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Beyond Good and Bad: Why Your Cholesterol Story Is More Complex Than You Think

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Introduction

Historically, low-density lipoprotein (LDL) has been dubbed the “bad” cholesterol and high-density lipoprotein (HDL) the “good” cholesterol in both clinical literature and public messaging. These simplifying labels have supported public health messaging for decades, but recent research reveals that the relationship between LDL, HDL, and cardiovascular risk is far more nuanced. This article examines contemporary evidence, biological functions, and therapeutic implications, urging a move beyond reductive categorizations toward personalized risk assessment.

Cholesterol’s Essential Functions

Cholesterol in general itself is vital for several physiological processes such as:

  • Structural Component of Cell Membranes: Cholesterol is a critical element in building and maintaining cell membranes. It modulates membrane fluidity and stability, allowing animal cells to maintain their structure and function across various conditions [1,2].
  • Precursor for Hormones: Cholesterol serves as the building block for the biosynthesis of steroid hormones, including sex hormones (estrogen, testosterone, progesterone) and adrenal hormones (cortisol, aldosterone). These hormones regulate crucial processes such as metabolism, immune response, salt, and water balance, and reproductive functions [2,3].
  • Production of Bile Acids: Cholesterol is converted in the skin, under the influence of sunlight, into vitamin D. This vitamin is essential for bone health, immune function, and overall metabolism [2-4].
  • Synthesis of Vitamin D: Cholesterol is abundant in the brain and is involved in forming myelin sheaths, which insulate nerve fibers for efficient electrical signal transmission [1].

These multiple roles highlight that cholesterol is not only necessary but also vital for healthy physiological function- well beyond its association with heart disease risk. While excessive cholesterol can contribute to disease, adequate levels are essential for life  [1-4].

Low-Density lipoprotein (LDL) Cholesterol

Low-density lipoprotein (LDL) is crucial cholesterol transporter in the body. Its main physiological functions include:

  • Cholesterol Delivery: LDL’s central role is to transport cholesterol from the liver to peripheral tissues, where it is used for building cell membranes, synthesizing steroid hormones and producing bile acids [5,6].
  • Cell Membrane Integrity: Cholesterol delivered by LDL is essential for maintaining cell membrane fluidity and structure- critical for normal cell function [6].
  • Hormone and Bile Acid Precursor: LDL-cholesterol provides the substrate for steroid hormone production (including cortisol, estrogen, and testosterone) and bile acid synthesis, which supports digestion and absorption of dietary fats [6].

While LDL is necessary for these processes, excess circulating LDL(>100 mg/dL), especially in the form of small, dense particles, can penetrate arterial walls and contribute to the formation of atherosclerotic plaques , increasing the risk of cardiovascular disease [5,7].

The LDL Paradox in Cardiovascular Disease

The “LDL paradox” refers to surprising clinical observations where lower LDL cholesterol levels are sometimes associated with worse cardiovascular or overall outcomes in specific populations-contrary to the traditional expectation that lower LDL is always better [8-10]:

  • Acute and Chronic Illness Populations: In patients with acute myocardial infarction (AMI) or those hospitalized with chronic diseases, some studies have found that lower LDL correlates with higher mortality rates- particularly in the presence of significant underlying inflammation or critical illness [9-11].
  • Older Adults: In elderly populations, studies have observed that individuals with higher LDL levels sometimes have lower rates of cardiovascular events or longer survival compared to those with low LDL, a phenomenon also called the “cholesterol paradox” [8,12,13].

Possible Explanations:

  • Reverse Causality: Severe illness or chronic inflammation can reduce cholesterol levels, making low LDL a marker of poor health, rather than a cause [8,10,14].
  • Heterogenesity of LDL Particles: Heterogeneity of LDL particles; smaller, denser LDL (rather than total LDL-C) may be most strongly atherogenic, so traditional LDL-C measures mau miss key risk [8].
  • Inflammatory States: Inflammation can alter cholesterol metabolism and exacerbate cardiovascular risk independent of LDL levels. In some cases, higher LDL may even provide protective effects by supporting immune function or cellular repair in acute illnesses [8,9].

