Circulation April 5, 2022 Issue

This week, please join author Zdenka Pausova and
Associate Editor Svati Shah as they discuss the article
"Circulating Metabolome and White Matter Hyperintensities in
Women and Men."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor, Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, have you ever wondered what white matter hyperintensities
in a brain are made of? Well, guess what? The feature discussion
is going to give us a little clue. Believe it or not from the
circulating metabolome, interesting, huh? Well, I'm going to keep
you in suspense, as we first discuss other papers in the issue.
And I want to go first, may I?


Dr. Greg Hundley:


Absolutely, but let's all grab a cup of coffee.


Dr. Carolyn Lam:


All right. You got yours. And here goes. This first paper reviews
the results of endovascular aneurysm repair in patients from the
Japanese Committee for Stent Graft Management registry, to
determine the significance of persistent type II endoleak and the
risk of late adverse events, including aneurysm sac enlargement.


Dr. Greg Hundley:


Ah, Carolyn, a very clinically relevant question. So what did
this study show?


Dr. Carolyn Lam:


Of more than 17,000 patients who underwent endovascular aneurysm
repair for abdominal aortic aneurysm from 2006 to 2015, 29% had
persistent type II endoleak. The cumulative incidence rates of
abdominal aortic aneurysm related mortality, rupture, sac
enlargement, and reintervention were higher in patients with
persistent type II endoleak. Specifically, the cumulative
incidence rates of rupture and abdominal aortic aneurysm related
mortality increased to 2% at 10 year follow up, which is
dissimilar to the previously reported frequency of only about 1%.
Cox regression analysis revealed older age, female sex, proximal
neck diameter, and chronic kidney disease as independent,
positive correlates of sac enlargement.


Dr. Carolyn Lam:


So these wonderful results are from Dr. Hitoshi Matsuda and
colleagues from the National Cerebral and Cardiovascular Center
in Osaka Japan, and really suggests that persistent type II
endoleaks are not always benign.


Dr. Greg Hundley:


Beautiful summary, Carolyn. Well, my paper comes from the world
of pre-clinical science. And Carolyn, in most eukaryotic cells,
the mitochondrial DNA is uniparenterally transmitted and present
in multiple copies derived from the clonal expansion of
maternally inherited mitochondrial DNA. All copies are therefore,
nearly identical or, as we would call homoplasmic.


Dr. Greg Hundley:


Now Carolyn, the presence of more than one mitochondrial DNA
variant in the same cytoplasm can arise naturally or as a result
from new medical technologies aimed at preventing mitochondrial
genetic diseases and improving fertility. The latter is called
divergent non-pathological mitochondrial DNA heteroplasmy, or
DNPH.


Dr. Greg Hundley:


Now Carolyn, these investigators led by Professor Jose Enriquez
from the Centro Nacional de Investigaciones Cardiovasculares
hypothesized that DNPH is maladaptive and usually prevented by
the cell.


Dr. Carolyn Lam:


Wow, that's really interesting, investigations from the world of
preclinical science. What did the investigators find?


Dr. Greg Hundley:


Right, Carolyn. So, the investigative team engineered and
characterized divergent non-pathological mitochondrial DNA
heteroplasmy, or DNPH, as we've talked about before, mice
throughout their lifespan. The authors found that DNPH impair
mitochondrial function with profound consequences in critical
tissues that did not resolve heteroplasmy, particularly within
cardiac and skeletal muscle. Progressive metabolic stress in
these tissues led to severe pathology results, including
pulmonary hypertension and heart failure, skeletal muscle
wasting, frailty, and premature death. And finally, Carolyn,
symptom severity was strongly modulated by the nuclear context.


Dr. Greg Hundley:


So in conclusion, Carolyn, these findings suggest that medical
interventions that could generate divergent non-pathological
mitochondrial DNA heteroplasmy, or DNPH, so to address potential
incompatibility between donor and recipient mitochondrial DNA.


