Cardiovascular disease (CVD) remains a significant global health threat. According to the Global Burden of Disease (GBD) Study 2019, the total number of CVD cases nearly doubled from 271 million in 1990 to 523 million in 2019 (1). Recent data from the American Heart Association (AHA) reveal that in 2021, CVD was responsible for ~19.91 million deaths worldwide, with an individual in the United States succumbing to CVD every 34 s on average (2). Furthermore, a recent European study forecasts that between 2025 and 2050, the prevalence of cardiovascular diseases will surge by 90%, with the number of cardiovascular-related deaths projected to reach 35.6 million by 2050 (3). These alarming statistics underscore the urgent need for enhanced global strategies and interventions to mitigate the impact of CVD.

Atherosclerosis is crucial in the development of CVD (4). Hyperlipidemia can impair arterial endothelial function and heighten the susceptibility to atherosclerosis. The association of CVD and lipid metabolism is intricate and intimate. Lipid metabolism disorder serves as one of CVD's risk factors and has been playing a crucial role in the pathophysiological processes. Exposure to low-density-lipoprotein cholesterol (LDL-C) and other mediators of cardiovascular risks in young adults raises the incidence of subclinical atherosclerosis and is related to elevated incidence of cardiovascular events in later life (5). Apart from high total cholesterol and low HDL-C, high LDL-C is a pivotal factor influencing both atherosclerosis and cardiovascular metabolism (6). The accumulation of cholesterol-rich residual particles in patients with hypertriglyceridemia can also cause atherosclerosis and trigger atherosclerotic cardiovascular disease (AsCVD) (7). It has been demonstrated that non-HDL-C can play the same crucial role as LDL-C in incidence prediction of atherosclerosis and CVD (8–12). The non-HDL-C comprises the total content of cholesterol found in very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL-C and lipoprotein(a) (all atherogenic lipoproteins) (8, 13). Some international guidelines recommended non-HDL-C for the risk assessment of ASCVD (14, 15). On the contrary, HDL-C, which is characterized by good antioxidant and anti-atherosclerotic performances, was negatively related to the incidence of ASCVD (16, 17). The non-HDL-C, as an independent predictor of residual cardiovascular risk, may provide additional information with its ratio to HDL-C (NHHR) to enhance CVD risk stratification (18). As a novel composite lipid metric, NHHR integrates proatherogenic (non-HDL-C) and atheroprotective (HDL-C) components, offering a holistic approach to cardiovascular risk assessment (19). The NHHR includes both atherogenic and anti-atherogenic lipid markers, providing a better understanding of lipid health. It can effectively evaluate the severity of atherosclerosis and holds predictive value in metabolic disorders such as diabetes and kidney-related disease (20–23).

CVD has been recognized as a metabolic disorder associated with atherosclerosis. A European prospective study involving 46,786 participants has suggested that NHHR served as a better risk marker for coronary heart disease than single LDL-C in patients with type 2 diabetes mellitus (24). To date, the association of NHHR as a comprehensive indicator with CVD remains unclear in American adults. Herein, we hypothesized a significant association of NHHR with CVD. Afterwards, a thorough analysis was performed to explore the association of the NHHR with the risk of CVD among American adults based on data collected from the NHANES (2003–2016).

This cross-sectional analysis is essentially the first study of the association between NHHR and CVD risk in American adults. The results indicated a J-shaped association of NHHR and CVD. Moreover, an inflection point (2.82) was revealed by threshold effect analysis. This finding suggests that higher levels of NHHR are associated with an increased risk of CVD. When NHHR > 2.82, NHHR and CVD had a significant association in American adults.

