Massive New Study shows Niacin and NAD+ cause Heart Disease?? Is this true? [Study 282]

Summary

This video discusses a study suggesting a link between the metabolite 4py, produced from the NAD metabolism pathway involving niacin (NIN), and an increased risk of heart disease. The research identifies a connection between 4py and the ACSMD gene, with higher levels of 4py associated with greater cardiovascular risk. Despite these findings, the video argues against condemning niacin supplementation, highlighting the need for more comprehensive studies and considering the potential for increased 4py levels with high niacin doses.

Takeaways

• 🧬 The study suggests a potential link between the metabolites of niacin (NYS) and heart disease, specifically through the accumulation of 2py and 4py.
• 🔍 Researchers conducted an untargeted metabolomics screen to identify unusual molecules associated with heart disease risk factors.
• 🧪 Mass spectrometry was used to determine the weight and composition of the unknown molecules, revealing their involvement in the niacin and NAD metabolism pathway.
• 📊 The study found that higher levels of 2py and 4py were associated with a greater risk of major adverse cardiovascular events (MACE), even after adjusting for other risk factors.
• 🧬 A gene-wide association study (GWAS) identified a gene, ACMSD, that is closely related to the metabolism of 2py and 4py.
• 🧬 The ACMSD gene was found to be associated with a specific mutation, RS10496731, which could impact the metabolism of niacin and NAD.
• 🐁 Animal studies using mice showed that inhibiting the ACMSD gene led to increased levels of 2py and 4py.
• 🧬 The study proposes that 4py, in particular, may contribute to cardiovascular disease by increasing the adhesion of immune cells to the endothelium, potentially leading to plaque formation.
• ⚠️ The study does not conclusively prove that niacin supplementation causes heart disease but suggests a potential mechanism that could be explored further.
• 🔎 More research is needed to understand the direct effects of niacin supplementation on cardiovascular health and the role of ACMSD gene mutations.

Q & A

What is the main focus of the study discussed in the video?

The study focuses on the potential role of niacin (NYS) and its metabolites in causing heart disease, specifically investigating the residual risk of heart disease even when controlling for known risk factors.

What is an untargeted metabolomics screen?

An untargeted metabolomics screen is a method of probing blood samples for thousands of molecules to identify any abnormal rise or drop in certain molecules, which can indicate potential health issues.

What are the two suspicious metabolites identified in the study that are involved in the niacin and NAD metabolism pathway?

The two suspicious metabolites identified are N1-methyl-2-pyridone-5-carboxamide (2py) and N1-methyl-4-pyridone-3-carboxamide (4py).

What is the significance of the metabolites 2py and 4py in relation to heart disease?

The study found that higher levels of 2py and 4py in the blood are associated with an increased risk of major adverse cardiovascular events (MACE), even after accounting for other risk factors.

What is a Gene-wide Association Study (GWAS) and how does it relate to the study?

A GWAS is a study that looks for associations between genes and particular conditions or diseases. In this study, a GWAS was used to find a gene (acmsd) that is tightly related to the metabolites 2py and 4py.

What is the function of the acmsd gene and how does it relate to 2py and 4py?

The acmsd gene is involved in the metabolism of tryptophan and is part of the pathway that can lead to the production of 2py and 4py. A deficiency or mutation in this gene can lead to increased levels of these metabolites.

What does the experiment involving injecting small hairpin RNA into mice demonstrate?

The experiment demonstrates that inhibiting the acmsd gene leads to an increase in the levels of 2py and 4py, suggesting a direct link between the gene's function and the levels of these metabolites.

How does the study suggest that 4py might contribute to cardiovascular disease?

The study suggests that 4py might contribute to cardiovascular disease by increasing the adhesion of immune cells to the endothelial cells lining blood vessels, which can lead to inflammation and the formation of plaques.

What is the conclusion of the video regarding the use of niacin (NYS) supplements and cardiovascular health?

The video concludes that while the study indicates a potential new mechanism of cardiovascular disease through 4py, it does not condemn niacin as a cardiovascular disease risk. The video suggests that the study's findings should be considered in the context of other research.

What mistake does the video claim the researchers made in their analysis?

The video claims that the researchers made a mistake by not considering the possibility that a functional acmsd enzyme might still lead to increased 4py levels if extremely high doses of niacin are supplemented, which could potentially raise cardiovascular risks.

