Author: Jeffrey Wacks, MD

TL;DR: Yes and no. Systemic hypercholesterolemia has an indirect and conditionally causal effect on atherosclerotic cardiovascular disease. Its degree of causality is dependent on the amount of systemic and local oxidative stress and the degree to which LDL becomes oxidized (oxLDL). Thus, to say hypercholesterolemia is the cause of CVD may be technically true but is misleading. CVD is a complex, multi-factorial process involving metabolic dysfunction, hepatobiliary dysfunction, oxidative stress, chronic inflammation, and stress hormone activation. By only recognizing hypercholesterolemia as the main risk factor, the medical establishment becomes hyper-focused on pharmacologic reduction of the serum LDL to the detriment of our patients, who would benefit more from a more holistic approach that addresses more of the underlying functional causes of CVD.

Figure 1. High level overview of the pathogenesis of Cardiovascular Disease (CVD) and its relationship with functional imbalances. 

Technical note: The main laboratory marker that is used in conventional medicine to determine whether a patient is “hypercholesterolemic” is called LDL-Cholesterol, which is the concentration of cholesterol in the atherogenic Low Density Lipoproteins (LDL). Cholesterol is the chemical that is used as raw material to create atherosclerotic plaque and LDL is the transport vehicle. Emerging evidence, however, suggests that the more relevant dysfunctional factor occurring in the blood is not the LDL-Cholesterol, but rather the number of atherogenic Apolipoprotein B-containing lipoprotein particles that carry the cholesterol. While they are not exactly the same thing, for the purpose of this discussion, we can take the idea of hyperlipoproteinemia and incorporate it into our discussion of hypercholesterolemia.  

The Mechanism for How Hypercholesterolemia Leads to Atherosclerosis is Complex

When we ask people why hypercholesterolemia causes atherosclerosis, the most common explanation is that it is a plumbing issue. In the same way that too much toilet paper clogs the toilet, too much cholesterol "clogs" the coronary arteries. This, however, is simply not true... that's just not the way it works. The original lipid plaque forms in the subendothelial space of the arterial wall. As the plaque grows, it puts pressure on the endothelium from the inside out. It is not until a more advanced stage of atherosclerosis in which the endothelial lining is ruptured that the lipid plaque has significant communication with the blood (and the serum cholesterol) that flows through the lumen of the artery.

Figure 2. The process of the formation of atherosclerosis.¹

Once the LDL particle enters the subendothelial space, the following events must also occur:

1. The LDL particle is taken up by macrophages and the resultant accumulation of cholesterol within the macrophages creates a foam cell.
2. The LDL particle is taken up by the smooth muscle cells causing the smooth muscle cells to proliferate and migrate, become inflamed, and ultimately undergo apoptosis (cell death).
3. The endothelial cells become dysfunctional (i.e., endothelial dysfunction), leading to increased endothelial permeability, clot formation, platelet aggregation, inflammation, immunologic activation, and vasoconstriction.

Interestingly, however, these events cannot be fully explained simply by systemic hypercholesterolemia. In the following sections, we will explain how in addition to increased LDL transcytosis into the subendothelial space, oxidative stress and specifically the oxidation of the LDL particle into oxLDL is likely an obligatory step in the development of atherosclerosis.

Figure 3. OxLDL interacts with smooth muscle cells, macrophages, and endothelial cells to ultimately cause atherosclerosis.²

Oxidation of LDL Particles is Required for Uptake by Macrophages and Smooth Muscle Cells

In order for the cholesterol to enter the macrophage and/or smooth muscle cells, it must interact with an LDL receptor on the membrane of these cells (i.e., the native LDL receptor). However, two observations call into question the simplicity of this mechanism. Firstly, patients with a genetic mutation in which they have a total deficiency of LDL receptors (homozygous familial hypercholesterolemia) still develop atherosclerosis.^3,4 Thus in these cases, the cholesterol must be accumulating in the macrophage and smooth muscle cells via a mechanism outside of the native LDL receptor. Secondly, these cell types should downregulate the expression of the native LDL receptor when the intracellular cholesterol concentration starts to build up.^5,6,7,8 To this point, incubation of these cell types with high concentrations of LDL does not induce elevated intracellular cholesterol levels.^9,10,11 In other words, the cells of the arterial wall should have a normal mechanism for preventing excessive cholesterol accumulation, therefore there must be a mechanism by which this negative feedback is bypassed.

