HIGH LDL! ... ALWAYS STATINS?? - Dissecting LDL As Never Before

 

# RKS: HIGH LDL! ... ALWAYS STATINS?? 

DISSECTING LDL AS NEVER BEFORE

RKS / 2024-2025 / Ser 5 / Blog 4

1st August 2024

WHY sdLDL MOST ATHEROGENIC?

A GUIDANCE FOR GUIDING THE GUIDES

Dear Reader,

The 'bad' cholesterol (C) is the low density lipoprotein (LDL) particles floating in the blood. This is more than a well-known fact and details relevant to this have been elaborated in the September 1, 2023 blog titled: # RKS: THE 'BAD' CHOLESTEROL - Is All LDL-Cholesterol Dangerous?

Going one step further, how does the LDL-C subtype levels influence the need for statins. This is indeed a tricky question and the same could even be countered by the medical professionals from their over-concerned dyslipidemic (suffering from abnormalities in lipid profile) patients.

LININGS OF BODY

There are two linings for the body:

1. EPITHELIUM: The coverings of body that are exposed to outside environment such as respiratory and digestive systems have linings called epithelia.
2. ENDOTHELIUM: These are coverings of those parts of the body which are not exposed to external environment eg. blood and lymphatic vessels.

The vascular endothelium supports 60,000 miles of blood vessels and includes at least 1 trillion cells. If all the endothelial cells are spread out these would cover 3,000-6,000 square meters of body surface.

DIMENSIONS OF ENDOTHELIUM CELLS

Each endothelium cell is:

• 30-50 micrometres (microns) long.
• 10-30 microns wide.
• 1-10 microns thick.

To get a sense of an endothelial cell’s size, imagine one strand of hair. A single strand is about 100 microns in diameter. So, even at its longest, an endothelial cell’s length of 50 microns is just one-half the diameter of a strand of hair. 

DAMAGE TO ENDOTHELIUM

There are only 2 end-factors capable of damaging the vascular endothelium. These are:

1. Oxidative stress
2. Inflammation

High blood glucose, high blood pressure, physical inactivity, tobacco smoking all cause oxidative stress mostly on account of excess free radicals generation. Sepsis and COVID-19 infections cause damage to the lining endothelium by eliciting inflammation.

Damage to endothelium reflects as:

1. Creation of small gaps of minimum of 4-5 microns which break the continuity of the lining.
2. Appearance of soluble marker proteins - SR-B1 and DOCK4.

SR-B1 stands for scavenger receptor protein class B, type 1 - a type of protein that binds LDL-C; DOCK4 refers to dedicator of cytokinesis 4 protein. DOCK4 promotes SR-B1–bound LDL-C particles entry to inside the wall of artery and thereby leads to creation of a thickened area called plaque. Here it is critical to understand that it is not the LDL particles that are internalized but only those caring cholesterol - LDL-C molecules enter and this is how the cholesterol of LDL gets carried right inside within the wall of the arteries.

LDL SUBTYPES

LDL particles are classified into 3 or 4 subclasses:

• Large LDL (LDL I)
• Intermediate LDL (LDL II)
• Small LDL (LDL III)
• Very small LDL (LDL IV)

The LDL particle density determines its categorisation:

• Large LDL: Density, 1.025-1.034 g/mL
• Intermediate LDL: Density, 1.034-1.044 g/mL
• Small LDL: Density, 1.044-1.060 g/mL

Accordingly 3 main phenotypes are defined:

1. Phenotype A: LDL I - Large buoyant LDL or lbLDL - diameter, 26.5-28.5 nm
2. Phenotype B: LDL III & IV - Small dense LDL or sdLDL - diameter, 24.2-25.5 & 22.0-24.1 nm
3. Phenotype A/B: LDL II - diameter, 25.6-26.4 nm

The gaps in damaged arteries is 4-5 microns which is just enough for the monocyte to squeeze into the damaged lining, and the space is more than enough for the sdLDL-C particle to enter inside the wall of the blood vessel. The diameter of sdLDL varies from 22.0-25.5 nm which equals 0.022-0.026 microns and this is very much lesser than the (4-5 microns) gaps in artery lining created by the damaging action of free radicals as well as inflammation.

THE SMALL & VERY SMALL LDL

Everyone is aware that LDL-C is responsible for atherosclerosis. But it is more important to understand how sdLDL predominates and is primarily responsible for arterial narrowing.

• TRIGLYCERIDE CONCENTRATION: High triglyceride (TG) amounts create a very low density lipoprotein (VLDL) subtype VLDL1 (TG-rich LP); in those with low amounts of TGs there is preponderance of VLDL2 (TG-poor LP). Since VLDL1 is preferentially converted to sdLDL, the levels of TGs determine the presence and quantum of sdLDL.

• CIRCULATION TIME: Apoproteins (apo) are proteins that bind with lipoproteins (LP) such as VLDL, LDL and HDL (high density lipoprotein - good cholesterol). This is because the lipoproteins being lipid in nature cannot mix freely with the aqueous blood and needs hand-holding by various apo types for circulating in body via plasma. For HDL there is apo A whilst apo B is required for VLDL and LDL. However, the apo B-100 that combines with sdLDL-C makes it more difficult for LDL receptor to recognise sdLDL. The lbLDL is thus easily removed from circulation by combining with LDL receptor in liver but this is not the case with sdLDL. The sdLDL therefore remains longer in circulation than lbLDL which allows more time for it to be oxidized. Hence, the LDL receptors rapidly cleanse the blood of lbLDL whilst the sdLDL continue to circulate for more time with resultant more opportunities to cause damage to the arterial lining.