Clinical Implications

The paradox highlights that LDL’s role in cardiovascular risk is  context-dependent:

  • Rigidly lowering LDL may not benefit-and might even harm- certain populations, particularly the frail, elderly, or those with high inflammation [8,9,11].
  • Modern risk assessment should consider inflammation, nutritional status, and overall health context alongside traditional LDL levels [8,10].

In summary, while LDL remains a primary target for cardiovascular prevention, these paradoxical findings underscore the importance of individualized medicine, careful patient selection, and holistic risk evaluation beyond a singular LDL focus [8-10].

High-Density lipoprotein (HDL) Cholesterol

High-density lipoprotein (HDL) cholesterol is commonly referred to as the “good” cholesterol due to its crucial role in cardiovascular protection. HDL’s primary function is reverse cholesterol transport (RCT): it removes excess cholesterol from cells, including those within the arterial wall, and transports it back to the liver for excretion or recycling. This process helps prevent cholesterol accumulation in blood vessels and reduces the risk of plaque formation and atherosclerosis [15-17]. In addition to RCT, HDL has several other protective functions:

  • Anti-inflammatory effects: HDL inhibits the expression of adhesion molecules and reduces vascular inflammation.
  • Antioxidant effects: HDL helps to prevent the oxidation of LDL and protects tissues from oxidative damage.
  • Endothelial protection: HDL increases nitric oxide production, supporting vascular health and reducing vascular dysfunction [16,17,18].

Multiple large-scale studies have consistently found that low HDL cholesterol is independently associated with an increased risk of coronary heart disease (CHD), even after adjusting for other cardiovascular risk factors:

  • In the Framingham Heart Study, each 5 mg/dL decrease in HDL was linked to roughly a 25% increase in the risk of myocardial infarction.
  • The Prospective Cardiovascular Münster Study, Quebec Cardiovascular Study, and findings confirmed in multiple cohorts, established that low HDL levels are associated with a higher incidence of CHD, myocardial infarction, stroke, and premature cardiovascular death [19-22].
  • Importantly, even among individuals with low total cholesterol or LDL cholesterol, isolated low HDL-C confers elevated cardiovascular risk [21].
  • A meta-analysis including over 300,000 individuals also demonstrated that the risk of CHD increases as HDL drops below 40mg/dL, with the risk rising most sharply at very low HDL levels [20].

While higher HDL has traditionally been considered continuously protective, recent evidence shows a plateau or even reversal of benefit at very high HDL concentrations:

  • Large cohort analyses, including pooled data and meta-analyses, demonstrate that CHD risk decreases with increasing HDL up to about 60 mg/dL (1.5mmol/L), but no further reduction in risk is seen above this threshold [20].
  • Specifically, a meta-analysis of 68 cohort studies found no additional decrease in coronary events for HDL values higher than about 60 mg/dL[20]. Wilkins et al. and other groups observed this “plateau effect” at even higher values- around 90mg/dL for men and 75mg/dL for women in some populations.
  • Notably, extremely high HDL levels may be associated with an increase, not a decrease, in all-cause and cardiovascular mortality- creating a U-shaped association [20,23,24].

For example, analysis from the UK Biobank showed individuals with HDL-C > 80mg/dL had a higher mortality risk in coronary artery disease patients as compared to the reference group with 40-60 mg/dL [24].

HDL Cholesterol LevelCHD Risk vs ReferenceStudy Reference
<40 mg/dL (low)Increased risk[19,20,21,22].
40-60 mg/dL (reference range)Baseline, lowest risk[20,24]
>60 mg/dLNo further risk decrease; possible U-shaped association with high levels[20,23,24]
Table 1. Summary Table: HDL Level and CHD Risk

In summary HDL is essential for cardiovascular health through multiple protective functions, especially via reverse cholesterol transport and anti-inflammatory actions. Low HDL is closely linked to increased risk of coronary heart disease, while HDL levels above 60mg/dL do not continue to confer additional protection- and extremely high levels may even be harmful according to recent cohort data.