In this study, we firstly compared the characteristics among participants across 4 quartiles of NHHR, and the results revealed the significant differences in lifestyles and NHHR. For instance, participants in the highest NHHR quartile had the highest BMI, and tended to current smoker and heavy drinker, consistent with previous lipid metabolism biomarkers (27, 28). And the results indicated the ability of NHHR serving as a indicator of lipid metabolism from another aspect. Then we conducted multivariate LR models to explore the associations between NHHR and CVD risk, but no significant associations in LR models were observed. Nevertheless, we additionally employed threshold effect analysis since total cholesterol and HDL-C were recommended to maintain at a medium level, and the results revealed the significant association when NHHR was more than 2.82. Meanwhile, the subgroup analyses further indicated the significant associations of NHHR and CVD prevalence in various subpopulations when NHHR reached 2.82. Nevertheless, the associations were not significant in male adults and participants with medium family income, which deserves in-depth explorations in subsequent studies. After consulting the literature, we found that the gender differences between lipid metabolism and CVD is controversial. For instance, a study involving 21 countries found that lipid markers and depression are more strongly associated with CVD risk in men than in women (29). Nevertheless, another study of ~2 million young adults demonstrated an association between the number of abnormal lipid profiles and incident CVD in both men and women, and no gender differences were found except for the associations of abnormal lipid profiles and incident myocardial infarction, which were more pronounced in men than women (30).

This study serves as an initial exploration of the direct association of NHHR and CVD. Our study is the first to demonstrate a non-linear association between NHHR and CVD risk, identifying a critical threshold of 2.82. When NHHR levels exceed this threshold, there is a significant increase in cardiovascular prevalence, which underscores the importance of early diagnosis and intervention in the management of cardiovascular diseases. The NHHR reflects the equilibrium of HDL-cholesterol and non-HDL-cholesterol, which play distinct roles in human body. Elevated NHHR could indicate disruptions in lipid metabolism. Previous studies have established dyslipidemia as a significant risk factor for CVD (31, 32). These findings align with our results demonstrating that this dyslipidemia is associated with an increased CVD risk. Elevated NHHR may be associated with decreased HDL levels, and may serve as a novel indicator of CVD. The Framingham Heart Study revealed a negative association of CVD and HDL-C (33) for the first time. Since then, it has been consistently held that HDL-C is negatively related to the risk of CVD, serving as a crucial component against CVD (34, 35). HDL performs a critical function in shielding against oxidative stress, particularly by inhibiting LDL from oxidative damage caused by ROS (36). This antioxidative role of HDL is partially mediated via the action of paraoxonase1 (PON1). PON1 activity aids in inhibiting formation of foam cells, thereby reducing the risk of atherosclerosis (37). Extensive research underscores the positive roles of HDL and PON1 in prevention of both atherosclerosis and CVD (36). Reduced HDL-C levels impair the lipoprotein's cholesterol efflux capacity while compromising its anti-inflammatory and antioxidant properties, as well as endothelial protective functions (38). This dual impairment contributes to elevated CVD risk. Non-HDL-C constitutes a significant component of NHHR, and a higher NHHR indicates an elevated level of non-HDL-C relative to HDL-C. Non-HDL-C represents the total cholesterol content of atherogenic lipoproteins that contain apolipoprotein B (ApoB), comprising very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), chylomicron remnants, and lipoprotein(a) [Lp(a)]. This composite measure of all atherogenic particles has emerged as a critical predictor of CVD risk (39). Its prognostic significance demonstrates enhanced predictive value particularly in younger populations and among individuals with well-controlled LDL-C levels (40). Prospective cohort studies have demonstrated that non-HDL-C constitutes an independent risk factor for ASCVD (41). Compared to LDL-C alone, non-HDL-C provides a more accurate assessment of atherosclerotic burden and demonstrates superior prognostic value for cardiovascular events (42, 43). Numerous studies indicate that high non-HDL-C levels are correlated with high risk of atherosclerosis and CVD (12, 44–46). In a study involving 21,448 participants from the EPIC cohort, patients with non-HDL-C levels > 130 mg/dL exhibited a hazard ratio (HR) of 1.84 for coronary heart diseases (95% CI = 1.12–3.04) (47). Elevated levels of non-HDL-C may increase the risk of CVD through several mechanisms. The lipoproteins in non-HDL-C, which contain ApoB, as well as remnants of VLDL and LDL particles, can freely cross the endothelial barrier and easily accumulate in the arterial wall, thereby triggering inflammatory response (48, 49). Additionally, oxidized low-density lipoprotein (ox-LDL) and LDL can bind to proteoglycans in the extracellular matrix of the vascular endothelium, leading to foam cell formation and exacerbating the inflammatory state within the arteries by recruiting circulating monocyte (50, 51). The oxidation of triglyceride-rich lipoproteins (TRLs) and the formation of residual particles can result in more pronounced inflammatory responses, which not only promote the progression of atherosclerosis but may also lead to plaque instability, thereby increasing the risk of cardiovascular events (52). When the NHHR exceeds 2.82, the risk of CVD significantly increases, which may be related to the cumulative effects of inflammation and vascular damage. Alyaydin et al. (53) found that elevated levels of residual cholesterol are associated with increased interleukin-6 levels (p = 0.025), indicating that residual cholesterol possesses pro-inflammatory properties. Furthermore, Li et al.'s (54) research emphasizes the relationship between non-HDL-C and inflammation, suggesting that an increase in non-HDL-C may serve as a marker of insulin resistance, which is itself a significant promoter of inflammation. The levels of non-HDL-C are elevated relative to HDL-C levels, suggesting a dominance of pro-atherosclerotic lipoprotein particle. This imbalance may lead to an increased risk of atherosclerosis and subsequently elevate the risk of CVD.

