Cholesterol, Oxidative Stress, and Cardiovascular Disease - Why Only LDL Cholesterol is "Bad"

 

Ir. CK Cheong an engineer friend of mine asked me this question two days ago:

"Why do doctors still prescribe statins after Harvard researcher Dr. Kilmer McCully found no relationship between high cholesterol and heart disease, and recently, 17 doctors from across the world say to stop prescribing statins?

Can we get a clear answer please. Thank you in advance. 

(Kilmer S. McCully joined the faculty of Harvard Medical School in 1965 and was Chief Pathologist)

I have already written many articles about cholesterol and heart disease.

Here are just two of them: 

Tuesday, August 17, 2021

Does cholesterol cause heart disease?

Here  are just two of them.

1. https://scientificlogic.blogspot.com/search?q=Cholesterol+does+not+cause+heart+disease+&m=1L

Saturday, December 16, 2023

2. https://scientificlogic.blogspot.com/2023/12/more-on-cholesterol-and-coronary-heart.html

Cholesterol per sec has been shown in numerous well-designed large scale studies does not cause coronary arterial disease. However, the only the low density lipoprotein cholesterol (LDL cholesterol)  may be a bit of a problem.

 Here is why. 

I have written this for both the lay readers, and for medical and scientific professionals 

 Title:

Cholesterol, Oxidative Stress, and Cardiovascular Disease:

Why LDL Harms, Why HDL Protects, and How Chemistry, Biology, and Lifestyle Intersect

by:  

lim ju boo, alias lin ru wu (林 如 武)

 

Summary for Lay and Non-Technical Readers

 

Cholesterol is often misunderstood and unfairly blamed as the direct cause of heart disease. In reality, cholesterol is an essential substance required for life. It forms part of every cell membrane, contributes to hormone production, helps digest fats, and supports many vital biological processes. The problem is not cholesterol itself, but how it is carried in the blood and how it behaves chemically inside the body.

Cholesterol travels through the bloodstream attached to particles called lipoproteins. The two most important are low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL is commonly referred to as “bad cholesterol” because it carries cholesterol from the liver to body tissues. When there is too much LDL, excess cholesterol can accumulate in the walls of arteries. More importantly, LDL is chemically fragile and can be damaged by free radicals—unstable molecules produced by normal metabolism, smoking, pollution, poor diet, and chronic inflammation. When LDL is damaged in this way, it becomes oxidized and highly dangerous to blood vessels.

Oxidized LDL is no longer recognized by the body’s normal clearance mechanisms. Instead, immune cells within artery walls ingest it uncontrollably, forming fatty deposits that gradually narrow arteries and increase the risk of heart attacks and strokes.

HDL, often called “good cholesterol,” performs the opposite function. It removes excess cholesterol from artery walls and transports it back to the liver for elimination. HDL also carries natural antioxidant enzymes that help prevent LDL from becoming oxidized in the first place. For this reason, higher HDL levels, generally 60 mg/dL or above, are associated with a lower cardiovascular risk.

Lifestyle choices strongly influence these processes. Diets high in refined sugar and white flour reduce HDL and worsen cholesterol balance. In contrast, diets rich in olive oil, fish, nuts, fruits, vegetables, and soluble fiber improve cholesterol handling and reduce oxidative damage. Regular exercise, maintaining a healthy weight, and not smoking significantly increase HDL and improve its protective function.

While medications such as statins can lower LDL cholesterol effectively, they do not replace the broad biological benefits of a healthy lifestyle and nutrition. Drugs may be necessary in selected high-risk individuals, but they should not substitute for natural, health-protective behaviors.

 

Scientific Discussion for Clinicians, Biomedical Scientists, Biochemists, Nutritionists, Dieticians and Allied Health Care Professionals

 

Cardiovascular disease is increasingly recognized as a disorder not merely of cholesterol concentration but of lipoprotein quality, oxidative stress, and chronic inflammation. Low-density lipoprotein derives its atherogenicity primarily from its susceptibility to oxidative modification rather than its cholesterol content alone. Native LDL particles consist of a lipid core rich in cholesterol esters and triglycerides, surrounded by phospholipids and a single apolipoprotein, ApoB-100. Under physiological and pathological conditions characterized by increased reactive oxygen species, LDL undergoes oxidative modification affecting both its lipid and protein components.

Oxidative modification alters the conformation of ApoB-100, rendering LDL unrecognizable to classical LDL receptors and impairing hepatic clearance. The resulting oxidized LDL is instead taken up by macrophages via scavenger receptors that lack feedback regulation. Progressive uptake leads to foam cell formation, which constitutes the earliest visible lesion of atherosclerosis and establishes the lipid core of atherosclerotic plaques. This process has been repeatedly demonstrated as a critical initiating event in atherogenesis.