Challenging the “Good Cholesterol” Paradigm

A landmark 2024 study by Pownall and Nasir at Houston Methodist Research Institute fundamentally challenges the traditional paradigm of HDL as universally “good” cholesterol. Their research demonstrates that HDL particles enriched in free cholesterol are likely dysfunctional, as shown by a strong link between elevated free cholesterol in HDL and increased accumulation in. macrophages- an early step in atherogenesis [25,26,27]. Notably, in individuals with high plasma HDL concentrations, the transfer of free cholesterol from HDL to white blood cells was associated with a higher risk of cardiovascular disease, overturning the longstanding assumption that raising HDL is always protective [26,27]. These result stress that HDL’s quality- specifically its free cholesterol content- should be integrated into advanced cardiovascular risk assessment and AI-driven models, not just total HDL quantity.

Evolving Perspectives on Lipoprotein Function

Recent research has greatly expanded our understanding of lipoprotein function, moving decisively beyond the simplistic “ good” (HDL) versus “bad” (LDL) cholesterol paradigm. Multiple contemporary studies have shown that both LDL and HDL exist as complex, heterogeneous particles whose biological effects depend on their size, composition, function, and context, rather than just absolute quantity.

Here are the few key evolving perspectives:

  • HDL Functionality Matters More Than Quantity: Traditionally, higher HDL cholesterol was seen as protective; however large studies and meta-analyses now show that simply increasing HDL levels does not always reduce cardiovascular risk. Modern findings highlight the importance of HDL particle functionality- particularly its anti-inflammatory and cholesterol efflux capacities-over the absolute concentration of HDL cholesterol. For example, a recent study demonstrated that individuals with the same HDL levels had markedly different cardiovascular outcomes depending on how well their HDL particles exerted anti-inflammatory effects, underscoring that function is more predictive that level alone [20,28].
  • Excessively High HDL may Be Harmful: New cohort studies have identified a U-shaped curve between HDL concentration and health outcomes. While low HDL is associated with higher cardiovascular risk, extremely high HDL levels (>80mg/dL) paradoxically correspond with increased all-cause and cardiovascular mortality, challenging the notion that “ more is always better” [1,20]
  • Quality, Not Just Quantity, for LDL: Advance in lipidology reveal that LDL particle type-especially particle size and density- matters more than simply the LDL-C value. Smaller, denser LDL particles are more atherogenic compared to larger, buoyant forms, and genetic and metabolic context can mediate individual risk. Beyond LDL-C, emerging attention is also given to markers like apolipoprotein B and non-HDL cholesterol for a more complete assessment.
  • New Lipoprotein Players and Complexity: Lipoprotein(a) [Lp(a)] has emerged as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent breakthroughs in Lp(a)-targeted therapies and ongoing clinical trials exemplify the field’s move from simplistic categorization toward nuanced, individualized risk assessment [29,30].
  • Context- Specific Effects: Emerging data show that the cardiovascular impact of both HDL and LDL can vary with age, metabolic health, inflammatory state, genetics, ethnicity, and even organ system. For example, recent studies have shown that high HDL may increase glaucoma risk in older adults, and LDL’s role in eye health is more complex than previously assumed [31].

In summary, modern lipid research emphasizes that the functions and health implications of lipoproteins cannot be accurately captured buy the traditional “ good” versus “ bad” cholesterol paradigm. Both HDL and LDL effects are mediated by particle type, function, and individual biological context. This complexity is now driving next-generation risk models, precision therapies, and guidelines that reflect a nuanced and highly personalized approach to cardiovascular health.

Beyond LDL and HDL: A Comprehensive Lipid Profile for Modern Cardiovascular Risk Assessment

While LDL and HDL remain the focus of traditional lipid management, a growing body of recent research emphasizes the importance of triglycerides (TG) and a comprehensive lipid profile in accurately assessing cardiovascular risk. This modern approach considers not only LDL and HDL levels but also triglycerides and non-HDL cholesterol, reflecting the complex interplay of lipid abnormalities in atherosclerosis and cardiometabolic diseases.