Figure 3. Mechanisms of cholesterol uptake by macrophages.¹²

So, it appears that native LDL by itself should not cause atherosclerosis.^13,14 But… modified LDL can.

In 1979, Goldstein et al.⁹ showed that acetylation of the LDL particle was taken up readily by macrophages via a receptor distinct from the native LDL receptor, and that the acetyl LDL receptor was not subject to downregulation. This showed how modified LDL could cause cholesterol accumulation in the subendothelial space; however, acetylation itself is not common in vivo. The most common modification to the LDL particle is oxidation. Various components of the LDL particle can be oxidized, including the cholesterol itself, phospholipids, triglycerides, and the protein components and the degree of oxidation can be variable. While certainly not all of the details have been worked out, it seems evident that oxidation of LDL (both systemically and in the subendothelial space) is a major factor causing LDL uptake, endothelial dysfunction, foam cell formation, and ultimately the development of overt atherosclerosis (referred to as the Oxidative Modification Hypothesis).^15,16,17

Figure 5. Summary of the role of oxLDL on atherosclerosis progression.¹⁸

Oxidative Stress is a Key Factor in the Development and Progression of Endothelial Dysfunction

The endothelium is a layer of endothelial cells that line the innermost portion of the arterial wall. Thus, it represents the interface between the blood in the lumen of the artery and the rest of the arterial wall. 

Functions of the endothelium:

• Controls the transport of nutrients out of and into the blood
• Controls blood fluidity, prevents clotting, and controls platelet aggregation
• Controls inflammation 
• Controls immunologic activation (leukocyte activation)
• Controls vasoconstriction and vasodilation, and therefore blood pressure

When there is something wrong in the endothelial cells, and these functions are not occurring properly, we call this “endothelial dysfunction.” It is well accepted that endothelial dysfunction is a early step in the pathogenesis in artherosclerosis.¹⁹ Oxidative stress is heavily involved in the pathophysiology of endothelial dysfunction via dysregulation of nitric oxide, generation of inflammatory cytokines, and induction of mitochondrial dysfunction of the endothelial cells.^20,21 Additionally, endothelial dysfunction likely increases the permeability of plasma lipoproteins into the vasculature, which exacerbates the vicious cycle.

Figure 6. Mechanisms by which oxidative stress (i.e., Reactive Oxygen Species, ROS) induce endothelial dysfunction-induced atherosclerosis.²² 

Because Oxidation of the LDL particle is an Obligatory Step in the Development of Atherosclerosis, it is Misleading to say (native) LDL Causes CVD

It is technically true that LDL causes ASCVD, but the nature of this causality is indirect and conditional. LDL causes CVD only if it is oxidized into oxLDL and the degree to which it is oxidized depends on the systemic and local levels of oxidative stress. In other words, hypercholesterolemia does not cause CVD in an environment where there is little oxidative stress.

Thus, it is misleading to say that LDL is the cause of CVD when oxidative stress is just as essential to the process of atherosclerosis. To this point, a 2006 study by Johnston et al.²³ showed that oxLDL was a significantly more potent biomarker for discriminating between subjects with and without coronary artery disease than the traditionally measured LDL-cholesterol (see Table 1). Multiple studies have shown that oxLDL is associated with all stages of atherosclerosis, coronary and peripheral artery disease, heart attacks and strokes.²⁴

Table 1. Odds ratios for various biomarkers for the presence of coronary artery disease.²³

Figure 7. Stages of atherosclerosis and their associated biomarkers. Note that the development of systemic oxidative stress, such as F₂-IsoP (discussed in next section), as well as the oxidation of atherogenic lipoproteins (oxLDL) are associated with the earliest stages of atherosclerosis development.²⁵

Systemic Oxidative Stress is an Important Functional Cause of Cardiovascular Disease

