key contributor to coronary heart disease. Contrary to our hypothesis, RC was not a primary mediator in this relationship at the population level. However, a weak inverse correlation between RC and coronary disease severity in males and patients with moderate/severe OSA suggests a complex, context-dependent role for RC in OSA-related atherosclerosis. As one of the first studies to concurrently evaluate OSA severity, angiographic coronary burden, and RC, our findings underscore the importance of OSA management in cardiovascular care and highlight the need for further investigation into the nuanced interplay between dyslipidemia and sleep-disordered breathing in specific at-risk subgroups.