Cholesterol has long been regarded as a significant risk factor for cardiovascular diseases, leading to widespread guidelines recommending lower cholesterol and triglyceride levels and increased high density lipoprotein (HDL) levels to reduce morbidity and mortality [1]. Historically, numerous studies have established a correlation between elevated levels of low density lipoprotein (LDL) cholesterol, low levels of HDL and elevated triglycerides being associated with increased risk of coronary artery disease (CAD) [2-4]. Traditional lipoprotein profiles have been used for risk assessment, stratification and treatment therapies, relying on these measures in clinical practice. Additionally, a number of studies have not reported a strong association with LDL or HDL and CAD [5-7]. More recent findings regarding cholesterol and CAD have been attempting to understand why LDL and HDL, in some instances are less predictive of morbidity and mortality [1,8,9]. It should be noted that traditional lipid measures of cholesterol content may not account for variations in cholesterol particle characteristics and quality, which has been reported to play a significant role in atherosclerosis and CAD events [10].

A new term labeled cholesterol paradox has emerged in an attempt to understand some findings that demonstrate a protective effect of elevated LDL cholesterol [11]. Cholesterol paradox refers to the observation that certain health outcomes exhibit an inverse relationship with traditional cholesterol risk factors when examined in specific populations. Study authors have reported that normal levels of LDL and high levels of HDL are linked with increased mortality in older adults [12]. It should be noted that this term has created significant controversy in the scientific literature and created significant debate [13-15].

There have been a number of suggestions, with clinical evidence, as to why cholesterol levels have been less predictive of morbidity and mortality in recent studies [16]. Explanations include nutritional deficiencies, inflammatory processes, cholesterol particle number and size, cholesterol quality and other factors. More recent explanations for a cholesterol paradox are presented in this commentary.

One such reason that has been presented is nutritional deficiencies in patients presenting with CAD. Many of the recent studies have focused on lower levels of LDL and increased levels of HDL and paradoxical findings. One study [6] examined data from over 40,000 patients with CAD in a hospital in China with the reported findings revealing an association between non-HDL cholesterol concentration and long term all-cause mortality. Yet, when controlling for nutritional status, non-HDL cholesterol was still considered a risk factor for all-cause mortality suggesting nutritional status is likely playing a role in lowered cholesterol levels yet may not be attenuating the risk associated with non-HDL cholesterol [17,18]. An additional large study of over 40,000 participants reported a cholesterol paradox occurred in patients with CAD but also was attenuated when nutritional status was measured and controlled for in the analysis [19]. Malnutrition was also identified as predictor of clinically normal total cholesterol levels and increased levels of CAD in a geriatric population [20]. It should be noted that nutritional deficiencies may contribute to lower total cholesterol and LDL cholesterol, yet with these clinically normal levels of cholesterol may be more likely to be contributing to higher rates of mortality and morbidity. It could be that nutritional deficiencies, especially in active disease states, may cause biomarkers like cholesterol to no longer be predictors of CAD [18].

Inflammatory states, common in chronic diseases, can alter lipid metabolism resulting in lower cholesterol levels while simultaneously increasing the risk of mortality [21]. In clinical practice inflammation is measured more readily as high sensitivity C-reactive protein (hs-CRP) with inflammation and cholesterol contributing to both CAD and all-cause mortality [21]. A large sample of over 30,000 research participants demonstrated that inflammation may play a larger role in CAD than LDL cholesterol [22]. The study authors reported that patients receiving statin therapy for cholesterol control reported higher risk for future CAD morbidity and mortality based on hs-CRP rather than LDL cholesterol. The inflammatory process may in fact reduce cholesterol values to the point of having a normal lipid profile, but due to the increased inflammation, more patients may have more CAD events. Additionally, it is important to remember that statin therapy may also have an effect on non-cardiac related all-cause mortality, which could possibly be associated with the cholesterol paradox [23]. Finally, inflammatory diseases and infections that can effect cholesterol levels resulting in a cholesterol paradox have included chronic kidney disease [24], COVID-19 [25], bacterial infections [26].

Cholesterol particle number (CPN) refers to the total number of lipoprotein particles carrying cholesterol in the circulation with cholesterol particle size referring to the diameter of these lipoprotein particles. Smaller, denser LDL particles have been linked to a higher risk of cardiovascular events compared to larger, less dense LDL particles [27]. This is primarily due to smaller and more dense LDL particles more easily penetrating the arterial wall causing arterial stenosis and greater susceptibility to oxidative modification [28]. In clinical practice the assays used to measure CAD risk via cholesterol is based on cholesterol that is found in lipoproteins. Though normal cholesterol levels can be present, it may be that the cholesterol lipoproteins such as LDL may be smaller, more dense and higher in number all of which increase the risk for CAD events even though cholesterol values as traditionally measured may be normal [29]. Additionally, research has demonstrated that CPN and particle size can independently predict cardiovascular risk beyond traditional lipid measures. For instance, study authors have reported that individuals with high CPN, even with normal LDL cholesterol levels, may still have a significantly elevated risk of CAD [30]. Conversely, individuals with larger, buoyant LDL particles may exhibit lower risk, despite elevated LDL cholesterol levels [31].

