Circulation April 20, 2021 Issue

For this week's Feature Discussion, please join author Marco
Vinceti and Associate Editor Wanpen Vongpatanasin as they discuss
the article "Blood Pressure Effects of Sodium Reduction:
Dose-Response Meta-Analysis of Experimental Studies."


TRANSCRIPT BELOW:


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
co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


I'm Dr. Greg Hundley, co-host and Associates Editor, Director of
the Pauley Heart Center, Richmond, Virginia, VCU Health


Dr. Carolyn Lam:


Dr. Greg, today's feature paper, super, super exciting. Everyone
has to listen to it because it's about blood pressure and sodium
intake. But you think you've heard it all? You haven't. You have
to listen to this feature discussion, and I'm sure you'll learn a
lot, just like I did. Seriously. But before that you got your
copy, I got mine. Let me tell you all about microRNA. Shall I?


Dr. Greg Hundley:


Absolutely.


Dr. Carolyn Lam:


MicroRNA, we know, have a remarkable influence on the physiology
of the heart and the remodeling of diseased hearts through
canonical RNA interference mechanisms. Now, the authors of
today's paper, co-corresponding authors, Dr. Fu and Deschênes
from Ohio State University in Columbus, Ohio, investigated if
microRNA one or mir-1 specifically binds with cardiac plasma
membrane proteins, and they revealed an evolutionarily-conserved
direct binding between this mir-1 and an inward rectifier
potassium channel called cure 2.1. Now, this is endogenously
existing in cardiomyocytes.


Dr. Carolyn Lam:


Now, the authors then used inside out and wholesale patch clamp
recordings to show the biophysical modulation of cardiac
electrophysiology by mir-1. They further studied the mechanism of
this physical interaction and investigated its pathophysiologic
relevance by using mir-1 deficient transgenic mice. In total,
their study demonstrated a novel mechanism of microRNA ion
channel biophysical modulation that regulates cardiac arrhythmia
risk.


Dr. Greg Hundley:


Wow, Carolyn really sophisticated work involving the
pathophysiology of some of these arrhythmias. What are the take
home message?


Dr. Carolyn Lam:


Ah, I'm glad you asked. Let me circle back to what I said
earlier. Cardiac electrophysiology is regulated by microRNAs. We
knew about the canonical RNA interference mechanisms, but that
needs hours to days to regulate gene expression. But now we have
the newly discovered biophysical mechanism that quickly, and that
is within seconds or minutes, modulates the function of the ion
channels. These microRNAs could prevent or trigger arrhythmias
through biophysical modulation of the ion channels, even before
its RNA interference regulation of protein expression occurs in
diseased hearts.


Dr. Greg Hundley:


Wow, Carolyn. Really interesting new basic science. Such an asset
for our journal. Well, I'm going to switch and talk a little bit
about really, really high coronary artery calcium scores,
something that sometimes we see. The work comes from Dr. Michael
Blaha from Johns Hopkins University in Baltimore, Maryland.
Carolyn, as you know, there are limited data on the unique
cardiovascular disease and non-cardiovascular disease and
mortality risk of primary prevention individuals with very high
coronary artery calcium scores. What do we mean by very high?
These are scores greater than or equal to a thousand. That's
especially true in comparison to rates observed in secondary
prevention populations. In this study, the investigators compared
the hazard ratios for coronary artery calcium scores greater than
a thousand in comparison with calcium scores of zero, those from
400 to 999, and they looked at this for those with cardiovascular
disease, non-cardiovascular disease, and also evaluated mortality
outcomes.


Dr. Carolyn Lam:


Oh, wow. That's interesting and those are very high coronary
artery calcium score. What did they find?


Dr. Greg Hundley:


Thanks, Carolyn. After full adjustment, coronary artery calcium
scores greater than or equal to a thousand demonstrated a 4.7 to
a seven and a half increase in the hazard ratio for outcomes
compared to individuals with calcium scores of zero, a 1.6 to 1.3
four-fold increase compared to those with calcium scores in the
400 to 999 range. Carolyn, with increasing coronary artery
calcium scores, the hazard ratios increased for all event types
with no apparent upper coronary artery calcium threshold. For
example, a coronary artery calcium of a thousand correspond to an
annualized 3-point MACE rate of 3.4 per a hundred person years
and that's similar to that of a for EA population of 3.3 and
higher than lower risk for EA subgroups.


Dr. Greg Hundley:


Carolyn, these results raise the thought that as we're thinking
and putting together future guideline statements, should we
consider a less distinct stratification algorithm between primary
and secondary prevention patients for these very high coronary
calcium scores? The high scores in the primary prevention group
for this study really mirrored those four EA scores that you see
in patients that are undergoing secondary prevention. They've
already had a heart attack. Should we start thinking about for
these very high scores, really aggressive preventive
pharmacotherapy, just like we would in a patient that was
undergoing secondary prevention?