Outlines

00:00

🧬 Investigating Niacin's Link to Heart Disease

The video discusses a study that explores the potential role of niacin in causing heart disease. Researchers conducted an untargeted metabolomics screen on blood samples to identify molecules associated with heart disease, controlling for factors like blood pressure, diabetes, and lipoproteins. They discovered unusual molecules, 2py and 4py, involved in niacin and NAD metabolism. These molecules were found to be linked to a higher risk of MACE (major adverse cardiovascular events), even after accounting for traditional risk factors. The study suggests that these metabolites might be a previously unrecognized contributor to heart disease.

05:02

🧬 Gene-Metabolite Connection in Cardiovascular Disease

The script continues with a gene-wide association study (GWAS) that identified a gene, ACMSD, related to the metabolites 2py and 4py. A specific mutation, RS10496731, in this gene was highlighted. Researchers then used a hairpin RNA technique to inhibit the ACMSD gene in mice, which led to an increase in 2py and 4py levels. Further experiments showed that 4py, in particular, may contribute to cardiovascular disease by increasing the adhesion of immune cells to the endothelium, a process that can lead to plaque formation. The video suggests that while there is a link between these metabolites and cardiovascular risk, the relationship is complex and not fully understood.

10:02

🧬 The Complex Role of ACMSD and Niacin in Cardiovascular Health

The final paragraph delves into the role of the ACMSD enzyme in niacin and NAD metabolism. It explains that a deficiency in this enzyme could lead to increased levels of 4py, which is associated with higher cardiovascular risk. However, not all mutations of the ACMSD gene lead to higher 4py levels; some may even enhance the enzyme's function. The video points out that the study's participants likely had pre-existing heart disease, which could skew the results. It also suggests that high doses of niacin supplementation could raise 4py levels, even in those with a functional ACMSD enzyme. The video concludes by stating that while the study indicates a potential new mechanism for cardiovascular disease, it does not definitively condemn niacin as a risk factor. The host also mentions a mistake made in previous analyses of niacin's effects on cardiovascular health and promises to address it in a linked video.

Keywords

💡Niacin (NIN)

Niacin, also known as vitamin B3 or NIN, is a water-soluble vitamin that plays a crucial role in converting food into energy. In the context of the video, it is discussed as a potential risk factor for heart disease when metabolized into certain compounds. The video script mentions that researchers are investigating whether high levels of NIN metabolites could be linked to heart disease, even when controlling for other known risk factors.

💡Heart Disease

Heart disease refers to a range of conditions that affect the heart, including coronary artery disease, heart rhythm problems, and heart failure. The video's primary focus is on the potential link between NIN and heart disease, specifically the risk of major adverse cardiovascular events (MACE). The script discusses how even after controlling for known risk factors, there may be a residual risk associated with certain metabolites.

💡Metabolomics

Metabolomics is the study of the chemical processes involving metabolites, the byproducts of cellular processes. The script describes how researchers conducted an untargeted metabolomics screen to identify unknown molecules in the blood that could be associated with heart disease. This approach led to the discovery of certain metabolites that were not previously linked to heart disease.

💡Mass Spectrometry (Mass Spec)

Mass spectrometry is an analytical technique used to identify and quantify molecules based on their mass-to-charge ratio. In the video, mass spectrometry is used to further characterize the unknown molecules found in the metabolomics screen. This technique helped researchers to determine the weight and composition of the molecules, which were later identified as NIN and NAD metabolites.

💡NAD Metabolism

NAD (Nicotinamide adenine dinucleotide) is a molecule found in all living cells and is essential for various cellular processes, including DNA repair and metabolism. The video discusses how NIN feeds into the generation of NAD and how certain metabolites of NIN and NAD might be associated with heart disease. The script mentions the role of NAD in cellular processes and how its metabolism might be affected by the presence of certain enzymes.

💡Residual Risk

Residual risk refers to the remaining risk of a disease after accounting for known risk factors. In the context of the video, residual risk of heart disease is the focus, as researchers sought to understand why heart disease persists even when controlling for factors like blood pressure, diabetes, and lipoproteins. The script explores whether NIN metabolites could account for this residual risk.

