Thread by @sam_soete

Unveiling the Paradox: Do Statins Fuel the Fire of Heart Disease?

This is a deep dive 🧵into the mechanistic relationship between statins and coronary heart disease.

#statins #CVD #heartdisease #cholesterol #mitochondria

The ‘bad & good cholesterol hypothesis’ has lost its foundation.

Although lowering the LDL-C/HDL-C ratio is possible with drugs such as statins, this is not effective in preventing cardiovascular disease (CVD).

Proxy measurements such as LDL-C are a breeding ground for scientific arrogance.

Does the measurement really mean what you think it means?

Have you looked into the assumptions that connect the proxy and the real thing?

Let's dig in.

Clinical trials on statins performed before and after 2004 (when new penal regulations were established in the EU) show a conflicting relationship between LDL-C and CVD.

These regulations were instituted in response to ethical concerns regarding industry-funded trials.

Post 2004, all clinical trials performed without conflicts of interest reported that statins reduce LDL-C but do not prevent CVD.

Interestingly, in Familial Hypercholesterolemia (FH), cellular damage to artery walls precedes lipid deposition and atherosclerosis.

Could it be that LDL-C is not the culprit, and that there is a different mechanism at work?

In FH defective LDL receptors hinder nutrient supply to peripheral tissues.

These nutrient deficiencies may lead to reduced ATP synthesis and ultimately cellular damage.

Statins also cause cellular damage by impairing ATP synthesis, albeit by different mechanisms.

Statins are a mitotoxin.

The inhibition of HMG-CoA reductase leads to a reduction in the bioavailability of prenyl-intermediates which synthesize heme A and CoQ10 in the cholesterol biosynthetic pathway.

If you want to learn the exact mechanisms of how statins nuke our mitochondria, check out this thread:

https://twitter.com/sam_soete/status/1657013095510966272?s=20

CoQ10 & heme A are essential to proper function of the electron transport chain.

Cardiac myocytes have an extraordinary metabolic demand, highlighting the importance of CoQ10.

Indeed, the concentration of CoQ10 in cardiac myocytes is higher compared to many other cell types.

Long story short, statins impair mitochondria in several ways:

1) CoQ10 depletion
2) Mitochondrial loss
3) Oxidative Stress
4) ETC complex impairment

(mtDNA is much more vulnerable to oxidative stress than nuclear DNA)

As in FH, statin induced mitochondrial dysfunction and subsequent impairment of ATP synthesis may cause cellular damage in coronary arteries.

We have covered one aspect of how statins can impact cardiac muscle and blood vessels: mitochondrial damage → cellular damage.

Let's look into a second: Vitamin K2

Seed oils and vegetables such as kale, spinach & broccoli are rich in vitamin K1.

When consumed, vitamin K1 is metabolised into vitamin K3 and then vitamin K2 by integration with an isoprenyl subunit.

Bear with me in this next part, it is important.

Vitamin K is a cofactor for vitamin K-dependent clotting factors such as factors II, VII, IX, X, protein c and protein s.

These vitamin K-dependent proteins undergo a post-translational modification known as gamma-carboxylation.

Specific glutamate residues are converted to gamma-carboxyglutamate (Gla) residues.

Vitamin K2 is the cofactor in the carboxylation of matrix Gla Protein found in bone, blood vessels and heart.

In gamma-carboxylated form, the matrix Gla Protein binds calcium protecting tissues from calcification.

Statins inhibit the conversion of Vitamin K3 to Vitamin K2 by limiting the supply of the isoprenyl intermediate.

Therefore, statin inhibit Vitamin K2 synthesis → accelerating artery calcification.

In a clinical study of diabetics, high-frequency statin users were shown to exhibit accelerated coronary artery calcification compared with low-frequency statin users.

Not to mention the effects that they have on insulin resistance, you can read about here:

https://twitter.com/sam_soete/status/1657880137155883011?s=20

A third mechanism connecting statins with heart disease is nitric oxide (NO).

NO is a vasodilative molecule synthesized in endothelial cells.
statins inhibit the prenylation of Rho Protein which up-regulate endothelial nitric oxide Synthase.

Here is a great thread by @zaidkdahhaj if you want more information on NO.

https://twitter.com/zaidkdahhaj/status/1603802900999782401

We have covered the pathophysiological mechanism in depth, now lets look at some trial data.

This is where it gets interesting.

Japan Lipid Intervention Trial:

All cause mortality rises as TC falls under 200mg/dl.

All cause mortality also rises as TC rises above 240mg/dl but this population included x12 proportion of FH compared to the general population.

US Veterans Study & Danish Study:

Although statin therapy reduced all-cause mortality, the study did not correct for total cholesterol (TC).

It is probable that the participants on statins had a higher TC level.

Since TC levels are inversely associated with all-cause mortality, TC might be the protective factor illustrated in this study.

Interestingly, despite statins users having a lower all-cause mortality in this study (potentially explained by protective TC levels), they did have an increased mortality attributed to CVD.

Furthermore, CVD mortality was correlated with length of statin use.

This data is not consistent with the trials performed prior to 2004 which observe a relative risk-reduction of 30% for CVD from statin use.

I wonder why results from trials before the EU penal regulations would conflict with those that took place after?

TLDR:

1) ‘Bad & good cholesterol hypothesis’ is on shaky ground
2) Statins may have a causal relationship with atherosclerosis and heart disease
• Mitochondrial damage
• Vitamin K2 impairment
• NO deficiency

Statins are a quintessential example of how big pharma has infiltrated our healthcare system.

Follow these sages to learn more:
• @holmanm
• @LDLSkeptic
• @DrAseemMalhotra

Thanks for your time.

If you enjoyed this content and want to learn more about health:

1. Follow me for more content

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https://twitter.com/sam_soete/status/1661732893989937152?s=20