Dr. Carolyn Lam:


Oh wow. That is fascinating. Well guess what? My next paper is
also about mitochondria, but this time looking at the role of the
mitochondrial calcium uniporter. So we know that calcium is a key
regulator of energy metabolism and impaired calcium homostasis
damages mitochondria, resulting in cardiomyocyte death,
pathological hypertrophy, and heart failure.


Dr. Carolyn Lam:


This study by Dr. Wang from University of Washington and
colleagues investigated the regulation and the role of the
mitochondrial calcium uniporter in chronic stress induced
pathological cardiac remodeling. In a series of elegant
experiments in the mitochondrial calcium uniporter knockout or
transgenic mice infused with isoproteronol, the authors found
that the mitochondrial calcium uniporter is up regulated in the
stressed heart to orchestrate mitochondria sarcoplasmic
reticulum, and cytosolic calcium handling, preventing cytosolic
calcium overload induced cardiomyocyte death.


Dr. Carolyn Lam:


Lack of mitochondrial calcium uniporter mediated mitochondrial
calcium uptake is detrimental. Whereas, transgenic over
expression is beneficial to the heart during chronic beta
adrenergic stimulation. The nuclear translocation of calcium/
calmodulin kinase II delta beta via calcineurin mediated
dephosphorylation of serine 332 activates CAMP response element
binding protein to promote mitochondrial calcium uniporter gene
expression in adult cardiomyocytes.


Dr. Greg Hundley:


Well, Carolyn, what's the take home here? What are the clinical
implications?


Dr. Carolyn Lam:


Ah, thought you might ask. Well, this study indicates that
enhancing mitochondrial calcium uptake could be a new approach to
prevent chronic beta adrenergic stimulation induced heart
remodeling. Targeting this cam kinase two delta beta KREB
mitochondrial calcium uniporter pathway could be a therapeutic
option for pathologic cardiac remodeling associated with chronic
adrenergic stress.


Dr. Greg Hundley:


Excellent description, Carolyn, and thank you for walking us
through that wonderful paper. Well, we've got some other papers
in the issue and from the mail bag, Professor Lusis has a
Research Letter entitled Identification of DNA Damage Repair
Enzyme, ASK II as Causal for Heart Failure with Preserved
Ejection Fraction. And Carolyn there's a cardiovascular case
series from Professor Barrett entitled, “The Unrepairable Infant
Mitral Valve, an Unexpected Case of Decompensated Heart Failure.”


Dr. Carolyn Lam:


Interesting. There's an exchange of letters between Doctors
Matrougui and Wang regarding the article, “Integrated Stress
Response Couples Mitochondrial Protein Translation with Oxidative
Stress Control” and a Perspective piece by Dr. Fatkin on “Fishing
for Links between Omega-3 Fatty Acids and Atrial Fibrillation.”
Wow. Super cool. Greg, let's go on now to a feature discussion,
shall we?


Dr. Greg Hundley:


You bet.


Dr. Carolyn Lam:


For our feature discussion today, we are talking about white
matter hyperintensities. Now that's the most common brain imaging
marker of small vessel disease. That may be known, but there's a
lot more to it. For example, what are they made of? Well, you're
going to so enjoy today's feature paper, and I'm so proud to have
the corresponding author with us, Dr. Zdenka Pausova from
Hospital for Sick Kids in Toronto, Canada, as well as our
associate editor, Dr. Svati Shah from Duke University. So welcome
ladies. And Zdenka, if I could start with, could you explain the
rationale for your study and what you did?


 


Dr. Zdenka Pausova:


Yeah. Thank you. Thank you for having me. Well, we were thinking
that it is important to know what the metabolic variables that
associate with white matter hyperintensities might be, simply
because we know that there are other studies that have shown that
whatever circulates in blood is in some way related to brain
health. For example, different lipids associated with Alzheimer
Disease, cognitive functioning and with structural properties of
the brain. So we were wondering what the metabolics that are
associated with white matter hyperintensities might be, simply
because we would like to know a little bit more about the
pathogenesis of the disease, because that's what metabolomic
profiling can provide. And also if one can identify biomarkers
that potentially could be used in the clinical setting.