The J-shaped association between NHHR and CVD risk may arise from the interplay of lipid metabolic imbalance, inflammatory responses, and immunometabolic dysregulation. At lower NHHR levels (< 2.82), non-HDL-C particles infiltrate the vascular intima, inducing monocyte differentiation into macrophages and foam cell formation, while activating inflammatory pathways and oxidative stress, progressively triggering endothelial dysfunction and early plaque formation (55).During this phase, HDL-C exerts predominant protective effects by maintaining cholesterol efflux through reverse cholesterol transport (RCT) and counteracting inflammation, thereby mitigating the atherogenic effects of non-HDL-C (56). Near the threshold (NHHR is close to 2.82), the metabolic balance between non-HDL-C and HDL-C reaches a critical point. Prolonged exposure to elevated non-HDL-C drives oxidative modification of LDL (ox LDL) and cholesterol crystal deposition, activating the NLRP3 inflammasome and promoting IL-1β/IL-18 secretion, which amplifies vascular inflammation (57, 58). As NHHR levels increase, chronic inflammation induces glycation of apolipoprotein A1 (apoA1) in HDL-C, replacing functional components with pro-inflammatory mediators (e.g., SAA1, apo CIII), transforming HDL-C into a pro-atherogenic particle (59).Cumulative LDL-C exposure (quantified as LDL-C burden, LCB) correlates positively with CVD risk (60), activating the TLR4/NF-κB axis and recruiting neutrophils via CXCL1/CXCR2 signaling, further destabilizing plaques (6, 57, 61, 62).An increase in NHHR may contribute to metabolic disorders. In patients with cholestasis, the formation of Lp-X not only exacerbates lipid metabolism disorders (63), but also leads to electrolyte imbalances, further impairing vascular function. Additionally, the deposition of bilirubin and bile acids may worsen vascular endothelial damage by inducing oxidative stress and promoting the release of inflammatory factors (such as IL-6 and TNF-α), thereby indirectly disrupting cardiovascular homeostasis (64, 65).

