Author: Malaina Morales, AP
This hypothesis has been met with disagreement and criticism since its inception, although it presently forms the basis for dietary guidelines on total and saturated fat consumption according to the American Heart Association. Subsequent epidemiological research has continued to show a correlation between high LDL and higher risk of ASHD; however, new research is helping to shed more light on the atherosclerotic process. LDL levels considered in isolation may not be as valuable in predicting ASHD as other factors, including fasting blood glucose, plasma insulin, blood pressure, hs-CRP, triglyceride-HDL ratio, and the lipid sub-fraction known as Pattern B (small, dense) LDL.2 3 4 5
72% of Patients Hospitalized For Coronary Events Have Normal LDL Levels (Below 130 mg/dl)
In one study, almost half of all patients admitted to the hospital with coronary artery disease (CAD) had LDL-C levels at or below the target acceptable level. Out of 136,905 patients admitted to hospitals nationwide in the US from 2000-2006 for coronary events, almost 50% of them had LDL levels below 100 mg/dl and 21.1% of them were already taking lipid-lowering medications. 72% had LDL-C levels lower than 130 mg/dl, which are viewed as acceptable for those without other health issues. Only 10% of them had HDL levels ≥ 60 mg/dl.6
Based on this data, sustaining target LDL-C levels does not appear to be sufficient in preventing coronary events considering that the majority of CAD patients had levels within the target range. Conversely, HDL levels seem to be more significant in risk assessment. Further research affirms that about 75% of patients who suffer myocardial infarctions have cholesterol levels considered to be low-risk. It has been proposed that it is the predominance of Pattern B LDL, not the total amount of LDL-C, that is more strongly associated with ASHD risk.4
How Omega-6 PUFAs in Vegetable Oils May Damage LDL Particles and Contribute to Heart Disease
Refined seed oils were not available until the early 1900s, when Proctor & Gamble patented and began to market these oils for consumption. A relatively recent addition to the human diet, these unsaturated fats have come into question for their role in modification of the LDL apolipoprotein B (apo B) and their contribution to heart disease. As unsaturated fatty acids are readily oxidized due to their double-bonded carbon atoms, they are potentially unstable once they are extracted and refined. Despite this, conventional dietary guidelines suggest that PUFAs from seed oils are the best fats to consume, even branding them as ‘heart-healthy’. This is primarily because unsaturated fats do not appear to raise LDL-C as much as saturated fats do in some individuals.
Linoleic acid is a polyunsaturated (PUFA) omega-6 fatty acid that is abundantly found in seed oils. Once absorbed, dietary linoleic acid is incorporated into all lipoprotein particles, which may contribute to damage of the LDL particle via oxidation. This damaged LDL particle, known as oxidized LDL or small-dense LDL, has been found to be highly atherogenic.7 It appears that this has not been the case for native LDL particles.4 8 This distinction between altered LDL and unaltered LDL is crucial considering that LDL is broadly referred to as ‘bad cholesterol’ and many drug therapies target this lipoprotein without consideration of lipid sub-fractions or other reliable indicators of ASHD risk.
Linoleic acid is the most abundant fatty acid found in atherosclerotic plaques and readily oxidizes when bound to cholesterol. Conversely, saturated fat helps to protect cholesterol from oxidation.10 Saturated fats contain no double bonds between carbon atoms, making them highly stable against damage. PUFAs are highly susceptible to oxidation, and as previously stated, their oxidation products can have toxic effects on the LDL particle protein apo B, the lipid contents within, and directly on the arterial endothelium.
Although LDL is often villainized, it actually serves many crucial roles in the body and is necessary for optimal health. LDL is an important lipoprotein that functions to transport fat-soluble vitamins (A, D, E, & K), cholesterol, and triglycerides throughout the body for the purpose of cellular repair, hormone synthesis, bile acid synthesis, immune function, and the distribution of lipid energy sources. In general, LDL particles become harmful when they have been damaged, which accounts for the significant difference in risk between the predominance of either Pattern A or Pattern B LDL. It appears likely that as the apo B protein becomes damaged via oxidation, LDL receptors located in the liver and peripheral tissues are no longer able to recognize the LDL particle. Subsequently, receptor-mediated uptake of the LDL particle does not occur. This is a possible explanation for the decreased binding affinity for small, dense LDL particles to LDL receptors.9 While not recognized by apo B receptors, damaged LDL is recognized and subsequently endocytosed by macrophages as part of a protective immune response. This process leads to foam cell formation, a classic feature of atherosclerosis.
In order to minimize damage to our LDL particles, avoiding Omega-6 PUFAs found in vegetable oils is important. In addition, choosing grass-fed, pastured animal foods may also help reduce consumption of Linoleic Acid (animals that are fed corn and soybeans contain significantly higher proportions of Linoleic Acid than animals fed Omega-3 rich grass).
