Massive New Study shows Niacin and NAD+ cause Heart Disease?? Is this true? [Study 282]
Summary
TLDRThis 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
🧬 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.
🧬 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.
🧬 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.
Mindmap
Keywords
💡Niacin (NIN)
💡Heart Disease
💡Metabolomics
💡Mass Spectrometry (Mass Spec)
💡NAD Metabolism
💡Residual Risk
💡Major Adverse Cardiovascular Events (MACE)
💡Gene-wide Association Study (GWAS)
💡Single Nucleotide Polymorphism (SNP)
💡Endothelial Cells
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
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