NHHR, emerging as a novel indicator in lipid management, has been widely recognized for its close relation with various metabolic diseases (21–23, 66, 67). In populations with type 2 diabetes, the NHHR has demonstrated superior effectiveness in predicting cardiovascular risk compared to non-HDL-C or HDL-C (68). This study expands the population scope and further compares the correlation between NHHR and CVD risk in the general adult population of the United States, highlighting its superiority over single indicators such as LDL-C or non-HDL-C. You et al. (69) demonstrated that high NHHR was related to high incidence of acute coronary syndrome. Mao et al. (70) reported that NHHR was independently associated with adverse cardiovascular events and coronary artery lesions. Liu et al. (71) found that in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), the NHHR is associated with the progression of coronary artery lesions. This study elucidates the nonlinear relationship between NHHR and CVD and establishes a threshold of 2.82, further emphasizing the clinical applicability of NHHR. Yu et al. (72) conducted a longitudinal cohort study revealing a non-linear association of NHHR and CVD-induced mortality with or at risk of diabetes, with a threshold effect of 2.83. In this study, a J-shaped association of NHHR and CVD was developed among the general population. Furthermore, a threshold effect analysis revealed that the inflection point was 2.82. Exceeding this threshold, the risk of CVD increased significantly. The consistent performance of NHHR across multiple validation cohorts, substantiates its clinical utility for CVD risk. Two studies also found the J-shaped association between NHHR and other outcomes shown as sarcopenia risk in individuals with cancer and prognosis in cancer survivors (73, 74). Moreover, the J-shaped association of lipid levels and all-cause and cause-specific mortality were substantially explored (75, 76). In fact, the J-shaped association of lipid markers are common since slight increase of LDL-C and decrease of HDL-C within the normal range would not significantly increase the risk of adverse outcomes. However, when it exceeds a threshold, the occurrence of hyperlipidemia would elevate oxidative stress (77) and promote chronic inflammation (78) and then lead to higher hypertension and CVD risk. Furthermore, multiple studies have illustrated the crucial role of lowering LDL-C and reducing hyperlipidemia risk in CVD management for primary prevention (79–81), indicating the potential utilization of NHHR as a novel biomarker in CVD prevention.

This study expands the understanding and application of lipid ratios by initially exploring and demonstrating a nonlinear relationship of NHHR and CVD, which holds significant implications for preventing and managing CVD from a lipid management perspective. In clinical practice, it is essential to prioritize the monitoring and management of NHHR, particularly when NHHR approaches or exceeds the established threshold, in order to implement proactive interventions aimed at reducing CVD risk. Moreover, this study also suggests that slight increase of NHHR would not elevate the CVD risk, reducing the excessive concerns of the public about the NHHR increase. Nevertheless, the role of NHHR as a target for lipid management and CVD prophylaxis and treatment shall be further clarified. This cross-sectional study, based on NHANES data, highlights the significance of integrating NHHR into a comprehensive risk assessment framework of CVD, rather than using it as a standalone metric. The findings suggest that NHHR may assist clinicians in developing personalized health interventions, particularly in modifying diet and lifestyle for high-risk individuals. Although lipid ratios are useful in population analyses, they should be employed cautiously and in conjunction with other diagnostic tools and biomarkers to provide a more thorough evaluation of cardiovascular and metabolic risk. It is crucial to acknowledge the limitations that, while cut-off points can yield clinically relevant information, employing quantiles within the cohort or population may be more logical for comparing ratios.

The clinical utility of NHHR extends beyond risk prediction to actionable prevention strategies. First, integrating NHHR into established frameworks, such as the ASCVD risk score or lipid management guidelines, could improve risk stratification. For instance, NHHR may serve as an additional marker for high-risk individuals to guide therapeutic decisions. A threshold of NHHR >2.82 should prompt intensified interventions, such as lifestyle modifications or pharmacotherapy. Second, automating NHHR calculation within electronic health records would enable real-time risk stratification without incurring additional costs. Third, prospective validation across diverse populations and clinical settings is essential to confirm its prognostic generalizability. Additionally, decision support tools could link NHHR levels to therapy escalation protocols, further enhancing its clinical applicability. Notably, NHHR's reliance on routine lipid measures makes it particularly valuable in resource-limited regions, helping bridge gaps in equitable risk assessment. By connecting risk assessment with therapeutic action, NHHR has the potential to reduce the global CVD burden through precision prevention.

In this study of American adults, a potential J-shaped association between NHHR and CVD was identified, with an optimal NHHR level of 2.82. Exceeding this threshold, higher NHHR may elevate the risk of CVD. This finding offers new insights into lipid management for CVD, although further cohort studies are necessary to validate these results.