• OXIDATION: sdLDL is more prone to damage by free radicals (oxidation due to oxidative stress because of excess of oxygen free radicals) because it is deficient with respect to the content of protective antioxidants. Oxidized sdLDL is more prone to cause inflammation and elicit immune responses.

• DESIALYLATION: Sialic acid is normally present in LDL particles. In blood, the enzymes (trans-silaidases) transfers silica acid to various components such as proteins and other lipids in plasma. The sdLDL is more desialylated and this serves to attract it more to proteoglycans (type of proteins) present in the arterial wall and thus more potential for it to cause damage to the lining.

• ELECTRONEGATIVE LDL: Oxidation of sdLDL-C results in formation of electronegative particles and LDL(-) predominates in those with heart disease suggesting that such negatively charged sdLDL-C is more contributory to atherosclerosis. The oxidized LDL and desialylated LDL are particularly electronegative which establishes a relation between LDL(-) and plaque formation.

It is therefore plausible that LDL undergoes multiple modifications to form sdLDL in the bloodstream, followed by desialylation, acquisition of the negative charge and thereafter oxidation to result ultimately in formation of highly atherogenic and proinflammatory sdLDL-C particles.

sdLDL & ATHEROSCLEROSIS - THE MASTER MECHANISM

The slower circulation time of sdLDL-C also ensures its availability for more time near the sites of the damaged artery.

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It is the plaque formation, on account of deposition of cholesterol within the blood vessel walls, that leads to thickening of the artery and narrowing of the lumen - the space through which the blood flows.

Lp(a)

Also called small 'a', this lipoprotein [Lp(a)] is related to LDL since it also bound by apo B. However, it differs from LDL since it contains an additional apo(a). Levels of Lp(a) closely relates to risk of cardiac events and stroke. 

It has now been demonstrated that the sdLDL concentrations are correspondingly higher in those with enhanced levels of Lp(a).

STATINS - WHEN ACTUALLY NEEDED?

The two phenotypes can be distinguished based on peak LDL particle diameters:

• Phenotype A pattern: >25.5 nm diameter of LDL (LDL I & LDL II)
• Phenotype B pattern: ≤25.5 nm diameter (small and very small LDL)

It is preferentially the small and very small LDL that enters the artery wall and causes plaque formation.

Let us take a live study case. A 58 year old statin-averse female patient Mrs Minal Sandesh Gandhi of Kolhapur (India) refused to take the popular cholesterol lowering pill inspite of having a high LDL-C 'kudos' to her being a member of the Dr Google tribe. Thankfully for her, she landed up in US and I had advised her to check her lipid profile for quantifying LDL subtypes.

It is very apparent that, although the concerned patient has LDL-C of 160 mg/dL, she is classifiable as having Phenotype A variety pattern of dyslipidemia. She can thus possibly escape taking statins because of the following explanations.

For the medical doctors:

sdLDL-C is the one that damages the endothelium of arteries because -

• sdLDL-C is the most oxidised LDL-C variety and more preferred by macrophages for transforming into foam cells.

• sdLDL induces inflammation of lining of artery and atherosclerosis is now designated as an inflammatory process.

• sdLDL downregulates the fibrinolytic system.

For those at risk:

• Higher sdLDL-C levels and occurrence of heart disease correlate strongly.

• The CA-IMT (carotid intimal-media thickness) risk parameter parallels the sdLDL concentrations.

• In pre-diabetics and diabetic patients, the insulin resistance as well as the risk of heart disease is closely associated with sdLDL amounts in blood plasma.

Statins can reduce sdLDL proportionate to decrease in total LDL and could be definitely justifiable in those with Phenotype B or even Phenotype A/B. Emerging data reveals that the role of statins in those with Phenotype A lipid profile seems to be questionable as far as reducing remarkably the risk of heart disease or atherosclerosis per se.

CONCLUSIONS

Statins are a boon but they are also prone to many side effects, particularly muscle-related, such as causing muscular pain commonly and, in rare case, even resulting in muscle tear or rhabdomyolysis - wherein muscles disintegrate. The blogger had himself experienced muscle tear on two occasions without any history of activity immediate prior to the tear!

It is thus not without basis that the consumers of statins are wary of taking the same given their access to digital platform revealing its side effects, and also because many have suffered from muscle pain and weakness since its incidence of occurrence is 1 out of 4 consumers of this cholesterol-lowering pill. In all such cases when the patient or an individual with risk factor becomes averse to accepting statins it would be worth the while doing the breakup profile of LDL before breaking one's head in going out of the way in convincing consuming these cholesterol pills.

Researching of drugs open up new vistas. But developing diagnosis of the mysterious ways the body functions can indeed enlighten optimal therapy prescribing.

Mrs Minal Gandhi should be thanked for having stimulated my re-visiting the blog of September 1, 2023 and dissecting the topic more minutely for the benefit of all those interested and concerned. However, she and many others with similar profile (and thought process) are advised to take the full quota of antioxidants daily to protect their LDL at the least.

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser

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