Triglycerides: Functions, Risks, and Recent Research Findings

Functions of Triglycerides

Triglycerides are the most common type of fat in the bloodstream. After eating, the body converts any calories it doesn’t use immediately into triglycerides, stored in fat cells. Later, hormones release these triglycerides for energy between meals. These are some of the key functions [32,33]:

  1. Energy Storage and Metabolism: Triglycerides function as the body’s primary form of energy storage, providing approximately 9 kcal/g—more than twice the energy density of carbohydrates or proteins. During periods of increased energy demand such as fasting or physical activity, triglycerides undergo lipolysis, breaking down into glycerol and fatty acids. This process is tightly regulated by hormones including insulin and glucagon, allowing for adaptive energy utilization based on the body’s needs.
  2. Structural and Protective Roles: Beyond their energetic functions, triglycerides contribute significantly to:
    1. Thermal regulation through adipose tissue insulation
    2. Cellular structure and function
    3. Protection of vital organs through cushioning
    4. Cell membrane integrity when incorporated into phospholipids
  3. Transport and Absorption: Triglycerides facilitate the absorption and transport of fat-soluble vitamins (A, D, E, and K) and are transported in the bloodstream via lipoproteins, primarily very low-density lipoproteins (VLDL) and chylomicrons.

Triglycerides and Cardiovascular Risk: Recent Research Highlights

Dose-Dependent and Independent Risk

  • Elevated TGs are independently associated with increased cardiovascular risk in multiple epidemiological studies, with a dose-dependent relationship: higher TG levels predict higher risk for coronary heart disease, ischemic stroke, and other atherosclerotic events [34-36].
  • A study in over 18,000 individuals found each two-fold increase in TG was linked to a 10-24% higher risk for overall CVD, ischemic heart disease, myocardial infarction [37].
  • Even when LDL-C is controlled by statins, high triglycerides remain a residual cardiovascular risk factor, supporting the value of their measurement [38].

U-Shaped Risk Profile

  • New research suggest a “U-shaped” association: Both high and very low triglyceride levels are linked to increased cardiovascular, or total mortality, especially in populations with heart failure. Optimal TG levels (in heart failure) ranged from 1.2-3.0 mmol/L (about 106-265 mg/dL) [39,40]
  • Lower than normal triglycerides may be a marker of malnutrition, frailty, or underlying disease, increasing risk in some settings. [39, 41,42]

Triglycerides and Atherogenic Dyslipidaemia

  • Raised TGs are often accompanied by low HDL-C and an increase in small, dense LDL particles- a combination termed atherogenic dyslipidaemia that is particularly harmful for cardiovascular health.
  • Triglyceride-rich lipoprotein remnants, generated when TGs are metabolized, directly contribute to arterial plaque formation [32,35]

Triglycerides Abnormalities: Causes & Associated Risks

Common Causes:

  • Obesity and metabolic syndrome
  • Poorly controlled diabetes
  • Physical inactivity, high carbohydrate intake
  • Excessive alcohol use
  • Certain genetic, endocrine, or medication related factors [33,43]

Risk associated with abnormal triglycerides:

  • Increased risk of atherosclerosis, myocardial infarction and stroke [34,35]
  • Severe hypertriglyceridemia (TG >500mg/dL) can induce acute pancreatitis [44].
  • Ectopic fat accumulation and metabolic dysfunction (such as fatty liver and insulin resistance) are strongly linked to elevated TGs, with risk likely rising until a high cutoff (3.98 mmol/L or ~ 350mg/dL) before plateauing or declining (an inverted U-shaped pattern for some metabolic endpoints).

Beyond Coronary Disease

  • Research from the Copenhagen studies (Kaltoft et al., 2020, European Heart Journal) demonstrated that elevated triglycerides and remnant cholesterol are associated with increased risk of aortic valve stenosis. Individuals with non-fasting triglyceride levels >5 mmol/L (>440 mg/dL) had approximately 1.5-fold increased risk for aortic stenosis compared to those with optimal levels (<1.0 mmol/L or <88 mg/dL).