Dr. Carolyn Lam:


Wow. Thank you. And Zdenka, this may be a very basic question,
but we hear a lot about the metabolome and sometimes it's not
very clear what metabolome profiling actually is. And could you
just say a little bit about the technique and your study
population and then your findings? Thanks.


Dr. Zdenka Pausova:


Yes. Sure. So we actually studied over 9,000 individuals from
eight different population based studies and all of those
individuals had metabolomic assays done with two main platforms.
It's mass spectrometry and nuclear magnetic spectroscopy. Mostly
these platforms are actually commercially available and
altogether across all platforms, there were over 2,200 different
metabolites. And from those we could study about 1200 that we had
at least in two populations. And what the metabolites are, these
are different metabolites of lipids, sugar, proteins, amino acids
that people put on those platforms or that designers put on the
platforms, in order to test some of their hypotheses, that they
were actually these metabolites of interest for different sorts
of diseases, including cardiovascular and cerebrovascular
disease.


Dr. Carolyn Lam:


Wow. So this is really large scale, massive, big data, if I may,
and if I'm not wrong, it's the first large scale study to
identify circulating metabolomic measures associated with white
matter hyperintensities. So could you please summarize the main
findings?


Dr. Zdenka Pausova:


Well, overall we actually found that there were 416 metabolites
that were nominally associated with white matter
hyperintensities, but as it is in epidemiology, you have to
correct for multiple comparisons. So when we did DR correction,
there were only 30 variables associated with white matter
hyperintensities. And when we wanted to check whether those
associations are independent of the risk factors for white matter
hyperintensities, such as hypertension, type two diabetes,
smoking, obesity, we actually ended up with seven markers, seven
metabolites that were significantly associated in the fully
adjust model.


Dr. Zdenka Pausova:


And the main one was actually a derivative of amino acid
hydroxyphenol that probably is a marker of ischemia in the brain.
And what actually I am coming to is, and one of the main findings
was, that many of those metabolites were associated with white
matter hyperintensities in a sex specific manner. That is that
they were detected in the pool sample, but essentially the signal
came from only one of the sexes. And so this one that was the
most significant was detected only in males essentially, and not
really in females.


Dr. Zdenka Pausova:


And that I think is an interesting, one of the most interesting
findings that we can expect that there are really sex specific
pathways, biochemical pathways, that accompany white matter
hyperintensities.


Dr. Carolyn Lam:


Wow. Zdenka, thank you so much. I have to bring Svati in right
now to share some perspective, Svati, especially to put these
findings into context, please.


Dr. Svati Shah:


Yes. Dr. Pausova, really wonderful paper. This is an incredible
study, if you think about it. The largest scale study that really
is trying to understand metabolic by biomarkers, but the
biomarkers actually tell us about the potential biology of what's
going on with these white matter hyperintensities. We know that
these hyperintensities in the brain are associated with increased
risk of stroke, increased risk of cognitive decline, but we don't
really understand stand what the risk factors are. There's been
some studies suggesting that there's genetic risk factors, but
this is really the first large scale study to say, "Hey, what's
in the blood that we can measure?" And just to be clear, these
technologies are measuring these biomarkers that are very, very,
very low levels in the blood, really granular snapshot of what's
going on with the human being.


Dr. Svati Shah:


And by looking at these blood markers that the authors were able
to find biomarkers that are associated with these brain
abnormalities, but really highlighting some of the important
biology as Dr. Pausova started to talk about. So I think what it
gets us to is we get to have our cake and eat it too. We get to
learn about biomarkers that might have clinical utility, but we
also have discovered, they've discovered new biology that could
lead to new therapies, for example, and a better understanding of
the mechanisms of why some people develop these hyperintensities
as they age. And some people do not.


