Richard Ferraro Profile picture
Feb 21, 2023 18 tweets 9 min read Read on X
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitors have changed the landscape of cardiology forever.

This is a Tweetorial🧵on why.

And it starts in 1999, with a French family named HC2. Image
At the time Varret and colleagues were evaluating familial hypercholesterolemia (FH) in a French pedigree.

Most known FH at the time exhibited mutations in APOB or LDLR genes. In the HC2 pedigree, neither of these genes were affected. But a third area was… Image
Fast forward to 2003. Abifadel and Varret discover mutations to a gene in this area called PSCK9.

PCSK9 encodes a newly discovered protease expressed in the liver and found to be important to cholesterol metabolism.

And mutations here could lead to some pretty wild stuff. How? Image
It’s all about low-density lipoprotein (LDL), the main thing we discuss on lipid panels and a major culprit of cholesterol badness

For more detail/explanation see:

And check out @CardioNerds lipid series, like this incredible episode with Dr. @a_l_bailey Image
Briefly, LDL is removed at the liver by LDL-receptors (LDLR) on hepatocytes. The more of these there are, the more cholesterol we remove

These lead to⬇️ bloodstream cholesterol, which means⬇️cholesterol around to cause #ASCVD

See excellent figure by Barale et al below: Image
Makes sense then why LDLR gene would be an early target for familial lipid disorders right?

Less LDLRs, Less hepatic uptake of LDL, and blood cholesterol stays ⬆️⬆️ causing heart disease and other badness Image
So. PCSK9.

PCSK9 is sneakier. Once the LDLR picks up LDL from the bloodstream, it drops it off at the lysosome for digestion and goes back to the cell surface to repeat the process

But some LDL particles, 1:500-1000, have a PCSK9 molecule attached. And it’s tragic… Image
When an LDLR snags one of these LDL/PCSK9 complexes they don’t go back to the surface. They get degraded at the lysosome too!

And so the overall surface density of LDLRs goes ⬇️ with ⬆️ PCSK9

Less LDL is absorbed, so blood cholesterol ⬆️⬆️ Image
And so a genetic mutation that⬆️ PCSK9, could worsen this process.

And the reverse is true as well.

Individuals with non-sense mutations, meaning PCSK9 is ⬇️ or nonexistent, exhibit huge reductions in CHD (88% by one @NEJM study below) Image
So let's recap:
⬆️PCSK9 in hepatocytes leads to⬇️LDLR on hepatocytes cell surface

⬇️ LDLR on the cell surface leads to⬆️ LDL in the bloodstream

⬆️ LDL in the bloodstream leads to ⬆️coronary artery disease, peripheral artery disease, and plaque generally
But what if we could inhibit PCSK9?

More LDLR gets recycled to the cell surface leading to ⬆️cholesterol absorption from the blood stream and ⬇️ LDL available to cause plaque. #ASCVD is over!

See another excellent graphic by @DrMichaelShapir and colleagues Image
So drug companies got to work addressing the issue.

And it took a long time, but today we have spectacular results and options for patients.

Take the FOURIER trial, which used the PCSK9 monoclonal antibody evolocumab in 27,564 pts ALREADY on statin showing a median LDL⬇️of 59% Image
Or the ODYSSEY OUTCOMES trial, which used alirocumab in 18,924 pts with recent ACS, ALREADY on high-intensity statin, and showed a 62.7% reduction in LDL and a 17% reduction in all-cause mortality

Incredible right, why wouldn’t we just use these on everyone? Image
Well $ is one issue, for sure. You’re not going to find these in the $4 aisle

The exact price varies all the time as well as across countries, making cost effectiveness studies obsolete very quickly. In the US, you can expect thousands of $ per year Image
Also, these monoclonal antibodies don’t stick around very long.

So subcutaneous injections need to be given frequently, every two weeks… Image
But what if there was another way. What if we could make the effects of PCSK9 inhibition last longer? What if we could make them last forever?

PCSK9 Tweetorial Part II. Coming soon Image
If you want to learn more about lipids and dyslipidemia in general, see our review Contemporary Management of Dyslipidemia below.

Thanks to Drs. @TLeucker, @maciejbanach, @SethShayMartin, Jones, and Toth for the mentorship!

pubmed.ncbi.nlm.nih.gov/35303294/
Thanks to the indefatigable @AmitGoyalMD for reviewing this and to all my #Medtwitter #CardioTwitter #FOAMed colleagues for the support Image

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More from @RichardAFerraro

Apr 22, 2022
So you've heard a lot of stuff, you've read a lot, maybe you listened to our podcast @cardionerds on it, and yet something is still missing.

TRIGLYCERIDES NEED A TWEETORIAL!

Let’s get right into it with 2 big points to start
#1: Lipids are insoluble in water. You’ve likely seen in this in science class or making salad dressing

What this means is that cholesterol and TG need to be transported with proteins in the body. So we add proteins + lipids and boom, we’ve got lipoproteins (LDL, ILD, VLDL, etc)
#2: The key to this TG story is Very Low-Density Lipoprotein (VLDL). VLDL is made by the liver of proteins, cholesterol, and TG

The ratio of TG to cholesterol depends on the size of the particle, with VLDL getting smaller as adipose and muscle pull TG out of circulating VLDL
Read 16 tweets
Feb 25, 2021
🔥QUICK TEACHING/MEMORY TRICK on FeNa! 🔥

Question: How can we remember FeNa and FeUrea calculations?
☑️Keep things on the UP and UP...
☑️...and HIGHER letters go first.

We'll get into that soon. First...what is FeNa and why it is classically used?
☑️FeNa is the fractional excretion (Fe) of Sodium (Na). That how we get Fe-Na. The FeNa is just the amount of Na our kidney lets leave the body

☑️It's value has been of some debate, but in theory it can help differentiate PRE-renal and INTRA-renal kidney injury

Why?
🔥In PRE-renal injury we're usually dry right? We need more water(volume)

✅Remember that H2O follows Na. So to get⬆️H2O we need to⬆️Na uptake

✅We get BOTH by⬆️Na uptake from the urine! H2O follows Na

✅So the the FeNa, goes⬇️! Less Na leaves, less H2O leaves, we're less dry
Read 12 tweets

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