Clinical Trial Insights

  • The JACC 2023 review of triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease noted mixed results from clinical trials targeting triglycerides. While the REDUCE-IT trial showed a 25% reduction in ASCVD events with icosapent ethyl (EPA), this benefit was unrelated to changes in plasma triglycerides. Conversely, the PROMINENT trial with pemafibrate showed no reduction in ASCVD events despite significant reductions in triglycerides and remnant cholesterol.
  • These findings suggest that the relationship between triglyceride-lowering therapy and cardiovascular outcomes is complex and may depend on the specific mechanism

Dose-Dependent Risk Across the Full Range

  • The risk of coronary heart disease increases along with higher TG values -up to about 200 mg/dL (2.3 mmol/L) and higher [35]
  • Importantly, recent studies identify that numbers previously considered “borderline” (100-149 mg/dL or 1.1-1.7mmol/L) still carry increased risk if associated with other metabolic disturbances [35,44]
  • Risk reduction is observed when TGs maintained near the lower end of the normal range-even moderate lowering through diet, weight loss, and select medication provides measurable cardioprotection [35].
Triglyceride LevelCardiovascular RiskRecommendations
Below 100mg/dLLowest riskOptimal ; maintain healthy lifestyle [35, 45]
100-149 mg/dLAcceptable, but not optimalMonitor; optimize diet/lifestyle[45]
150-199 mg/dLIncreased riskLifestyle changes recommended[44]
200-499mg/dLSignificant riskMedical evaluation; possible medication [44]
> 500 mg/dLVery high; pancreatitis riskImmediate intervention, medical treatment [44]
Table 2. Optimal Triglyceride Range

The ideal range of triglyceride is <100mg/dL (1.1mmol/L) for maximal risk reduction, per AHA and recent studies. Values >200mg/dL (2.3mmol/L( signal substantial risk, even in the absence of high LDL-C [35].

In conclusion, modern cardiovascular risk assessment demands a comprehensive lipid profile, not just focusing on LDL and HDL but also incorporating triglycerides as a central player. Triglycerides are both a marker and mediator of atherogenic risk, and abnormalities- high or unusually low- are associated with worse outcomes. Dose-dependent and U-shaped risk patterns have important implication for clinical management. The optimal triglyceride range for adults is now considered to be below 100 mg/dL for the lowest cardiovascular risk. Future guidelines and AI-driven risk algorithms increasingly rely on this nuanced, multi-marker strategy to advance personalized prevention and treatment [32-36,44,45]

Apolipoprotein B in Cardiovascular Disease Prevention: Functions, Risk Stratification and Emerging Evidence

Apolipoprotein B (ApoB) has emerged as a central biomarker in modern cardiometabolic risk assessment. As the primary structural protein of all atherogenic lipoproteins including very low-density lipoprotein (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and lipoprotein(a) [Lp(a)]-ApoB provides a direct measure of circulating particles that contribute to atherosclerotic cardiovascular disease (ASCVD) [45,46].

Physiological Functions of ApoB

ApoB is essential for the assembly and secretion of atherogenic lipoproteins from hepatic and intestinal tissues. Specifically, ApoB-100, synthesized in the liver, serves as a ligand for the LDL receptor, thus mediating receptor-dependent uptake of LDL particles into peripheral cells. This uptake is crucial for maintaining lipid homeostasis, enabling delivery of cholesterol and triglycerides for membrane synthesis, steroid hormone production, and energy metabolism.

ApoB and Cardiovascular Risk

Converging evidence delineates a dose-dependent relationship between ApoB concentration and ASCVD risk. Unlike LDL-cholesterol (LDL-C), which estimates cholesterol content within LDL particles, ApoB quantification provides an exact count of all circulating atherogenic particles, each capable of penetrating the arterial intima and initiating plaque formation. Recent cohort studies, including data from the Copenhagen General Population Study and the UK Biobank, consistently demonstrate that plasma ApoB is superior to both LDL-C and non-HDL cholesterol in predicting future myocardial infarction and cardiovascular events, particularly among those with elevated triglycerides or discordant LDL-C and ApoB levels [47,48].