The chemical susceptibility of LDL to oxidation is strongly influenced by the degree of unsaturation of its constituent fatty acids. Polyunsaturated fatty acids contain multiple carbon–carbon double bonds, creating bis-allylic hydrogen atoms that are particularly prone to abstraction by free radicals. This initiates lipid peroxidation chain reactions, generating lipid hydroperoxides and secondary reactive aldehydes such as malondialdehyde, which further modify ApoB-100 and amplify inflammatory signaling within the vascular wall.

In contrast, saturated fatty acids contain only single bonds and are comparatively resistant to oxidative attack. Monounsaturated fatty acids, such as oleic acid, contain a single double bond and exhibit substantially greater oxidative stability than polyunsaturated species. LDL particles enriched in monounsaturated fats demonstrate reduced susceptibility to oxidation, providing a biochemical rationale for the cardioprotective effects observed with diets rich in olive oil and similar lipid sources.

High-density lipoprotein exerts its protective effects through multiple mechanisms extending well beyond reverse cholesterol transport. HDL facilitates cholesterol efflux from macrophages and peripheral tissues via ATP-binding cassette transporters and scavenger receptor class B type 1, returning cholesterol to the liver for conversion to bile acids and eventual excretion. Additionally, HDL carries antioxidant and anti-inflammatory enzymes, including paraoxonase-1 and platelet-activating factor acetylhydrolase, which neutralize lipid peroxides and inhibit LDL oxidation.

It is now evident that HDL functionality is at least as important as HDL concentration. Under conditions of excessive oxidative stress, HDL itself may become structurally and functionally impaired, losing its anti-atherogenic properties and, in some contexts, becoming pro-inflammatory. This underscores the importance of metabolic health, antioxidant balance, and lifestyle factors in preserving HDL quality.

Dietary influences play a central role in modulating these processes. High consumption of refined sugar and white flour products has been shown to lower HDL levels and worsen lipid profiles, observations presciently highlighted by John Yudkin early in the 1960's. 

(Professor Dr John Yudkin, BA (Cambridge), 

MBBCh (Cambridge), MD (Cambridge),  FRCP (London), PhD (Cambridge), FRSC (London) was my professor at Queen Elizabeth College, University of London when I was doing my postgraduate under him). 

In contrast, diets emphasizing monounsaturated fats, omega-3 fatty acids from fish, soluble fiber from legumes and fruits, and antioxidant-rich plant foods improve HDL levels, enhance LDL resistance to oxidation, and reduce systemic inflammation. Tropical fruits commonly consumed in Malaysia, including guava, papaya, mango, passion fruit, bananas, dragon fruit, and soursop, provide soluble fiber and polyphenols that favorably influence lipid metabolism.

Physical activity remains one of the most effective non-pharmacological interventions for increasing HDL concentration and improving HDL functionality. Smoking cessation, modest weight loss, and metabolic control further augment these benefits. Although moderate alcohol intake has been associated with higher HDL levels, it should not be recommended as a therapeutic strategy.

Pharmacological interventions, particularly statins, effectively reduce LDL cholesterol and are widely prescribed, including atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, and fluvastatin. While generally well-tolerated, statins are associated with a spectrum of adverse effects ranging from myalgia and gastrointestinal symptoms to rare but serious complications such as rhabdomyolysis and hepatic dysfunction. Mild increases in blood glucose and reversible cognitive complaints have also been reported. Consequently, statin therapy should be individualized, carefully monitored, and viewed as complementary to rather than a substitute for lifestyle and nutritional interventions.

In conclusion, cardiovascular disease reflects a complex interplay between lipid chemistry, oxidative stress, inflammation, and lifestyle. LDL becomes pathogenic primarily through oxidative modification, whereas HDL confers protection through cholesterol efflux and antioxidant activity. Strategies that reduce oxidative burden, improve lipid composition, and preserve HDL function provide a biologically coherent and clinically sound approach to cardiovascular prevention.

 

Selected References

 

Steinberg D. The LDL oxidation hypothesis of atherogenesis. Circulation.
Parthasarathy S et al. Oxidized LDL and the pathogenesis of atherosclerosis. Annual Review of Medicine.
Yudkin J. Pure, White and Deadly.

Esterbauer H et al. Chemistry and biochemistry of lipid peroxidation. Free Radical Biology & Medicine.
Barter P et al. HDL cholesterol and cardiovascular events. New England Journal of Medicine.
Libby P. Inflammation in atherosclerosis. Nature