Dr. Carolyn Lam:


I like that explanation. Thanks, Greg. Well, this next one really
speaks to my favorite topic, sex differences in cardiovascular
physiology and disease outcomes. Greg, here's the quiz question.
Do you think progesterone receptors in cardiac cells play a role
in determining the difference between you and me?
Co-corresponding authors Dr. Porrello from Murdoch Children's
Research Institute in Melbourne, Australia and Dr. Hudson from
the Berghofer Medical Research Institute in Brisbane, Australia,
and their colleagues, hey performed single nucleus RNA sequencing
to capture transcriptional changes across multiple cardiac cell
populations during the human heart development from fetal stages
to adulthood. Their data revealed six specific transcriptional
mechanisms governing maturation of multiple cell types in the
heart, including a previously unrecognized role for the
progesterone receptor in human cardiomyocyte maturation. These
data really provide a blueprint for understanding human heart
maturation in both sexes and reveal an important role for the
progesterone receptor in human heart development.


Dr. Greg Hundley:


Oh, great, Carolyn. Very nice. Well, Carolyn, my next paper
really involves an assessment of air pollution. As you know, many
of the studies today have really focused on short-term exposures
to air pollution. But this group headed by Dr. Yazdi at the
Harvard T.H. Chan School of Public Health began to evaluate
long-term or chronic exposure to air pollution. Carolyn, the
study examined the relationship between the long-term exposure to
find particulate matter with an aerodynamic diameter of less than
2.5. micrometers also from nitrogen dioxide and from ozone, and
they evaluated all three of those relative to hospital admissions
for four cardiovascular and respiratory outcomes: myocardial
infarction, ischemic stroke, the development of atrial
fibrillation or flutter, and the development of pneumonia. They
looked at this in the Medicare population within the United
States.


Dr. Carolyn Lam:


Hmm, interesting. What did they find?


Dr. Greg Hundley:


Okay, Carolyn, so a couple things. First, long-term exposure to
that fine particulate matter was associated with an increased
risk of all outcomes with the highest effect seen for those that
incurred a stroke. The findings translated to 2,536 cases of
hospital admissions with ischemic stroke per year, which can be
attributed to each one unit increase in fine particulate matter
levels among the study population. Also, the nitrogen dioxide was
associated with an increase in the risk of admission for stroke
and atrial fibrillation. Then, the ozone was associated with an
increase in the risk of an emission for a pneumonia.


Dr. Greg Hundley:


Carolyn, what this study showed, at lower concentrations, a
chronic exposure, long over time of all these pollutants, were
consistently associated with an increased risk for all of the
study-related cardiovascular and cardiopulmonary studied
outcomes. New important information regarding long-term as
opposed to short-term exposure of these pollutants.


Dr. Carolyn Lam:


Yikes, yikes. Important to pay attention to. Thanks, Greg. Let me
now go to the other articles in today's issue. There is a
beautiful Perspective piece by Dr. Shah titled Transcatheter
Closure of the Patent Foramen Ovale: Not Always an Open or Shut
Case. There is a Research Letter by Dr. Davis on engrafted human
induced pluripotent stem cell derived cardiomyocytes undergoing
clonal expansion in vivo.


Dr. Greg Hundley:


Great, Carolyn. I've got two publications to discuss. First, Dr.
Ransom has an EKG challenge entitled Palpitations in the Clinic.
Then, finally, our own editor in chief, Dr. Joe Hill has a
wonderful in memoriam to Dr. Jim Willerson, a prior
editor-in-chief of circulation, and really a guiding light for
many of us in cardiovascular diseases for much of his life. Well,
Carolyn, on that note, how about we now transfer to that feature
discussion and learn a little bit more about sodium intake and
high blood pressure.


Dr. Carolyn Lam:


Let's go, Greg.


Dr. Carolyn Lam:


Now, most of us would agree that dietary sodium has a role in the
modulation of blood pressure levels. That we've agreed on.
However, we still debate over the magnitude of the effect, who it
applies to, and the importance of sodium-driven blood pressure
changes for global disease burden. Well, today's feature paper
does a lot to address many of the remaining questions that are
revolving around sodium intake and blood pressure. I'm so pleased
to have with us the corresponding author of the feature paper,
Dr. Marco Vinceti from University of Modena and Reggio Emilia in
Italy, as well as our associate editor, Dr. Wanpen Vongpatanasin
from UT Southwestern. Welcome both. Marco, if I may and begin
with you, please, could you tell us the inspiration for your
study and what you did?