Recent Research Developments

Recent large-scale meta-analyses and randomized clinical trials reinforce the importance of ApoB-directed risk stratification and intervention. Not only does ApoB independently associate with incident coronary heart disease and all-cause mortality across diverse populations, but new therapies specifically lowering ApoB-containing particles are under investigation for greater incremental risk reduction. ApoB’s role as a therapeutic target is further highlighted by the realization that certain populations-such as those with familial hypercholesterolemia or diabetes- may derive the greatest preventive benefit from ApoB-tailored management [49].

So in conclusion ApoB is now recognized as the most specific and functionally relevant marker of atherogenic particle burden, integrating into contemporary lipid guidelines and precision medicine algorithms. Clinical implementation of ApoB quantification enhances cardiovascular risk assessment and enables more nuanced, effective strategies for ASCVD prevention.

Lipoprotein (a): An Independent Genetic Risk Factor for Cardiovascular disease

Lipoprotein(a) [Lp(a)] is a unique, genetically determined lipoprotein and a strong, independent risk factor for atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease and stroke [50,51,52]. Unlike LDL, Lp(a) levels are mostly set by inherited variation at the LPA gene and are only minimally affected by lifestyle [50,51]. High Lp(a) contributes to plaque formation and clotting due to its LDL core and attached apolipoprotein(a), which has prothrombotic properties [51,52]. The relationship between Mendelian randomization studies [50,51,52]. Major guidelines now recommend one-time Lp(a) testing, especially for individuals with a family history of early CVD or unexplained high risk [50]. Currently, specific Lp(a)- lowering therapies are in development, but general risk reduction remains the strategy of choice for elevated Lp(a) [50,52].

Intermediate-Density Lipoproteins: Overlooked Contributors

Intermediate-density lipoprotein (IDL) is an often overlooked but important contributor to cardiovascular disease. IDL represents a transitional lipoprotein formed when very low-density lipoprotein (VLDL) is metabolized, on its path to becoming low-density lipoprotein (LDL). Like LDL, IDL particles are rich in cholesterol and contain apolipoprotein B.

Recent research demonstrates that elevated levels of IDL cholesterol (IDL-C) or IDL particle concentration (IDL-P) are independently associated with the progression of atherosclerosis and increased risk for coronary heart disease and stroke-even after adjusting for LDL or VLDL levels[53,54,55]. In key studies, IDL-C showed a stronger association with myocardial infarction risk than both LDL-C and VLDL-C, suggesting a uniquely atherogenic role. This heightened risk appears related to the ability of IDL particles to penetrate and remain within the arterial wall, promoting foam cell formation and vascular inflammation, leading to plaque build-up and arterial narrowing [54,56].

Furthermore, progression of carotid artery thickening and plaque-a surrogate for atherosclerosis- has been linked more closely with IDL than with LDL or VLDL in both community and clinical cohorts [55,57]. This evidence is supported by advanced lipoprotein analyses, which show IDL particles carry more cholesterol per particle than LDL and are more likely to adhere to artery walls, contributing to early and progressive vascular injury [54,58].

In summary, IDL is significant, independent predictor of cardiovascular risk, and its measurement may improve identification of individuals at high atherosclerotic risk, especially when traditional metrics like LDL and VLDL do not fully account for disease progression [53,54,56].

Very Low-Density Lipoproteins: Beyond Triglyceride Transport

Very low-density lipoprotein (VLDL) is more than just a carrier of triglycerides; it plays diverse roles in metabolism and cardiovascular health.

VLDL is synthesized in the liver to transport not only triglycerides but also cholesterol and specific proteins to peripheral tissues for energy utilization and cellular function [59,60,61]. Once secreted, CLDL particles contribute to metabolic cross-talk-undergoing complex remodelling as they interact with enzymes (like lipoprotein lipase), other lipoproteins, and cellular receptors throughout the circulation [60,61].