💡Major Adverse Cardiovascular Events (MACE)

MACE is a term used to describe a composite of serious cardiovascular events, including heart attack, stroke, and death due to cardiovascular causes. The video script uses MACE as a measure of cardiovascular risk associated with high levels of certain NIN and NAD metabolites. The data presented in the video shows a correlation between higher levels of these metabolites and increased MACE risk.

💡Gene-wide Association Study (GWAS)

GWAS is a research method used to identify genetic associations with specific diseases or conditions. In the video, a GWAS was conducted to find the association between the metabolites and different genes across tens of thousands of individuals. The script mentions that a gene called ACMSD was found to be tightly related to the metabolites of interest.

💡Single Nucleotide Polymorphism (SNP)

A SNP is a variation at a single position in a DNA sequence among individuals. In the video, a specific SNP (rs10496731) in the ACMSD gene is highlighted as it is associated with the levels of certain metabolites. The script explains how this genetic variation could potentially affect the function of the ACMSD gene and, consequently, the levels of metabolites linked to heart disease risk.

💡Endothelial Cells

Endothelial cells are the primary cell type lining the interior surface of blood vessels and lymphatic vessels. The video discusses how the injection of 4py into mice led to an increase in immune cells binding to endothelial cells, which could potentially lead to inflammation and the development of plaques associated with cardiovascular disease. The script uses this example to illustrate the potential mechanism by which certain metabolites could contribute to heart disease.

Highlights

A study suggests a potential link between Niacin (Nin) and heart disease.

Researchers conducted an untargeted metabolomics screen to identify unknown molecules associated with heart disease.

Suspicious molecules named N1 methyl 2 pyone 5 carboxamide and N1 methyl 4 pyone three carboxamide (2py and 4py) were found to be involved in Nin and NAD metabolism.

The study aimed to understand the residual risk of heart disease even after controlling for known risk factors.

Mass spectrometry was used to define the weight and composition of the suspicious molecules.

Higher levels of 2py and 4py in the blood were associated with increased risk of major adverse cardiovascular events (MACE).

The study controlled for factors like blood pressure, cholesterol, diabetes, and others to isolate the effect of 2py and 4py.

A gene-wide association study (GWAS) identified a gene, acmsd, related to the metabolites 2py and 4py.

A mutation in the acmsd gene, RS 10496731, was highlighted for its significance.

The acmsd gene's function was explored through the injection of small hairpin RNA into mice to inhibit its protein production.

Inhibition of the acmsd gene led to an increase in 2py and 4py levels.

4py, but not 2py, was found to increase the adhesion of immune cells to endothelial cells, potentially leading to plaque formation.

The study suggests that a deficiency in the acmsd enzyme might lead to higher 4py levels and worse cardiovascular outcomes.

The potential impact of high-dose Niacin supplementation on 4py levels, even with a functional acmsd enzyme, was discussed.

The study does not condemn Niacin as a cardiovascular disease risk but suggests a need for further research.

The video concludes with a critique of the study's methodology and a call for more direct investigation into Niacin's cardiovascular effects.