HDL levels, especially elevated HDL levels have been associated with decreased CAD, but there are some studies where higher levels of HDL do not provide a protective effect [32]. More recent studies outcomes have reported the functionality of HDL, rather than its quantity, is an important determinant of cardiovascular protection. Recent studies have reported that HDL quality or a term know as HDL dysfunction may play a role in the development of CAD [33] with increasing evidence suggesting that HDL dysfunction, rather than HDL levels, may play a significant role in the pathogenesis of CAD [34]. HDL particles can become dysfunctional and lose their protective properties despite normal and elevated levels of HDL lipoproteins in circulation. HDL dysfunction can result from alterations in HDL particle composition, structure, and function, and is often driven by systemic factors such as inflammation, oxidative stress, and metabolic diseases [35].

Several factors can be associated with dysfunctional HDL. Oxidative modifications of Apo A-I, the major apolipoprotein in HDL, reduces its ability to mediate cholesterol efflux from macrophages and impair HDL antioxidant properties [36]. Additionally, decreased phospholipid content in HDL can affect the stability and structure of the particles, limiting their ability to engage in reverse cholesterol transport and enhance endothelial function [37]. Another factor in HDL dysfunction is elevated triglyceride levels in HDL lipoproteins are associated with increased hepatic lipase activity, which can lead to the formation of small, dense HDL particles that are less efficient in cholesterol efflux and have pro-inflammatory properties [38].

Extracellular vesicles (EV) are membrane-bound particles that vary in size and density and are released into the extracellular space. EVs carry molecules such as proteins, RNA, DNA and importantly for this paper, lipids. Thought studies regarding EVs and the cholesterol paradox are wanting, the emerging understanding of EVs, inflammation and CAD demonstrates promising findings regarding a better understanding of the cholesterol paradox [39,40].

Despite the most recent understandings of cholesterol, most of the emphasis in clinical practice is on traditional cholesterol measurement that measure cholesterol content only and does not consider other measures such as particle number, size and functionality. There is need for an update to clinical guidelines that include the inclusion of these new measures of LDL and HDL and how other factors such as inflammation and disease states affect CAD morbidity and mortality. More advanced lipid testing is available yet is not used routinely in clinical practice. Reasons include laboratories not running the assays as they are expensive and presently are rarely reimbursed by insurance plans. Additionally, there is need for provider and patient education regarding changes in our understanding of cholesterol and CAD prevention. As such the following is proposed for the inclusion of more predictive measures of cholesterol in clinical practice.

1. Updated clinical guidelines: The National Cholesterol Education Program (NCEP) should update their ATPIII guidelines [41] that address the latest understanding of cholesterol, cholesterol measurement and prediction.
2. New risk stratification categories: New ATPIII guidelines would need to create new stratification categories for CAD prediction based on non-traditional measures of cholesterol.
3. Increased access and affordability: With the creation of new guidelines by the NCEP there would need to be an investment in others means of cholesterol measurement and reimbursement models by US government and private insurance providers.
4. Provider training: Continuing medical education should focus on increased awareness among clinicians about changes in our understanding of cholesterol and disease predictions including an increased understanding of forms of measurement for cholesterol. This could include more personalized treatment strategies inclusive of statin therapy and lifestyle interventions
5. Patient Awareness: Education programs are needed for patient and general populations about the new understanding of cholesterol prediction and measurement.
6. Monitoring of outcomes: Continued monitoring of treatment strategies to have a better understanding of how new measures of cholesterol predict CAD outcomes.
7. Patient education: Educating patients about the significance of cholesterol particle characteristics can empower them to engage in discussions with their healthcare providers.
8. Patient and general population outreach: More information about cardiovascular risk through screening programs and educational campaigns is needed.
9. Research: Increased research funding to gain a better understanding of new ways to measure cholesterol and the implication on various chronic diseases.
10. Inclusion of cholesterol particle number, size and quality in federal databases such as the National Health and Nutrition Examination Survey.

As more studies are being published that suggest our traditional understanding of cholesterol measurement and prediction are counterintuitive in the associations with CAD, more emphasis is needed on education and changes in clinical practice. A renewed focus on creating new cholesterol guidelines and risk stratification is warranted to lower morbidity and mortality outcomes related to CAD.