Beyond triglyceride transport, recent research has highlighted several important VLDL functions and clinical implications:

  • Atherogenicity: Large VLDL particles, and especially the cholesterol content within VLDL, are strongly linked to the development of atherosclerosis and coronary heart disease-independent of triglyceride levels or LDL cholesterol [60,61,62],. These particles can penetrate the arterial wall, deliver cholesterol to plaques, and trigger vascular inflammation [62].
  • Cardiometabolic Disease: VLDL is associated with insulin resistance, type 2 diabetes, and metabolic syndrome. Both the size and electric charge of VLDL subfractions correlate with risk of diabetes and CVD. Certain postprandial (after eating) modifications make VLDL particularly harmful in the setting of obesity and metabolic syndrome [60,61].
  • Endothelial and Hormonal Effects: VLDL modulates vascular function-affecting nitric oxide signalling and blood pressure regulation-and can stimulate hormone synthesis, such as aldosterone, in peripheral tissues [60].
  • ApoB Carrier: Like LDL, each VLDL particle contains one molecule of apolipoprotein B, which is a direct count of potentially atherogenic particles. Recent studies emphasize that VLDL cholesterol explains a significant portion of the cardiovascular risk attributable to apo B-containing lipoproteins [62].
  • Progression to Remnants and LDL: As VLDL sheds triglycerides, it transforms into intermediate-density lipoprotein (IDL) and then LDL, further contributing to the spectrum of atherogenic lipoproteins [60].

In summary, modern research recognizes VLDL as a central player in lipid metabolism, cardiovascular risk, and metabolic disease-well beyond its classical role as a triglyceride transporter [60,61,62].

Chylomicrons: The Postprandial Risk

Chylomicrons are large, triglyceride-rich lipoproteins that circulate in the blood after eating, carrying dietary fats from the intestine to other tissues. Traditionally considered too big to enter artery walls, evidence now shows that their partially metabolized remnants can be highly atherogenic, especially in the postprandial (after meal) state.

After meals, chylomicron and remnant levels rise sharply, contributing to “postprandial lipemia”. Recent studies demonstrate that these remnant particles can cross the arterial wall, deposit cholesterol, and trigger vascular inflammation, promoting plaque formation-sometimes carrying even more cholesterol per particle than LDL [63,64]. The cholesterol-rich chylomicron remnant are efficiently retained in the vessel wall and taken up by macrophages, fostering foam cell and atherosclerotic plaque development [63,64]. People with delayed chylomicron remnant  clearance, insulin resistance, or metabolic syndrome are at higher risk for such post prandial atherogenesis. Epidemiological studies confirm that elevated postprandial triglycerides and remnant cholesterol are associated with higher risk for myocardial infarction and other cardiovascular events, independent of fasting LDL-C levels [64,65].

Modern research positions chylomicrons and their remnants as important often underappreciated-contributors to the progression of atherosclerosis, highlighting that postprandial metabolism is a key period of cardiovascular risk, especially in patients with metabolic dysfunction or diabetes [63,64].

Clinical Implications and Future Directions

This evolved understanding has significant implications for clinical practice:

  1. Personalized Risk Assessment: Comprehensive lipid profiling enables more accurate cardiovascular risk stratification and personalized treatment strategies.
  2. Targeted Interventions: Beyond LDL-C reduction, addressing elevated ApoB, triglycerides, and Lp(a) may provide additional cardiovascular benefit, particularly in patients with residual risk despite optimal LDL-C levels.
  3. Functional Testing: Future lipid assessment may incorporate measures of lipoprotein functionality rather than merely quantifying concentrations.

The transition from a binary “good versus bad” cholesterol paradigm to a comprehensive lipid profile approach represents a significant advancement in cardiovascular medicine. This nuanced understanding enables more precise risk assessment and targeted therapeutic strategies, ultimately improving cardiovascular outcomes through personalized prevention and treatment approaches.

Conclusion

Modern lipid research has moved far beyond the outdated “good” (HDL) versus “bad” (LDL) cholesterol paradigm. Contemporary evidence highlight that the atherogenic risk posed by lipoproteins is determined by particle number, composition, functionality, and genetic context. Triglycerides, apolipoprotein B, lipoprotein(a), and remnant particles like VLDL, IDL and chylomicron remnants all play distinct, independent roles in cardiovascular disease. Optimal risk assessment now requires a comprehensive lipid profile-not a singular focus on LDL or HDL-enabling more personalized, effective prevention strategies. This nuanced approach underpins future innovations in cardiovascular care and the integration of lipid data into advanced risk models and targeted therapies.

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