Transcripts

well well this was quite a surprise I

was sent this study by a number of

people in the physionic community so I

read it I analyzed it I brooded over it

and then quickly scrambled to get this

video out because there's a tremendous

amount to cover here is it true is nin

causing heart disease I'm talking about

this study where in the researchers

identified a Sinister role of NYS in

potentially causing heart disease okay

so they used data from several groups of

people including validation cohorts and

wanted to know if we control for

lipoproteins that are linked to heart

disease blood pressure diabetes and

several other factors why is there

residual risk of heart disease which is

a great question why do people

experience heart disease if we're

controlling for all these factors well

that isn't to say that these factors

don't play a role researchers

acknowledge that heart disease rates are

are typically improved when controlling

for these factors but heart disease

still persists so

why so to find out they did an

untargeted metabolomics screen which

means that they probed the blood from

these groups of people for thousands of

molecules to find where there might be

an abnormal rise or drop in certain

molecules ultimately they found the

usual suspect so they ignored those but

focused on a suspicious group of unknown

molecules they're unknown because they

aren't defined by this metabolomics

experiment but can be defined by another

experiment called mass spectrometry mass

spec which is what we abbreviated as the

too cool to say the full name scientists

so Mass Spec allows us to figure out the

weight as well as composition of the

molecules by determining the mass to

chemical charge charge of the molecule

and what they found is that these

molecules are tightly involved in the

nin and NAD metabolism pathway these

molecules are called N1 methyl 2 pyone 5

carboxamide and N1 methyl 4 pyone three

carboxamide which are I'm sure on the

top of everyone's baby name list for

twins if you'll allow me I'll abbreviate

them to 2py and 4py anyway if we into

our metabolism of B vitamins we know

that nin feeds into this generation of

NAD which is a common molecule in our

cells involved in a huge number of

cellular processes from DNA repair to

metabolizing fats and much more on the

other hand n is then converted to

nicotinamide and when nicotinamide is

catabolized it turns into 2py and

4py dun dun dun the

horror

anyway joking aside the researchers

Quantified the risk of Mace which stands

for major adverse cardiovascular events

which is a grouping of cardiovascular

vents in composite if we look at the

data we can see some of the worry here

we're seeing the amount of Mace so the

higher the worse the horizontal axis

shows the time elapsed and the Q4 is the

people with the highest circulating 2py

and 4py levels clearly you can see the

red the Q4 with the greatest blood

concentration of 2py and 4py Associates

with the greatest levels of Mace now

this data does not account for other

factors like blood pressure cholesterol

containing lipoproteins diabetes and so

on so they also show us an adjusted

model accounting for those factors

reading this data we have the amount of

risk on the bottom the horizontal axis

and then we have our different 2py and

4p py concentrations listed on the

vertical the Q4 is again our highest

concentration if the lines move to the

right there is an increase risk

confirmed by statistical analysis via P

value for those stats nerds out there

like myself the black line is the

unadjusted data so just straight

correlation between these nice and an

NAD metabolites and mace risk the red

line is the association when controlling

for the aforementioned CBD risk factors

blood pressure diabetes Etc as we can

see they both indicate risk even when

other factors are accounted for now I

won't show you the data for time sake

but they show the same results when

separating out these metabolites so when

just looking at 2py or just looking at

4py confirming the data that we just

went over okay if you've been

supplementing with niin or NAD boosters

you might be uh sweating a bit under the

collar not looking too bright is it well

there might be a light at the end of the

tunnel maybe I don't want to promise

anything so keep your seat Bel fastened

because we might also be headed for a

wall so there's this link between these

NYS and and Ned metabolites and

cardiovascular disease but the

researchers took several more steps by

performing a gwas or Gene wide

Association study which essentially

finds the association between these

metabolites and different genes across

tens of thousands of individuals and as

we can see the GW was picked up a gene

that was tightly related to both of

these metabolites that Gene is

acmsd found on your chromosome

2 then if we take a closer look around

that Gene we see one mutation is

highlighted called RS

10496

731 each one of those dots is a mutation

but some belong to other genes and some

don't reach significance so they focused

on the most prominent one this one full

disclosure uh they found another

mutation that was also tightly related

to 4py metabolite but since they both

shared this acmsd gene mutation they

focused on this one okay so we now know

that these metabolites are linked to

this Gene and this gene mutation called

a single nucleotide polymorphism so you

might be wondering what this Gene does

and why it's important and why it

matters to us figuring out if nin and

NAD is poisoning our hearts for that the

researchers figured out how this Gene

affects these metabolites by injecting a

small hair pin RNA into mice this

hairpin RNA which technically for my

molecular biologists out there was

delivered through an adino virus will

bind to the RNA produced by the acmsd

Gene and inhibit it from being produced

into a protein okay I can't help myself

so I'm going to explain how this

molecular biology Works in case you're

interested if you're not interested skip

to this timestamp and I'll be as brief

as possible I'll meet you over there

with my posy of fellow nerds essentially

the researchers injected a virus

containing the genetic information to