Figure 1: Omega-6 polyunsaturated fatty acids (PUFAs) are the most abundant type of fatty acids found in atherosclerotic plaques. Omega-3 PUFAs and saturated fatty acids comprise the least abundant types of fatty acids in atherosclerotic plaques. Data from Felton, C. V., Crook, D., Davies, M. J., & Oliver, M. F. (1997). Relation of Plaque Lipid Composition and Morphology to the Stability of Human Aortic Plaques. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(7), 1337–1345. doi: 10.1161/01.atv.17.7.1337
Figure 2: Cholesterol esters bound to linoleic acid are the most predominant type of lipid found in atherosclerotic plaques. Data from Felton, C. V., Crook, D., Davies, M. J., & Oliver, M. F. (1997). Relation of Plaque Lipid Composition and Morphology to the Stability of Human Aortic Plaques. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(7), 1337–1345. doi: 10.1161/01.atv.17.7.1337
Oxidation and Glycation: Effects on LDL Particles and the Endothelial Glycocalyx
Glycation occurs when a sugar molecule inflicts damage by covalently bonding to a lipid or protein. Glycation (much like the process of oxidation) can alter the structure of an LDL particle and damage the apo B protein. In addition, it has damaging effects on the Endothelial Glycocalyx (EG), a network of glycoproteins, glycolipids, and proteoglycans that line the lumen of the vascular endothelium. This crucial structure serves many functions, including reinforcing the vessel walls and shielding them from adhesion by inflammatory mediators, reducing oxidative and mechanical stress on the endothelium, and regulating permeation and fluid balance.11
Dysfunction of the EG can be induced by glycation from hyperglycemia or by oxidized LDL particles. This damage can be measured by the amount of its components are shedding. These components include heparan, syndecan, and hyaluronan (HA). During acute hyperglycemia, the size of the EG can be reduced by 50% to 80% and the plasma HA concentration can be increased by 30% to 80%.11 Damage to this important structure due to oxidized cholesterol and glycation appears to be implicated in the formation of atherosclerotic plaques.
This demonstrates that high blood sugar and oxidized cholesterol may contribute to the formation of atherosclerosis. Avoiding vegetable oils and high-carbohydrate diets may help prevent damage to LDL particles and blood vessels.
Reliable Markers that Contextualize LDL-C Levels
If it is the case that isolated LDL-C is not a reliable marker for ASHD risk, clinicians should consider LDL-C within proper context. Plasma insulin, hs-CRP, and lipid sub-fractions and ratios can help put LDL-C into context and may be more accurate in predicting ASHD risk.2 5 8 These additional clinical findings may also reduce the need to prescribe lipid-lowering medications in some patients.
Plasma insulin and HDL levels appear to be high-quality predictors of ASHD risk. In the Quebec Cardiovascular Study, higher plasma insulin levels were more closely associated with increased risk of Ischemic Heart Disease than Apo B levels (LDL-P or LDL particle number). Also demonstrated in this study was the importance of HDL as an independent risk factor. Subsequent analysis of the Quebec cardiovascular study posits that a reduced HDL level has a greater influence on risk than high LDL. It is important to note that low HDL does not appear as an isolated feature of IHD, but that it is present in insulin-resistant individuals with hypertriglyceridemia, increased Apo B, visceral adiposity, and an increased proportion of small, dense LDL particles.3
A follow-up study was performed on the cohort of 2,072 men from the Quebec Cardiovascular Study population. At baseline, all of the subjects demonstrated no evidence of Ischemic Heart Disease (IHD). During the 13 years of follow-up, 262 initial IHD events occurred. It was found that while elevated large LDL-C levels were not associated with an increased risk of IHD, there was a strong association between the increased prevalence of small, dense LDL and an increased risk of IHD.8
Evolving Dietary Guidelines: Beyond LDL-C
Moving towards dietary guidelines that will increase HDL, decrease triglycerides, shift small LDL to large LDL, and normalize insulin and glucose levels may be an important step in minimizing ASHD risk. A low-carbohydrate, high-fat (LCHF) diet has been demonstrated to favorably shift lipid profiles, decrease insulin and glucose levels, and reduce inflammation as measured by hs-CRP.12 13 14 Minimizing the occurrence of oxidation and glycation is also important, as these processes may fuel damage to the LDL protein (Apo B) and the arterial endothelium. Accordingly, a properly-planned therapeutic LCHF diet for high-risk individuals should aim to reduce carbohydrate intake to comprise 0-5% of daily calories and exclude seed oils altogether. Implementing an appropriately-planned LCHF diet may be a valuable therapeutic tool for patients with the aforementioned risk factors.
Despite contrary evidence, there exists a widely-accepted body of primarily non-interventional epidemiology that continues to show a correlation between high LDL-C levels and higher risk of ASHD. This correlation is still used to shape public health policy towards dietary guidelines. To settle the controversy, it is necessary to further explore the factors that may contribute to the development of ASHD through an emphasis on clinical, observational, and interventional research in humans rather than relying predominantly on cohort studies to inform public health policy. The presence of confounding variables could potentially limit the validity of some epidemiological research and the ability to isolate one causal factor.
Isolated LDL-C levels may not be the most valuable independent factor when assessing risk. HDL, plasma insulin, hs-CRP, and lipid sub-fractions may be important clinical markers of risk. In addition to LDL-C, these markers should be further explored in each patient in order to achieve optimal risk reduction and improve targeted therapies. This includes a healthy diet, weight loss, and regular exercise. Appropriate pharmacotherapy may be useful if necessary. Placing LDL-C measurement into proper context can help clinicians gain a more informed perspective on a patient’s risk and create an avenue for optimal risk management.