Because oxidation of the LDL particle is a necessary step in the pathogenesis of ASCVD, in addition to looking at serum oxLDL levels, we should also look at biomarkers that can assess the systemic levels of oxidative stress. Currently, an increasing number of studies suggest that levels of oxidative stress markers in body fluids correlate with atherosclerotic disease activity.²⁶ Oxidative stress is the imbalance between reactive oxygen species (ROS) and antioxidants. In clinical practice, there are various biomarkers that can be used to evaluate systemic oxidative stress levels. One in particular, the serum or urinary level of F₂-Isoprostane level, is a byproduct of omega-6 PUFA oxidation and is often considered the "gold-standard" for measuring oxidative stress. F₂-Isoprostane levels have clearly been shown to be associated with cardiovascular disease.²⁷

In addition, oxidative stress also has a causal relationship with the LDL-C level itself. It is well accepted that oxidative stress is a cause of mitochondrial dysfunction²⁸ and hepatobiliary dysfunction.^29,30

Hypercholesterolemia Indirectly and Conditionally Causes CVD; However, the Cause of the Hypercholesterolemia Matters

Figure 8. Causes of Elevated Serum LDL-Cholesterol.

In our practice, when we see elevated cholesterol levels, we tend to think of it more as a marker of underlying dysfunction. Our goal is to understand why the cholesterol is elevated and then address the root cause. This idea is important because in reality, there are some causes of hypercholesterolemia that are worse than others. For example, consider the situation in which the elevated cholesterol is caused by mitochondrial dysfunction. Studies show that hypothyroidism is a cause of elevated cholesterol and thyroid hormone replacement lowers it.³¹ Because the thyroid controls the metabolic rate, it is likely that hyperlipidemia is a direct result of metabolic dysfunction. Additionally, because cholesterol is converted into bile acids in the liver and excreted via the biliary system, hepatobiliary dysfunction can also cause elevated cholesterol. These foundational imbalances are highly problematic because they interact with other imbalances in a holistic way. For example, metabolic dysfunction not only creates its own set of issues, but also causes oxidative stress, stress activation, and inflammation, which themselves are independently associated with CVD.

Contrast these causes with the situation in which a patient has elevated cholesterol because of high saturated fat intake. Interestingly, high saturated fat intake does increase the serum cholesterol, but a 2014 meta-analysis by Chowdhury et al.³² showed that it does not significantly increase the risk of CVD. Thus, it is apparent that the degree of risk for CVD associated with hypercholesterolemia is dependent on its underlying cause, with some causes being more problematic than others.

Inflammation and Stress Hormone Activation are Also Causal Factors in Cardiovascular Disease

Inflammation is well-known to be a risk factor for CVD and is likely mandatory for the development of cardiac and vascular events.³³ Specifically, inflammation clearly induces endothelial dysfunction, resulting in increased endothelial permeability, leukocyte recruitment, and platelet activation.³⁴ Local inflammation also results from the interaction of oxLDL and the macrophages and smooth muscle cells as described above. Elevated serum C-reactive protein (CRP) levels, which is a marker of systemic inflammation, is a risk factor for CVD and therapeutics that target inflammation have been shown to reduce CV risk.³⁴ It is also generally thought that stress hormones are involved in the pathophysiology of CVD due to the influence of stress hormones on blood pressure as well as their influence on other metabolic parameters such as blood sugar, cholesterol, and triglycerides over time.^35,36  Subjective psychological stress has also been shown to be a risk factor for CVD.³⁷

Why This Matters

If we believe that hypercholesterolemia is the primary cause of CVD, then that incentivizes us to focus our attention on cholesterol-lowering therapeutics for prevention. What we see in clinical practice is a one-tracked focus on pharmacologically lowering the LDL-C and a complete disregard for any of the other causative factors such as overall metabolic function and oxidative stress. In our opinion, this is not a good strategy and discredits the field for patients who have done more research on this topic.

To be clear, we are not against statin medications. They are valuable tools and we agree that they should generally be prescribed for patients at high risk for CVD. We discuss statin medications in detail in Volume 3 of the training program. But in order to really tackle this problem, we need to layer in a more comprehensive approach the addresses the underlying functional imbalances that cause it.

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