produce an RNA molecule if you don't

remember here's a brief rundown on RNA

and genes when your genes are read or

expressed to generate the protein that

genes hold the information for it first

has to be transcribed into an RNA

molecule which is then converted to a

protein that then functions within your

cells so the liver cells of these mice

have been infected to produce an RNA

called a silencing RNA but instead of

going on to create a protein this

silencing RNA is designed to Target the

RNA produced by the acmn D Gene it will

literally bind to it with the help of a

protein called risk and degrade it

instead of allowing the acmsd RNA to

continue to produce the acmsd protein

and serve its function in the cell okay

so these researchers inject these mice

with this RNA that blocks the production

of the acmsd gene which we can see here

the amount of Gene RNA is dramatically

reduced in red called a knockdown and

what happens to the metabolites the 2py

and 4py they increase and buy a lot as

well at least for the 2py so there's

this connection between the Gene and the

metabolites this tells us that if the

gene is not functioning correctly like I

don't know from a mutation maybe that a

person's 2py and 4py levels might rise

now we understand the link but how

exactly does 2py and 4py lead to worse

mace outcomes worse cardiovascular

disease they figured that out too I'm

telling you these researchers did a lot

of work they did a number of experiments

but I'm going to show you the Salient

one because I'd like to wrap this up

with some bigger picture takeaways for

you including a few areas that I think

the researchers actually missed the mark

what they did was inject mice with 2py

and 4py which is a way to get the cause

and effect relationship instead of

speculating on possible other

confounding factors what they then

measured was the amount of Lucy adhesion

lucaites or immune cells will roll and

bind onto cells that line your blood V

vessels these cells called endothelial

cells will Express and produce proteins

that allow the lucaites to adhere to

them like anchors or attachment points

an overabundance of these attachment

points in this case a protein called

vcam the more of these immune cells bind

to the endothelial cells to invade past

the endothelial layer into the

subendothelium which is where plaque

begins to grow there are other factors

involved in this process but one is

inflammation these immune cells and if

inflammation is increased by more of

these vcam proteins being expressed on

the endothelium the more of these

lucaites will adhere and potentially

invade into the

subendothelium so is that what they

showed yes as we see here we're

measuring adherent cells so the number

of lucaites that are at that adhesion

stage the higher the worse in this

context interestingly 2py injection did

not lead to this effect but 4py

injection did if we compare them against

the control condition there which did

not receive 2py or 4py injection so this

might imply that 2py is a passenger to

the problem and the real problematic

culprit is 4py the reason earlier data

showed a relationship when just looking

at 2py is because that is not adjusted

for 4py concentrations so it stands to

reason that they might both increase

similarly and inextricably

all right all that leaves us pretty numb

I imagine well let's avoid the Green Day

Novae and see what we can determine from

this data and how it fits into the grand

scheme of things well we have some

evidence that having a deficient enzyme

ACS MD is linked to increased levels of

these metabolites especially 4py we also

know that 4py tracks increased

cardiovascular risk even when accounting

for certain other factors like diabetes

LDL blood pressure and more now this

Gene acmd is part of an ancillary niin

NAD metabolism pathway related to

tryptophan usually tryptophan would be

converted to acetyl COA by partly this

acmd enzyme which then allows acetal COA

to enter the mitochondria to be used for

energy fine however if acmd is out of

commission tryptophan metabolites are

probably incapable of being converted to

cetal COA so they get shuttle to this

NAD synthesis in a pathway called the

price Handler pathway ultimately what

you need to know is if this acmd enzyme

is deficient in some way then you have

excess substrate to produce NAD but did

you know that not all mutations of this

acmd enzyme lead to higher 4py some

mutations of the very same location on

the gene the same single nucleotide

polymorphism that we discussed earlier

do not impede its function and may

actually increase its function you might

also be interested to know that the

people included in this study most

likely had some form of heart disease

already and if you look at the data

again from these individuals is it

possible that the people in the Q4 have

the deficiency in this acmd enzyme or

some other related enzyme and therefore

they see these high 4py values because

notice how three other groups do not

have overly High I4 py values and they

do not differ in Risk so it may be that

if you are in the majority of people

with this functional enzyme you may not

see these increases in 4py we can't say

based on this data but we can say

something far more powerful it stands to

reason that even with a functional

version of this enzyme if we supplement

with extremely high doses of nin we

might still raise our 4py regardless

unfortunately the researchers mentioned

that n studies show no positive effects

on cardiovascular outcomes but uh notice

how I frame that no positive effects if

Nyon leads to this devastating increase

in 4py we'd likely expect worse outcomes

not neutral overall this study indicates

a potential new mechanism of

cardiovascular disease through 4py but

does it condemn nin as a cardiovascular

disease risk my answer is no I'm not

worried and that's because the

researchers made a mistake that I almost

made several months ago when I analyzed

many studies to find out if nin protects

against cardiovascular disease I'll

explain the mistake and show you the

direct effect of nin on cardiovascular

disease in this linked video I'll see

you over there

bye

sh