Dr. Carolyn Lam:


Wow, Svati, you put that so eloquently and just to put it out
there for everyone, that significant metabolite hydroxyphenol
pyruvate explain 14% of the variants of white matter
hyperintensity volumes in males. Whereas, the proportion of
variants explained by hypertension is only 1% or type two
diabetes is only 1 to 3%, or smoking is even less than 0.1%. So
this is, as you said, Svati, it's a significant discovery as
well. Zdenka, though, how do we apply this clinically?


Dr. Zdenka Pausova:


Well, it could be a marker that is measured in circulation and it
is a marker that can be measured in blood and can indicate early
stages of white matter hyperintensities. But I think before we
get there, it would be of high value to actually carry out some
longitudinal studies, because it would be really interesting to
know if it is an early marker before the white matter
hyperintensities extent is enlarged. And so that would one thing.
But other than that, I think if that would be the case, we can
just measure it in blood and see how predictable it is.


Dr. Carolyn Lam:


Can I ask what about the women? Did anything predict it in women?


Dr. Zdenka Pausova:


That's a good question. There was only actually one variable. To
our surprise, only one variable that was significantly associated
with white matter hyperintensities in women. And it is really
surprising because the sample size was the same. The extent, the
volume of white matter hyperintensities was quite similar. They
were of similar age, similar adiposity. So there were no huge
differences, yet we could not actually detect too many
metabolized associated with white matter hyperintensities in
women. Really surprising. And I don't have a good answer for it
now.


Dr. Carolyn Lam:


Wow. Thank you. Svati, did you have further thoughts on the
clinical applications and implications of these tremendous data?


Dr. Svati Shah:


Yeah. I think the ability to have a biomarker as Dr. Pausova
nicely articulated that would potentially prevent people from
having to get an MRI. And we would be able to identify people
hopefully at an earlier stage in the process. In this lovely
study, they were looking at biomarkers in people who already had
the hyperintensities. I think the next step as Dr. Pausova
outlined to be able to identify whether these predict high risk
people who will develop them in the future and then try to target
therapies. A potential advance in precision medicine in the
neurologic space, that we could use this biomarker to say, "You
need this particular medication."


Dr. Svati Shah:


Some of the biomarkers that Dr. Pausova's group discovered were
actually just cholesterol measures. So maybe we need to be
instituting more aggressive cholesterol therapies in these
patients who are at high risk. I'm not saying we can do that yet,
but these provocative results suggest that this could lead to a
more personalized approach to high risk individuals who may have
consequences and develop these white matter hyperintensities.


Dr. Carolyn Lam:


And Zdenka, did you have anything to add to that?


Dr. Zdenka Pausova:


Perhaps one interesting aspect of the study that I actually was
nicely surprised at the end of the study that the markers, one
could the different lipids or the different derivatives of amino
acids, the literature provided actually a possible pathways, how
those could be involved in the development of white matter
hyperintensities. Some of them actually, we could possibly link
to impairment of myelination of a neuronal axons, or actually the
axons themselves could be the metabolized could reflect damage of
those axons.


 


 


Dr. Zdenka Pausova:


And also, one suspicious pathway or one pathway that is suspected
to be big part of the development of white matter
hyperintensities is the disruption of blood brain barrier and
some of the markers could be actually linked to that vascular
dysfunction.


Dr. Carolyn Lam:


Aw, that's wonderful. Thank you so much, Zdenka, for publishing
this beautiful work with us in Circulation. And thank you, Svati,
for taking this paper through and inviting this beautiful
editorial. In fact, it quite summarizes our discussion. It's
entitled, What Turns White Matter White? Metabolic Clues to the
Origin of Age-Related White Matter Hyperintensities and it's by
Dr. Eric Smith from University of Calgary and I invite everyone
to read this.


Dr. Carolyn Lam:


So thank you once again for joining us today on Circulation on
the Run. From Greg and I, it's been wonderful having you. Don't
forget to join us again next week.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2022.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.