Dr. Marco Vinceti:


Thank you by the way, for inviting me and good morning to
everybody. Our inspiration was being aware that as you already
say, there may be an association, there is an association between
sodium intake and blood pressure, but that maybe not all the
details about such relation are being explored and carefully
investigated, also for the lack of adequate statistical tools.
Also, because we know that health endpoints and exposures, both
dietary and environmental factors, I mean, may have a relation
that is not linear, that is, just has some kind of different
shape, U-shaped curve, J-shaped curve, and so on. Our thought was
to investigate better this relation between sodium intake and
blood pressure, even in a category of people which is wide. Also,
there isn't such a large consensus about the relation; that is,
people without high blood pressure and to shape that association
using new statistical tools in non-linear fashion, if
appropriate.


Dr. Carolyn Lam:


Very nice. Could you tell us what was special about your study
design? Because it is true that the methodology you used was very
unique and then perhaps the top line of what you found.


Dr. Marco Vinceti:


We took advantage of from a recent, let's say, discovery. I don't
know if the term is correct, but we consider it like a discovery,
of a colleague of ours at the Karolinska Institute of Stockholm.
He is a statistician named Nicola Orsini. He published it in
2019. A new tool, a new approach, call it a one stage dose
response meta-analysis that is able to shape the relation between
exposures, in this case, sodium intake, and health endpoints or
outcomes. We're talking here of continuous endpoint such as blood
pressure. We can maybe talk about an outcome, almost outcome
hypertension, even in the whole range of exposure from very low
intake up to a high intake.


Dr. Marco Vinceti:


Until recently the only meta-analysis that you could perform was
just comparing high versus low sodium intake across trials or
observational studies. But in each trial, the high exposure
category is different from another trial so you are comparing
across trials categories that are not the same categories, are
not corresponding each other. This is a major limitation. So far,
there are no publication able to shape the entire range of
exposure, the result of experimental studies. For experimental
studies, I mean the gold standard in medical research, in human
medicine that are randomized controlled trials.


Dr. Carolyn Lam:


I love that. That is really spot on, I think, of what makes your
meta-analysis so important. Could you maybe then now tell us
about the results?


Dr. Marco Vinceti:


Well, yes, the results, if I go back to one last detail about our
statistical approach, if I can add, in addition to what I said
before, we also wanted to use extensively what in 2016, the
American Statistical Association just declare it, that to avoid
the systematic use of p-values and statistical significant
testing, just a black and white approach or something which is
statistically significant or not statistically significant, and
to shape the relation in a smooth, in a different way, looking
graphically their religion and not having a dichotomous black and
white approach, exactly as recommended by the American
Statistical Association in it's very important statement in 2016.


Dr. Marco Vinceti:


About the results. I think that the main results were that the
relation was, unfortunately, I will say linear. Because we were
looking at non-linear association and that we tried in any way to
find out if there was some kind of non-linearity in the
association and I'm saving unfortunately only because we used a
tool that is suitable to test a non-linear association. But we
found evidence confirming here at previous meta-analysis and
previous studies that say that there is a linear association
between intake, that is exposure to sodium, and blood pressure.
But this association also holds for people without hypertension,
participant in these trials without high blood pressure. This put
there that this consensus is not exactly well established all
over the world; that there are investigators claiming that in
people without hypertension, there is no relation, particularly
for diastolic blood pressure and sodium intake. Our analysis
showed, in my opinion clearly, that such association exists also,
even if it is slightly weak, let's say in terms of strength
compared with people with hypertension, with at least a high
blood pressure.


Dr. Marco Vinceti:


There is an association for people with and without high blood
pressure for diastolic and systolic blood pressure, and it exists
across the entire range of usual exposure in the Western world.
Because we were talking about mainly Western population. Most
studies were carried out in Europe, in Australia and North
America. The large majority or the 85 trials, which is the
largest amount of trials ever analyzed in meta-analysis so far,
were carried out in Western population. In those populations, the
relation exists and is really detectable across the entire range
of association even at very low intakes.


Dr. Carolyn Lam:


Wow, thank you. Thank you so, so much, Marco. So indeed a large,
extremely well done meta-analysis, 85 trials, basically showing a
positive and approximately linear association between dietary
sodium consumption and blood pressure. Wow!


Dr. Carolyn Lam:


Wanpen, please. I mean, Marco is so just delightful in sort of
saying that we'd look really hard for that J and U shape that
everyone else talks about. We didn't find it, but that's exactly,
I think, why we editors found this paper so, so important.
Wanpen, I know you can express this better than me, so please.


Dr. Wanpen Vongpatanasin:


Sure. I agree. This is a very important study for the precision
in comparing different levels of sodium intake and what it means
for blood pressure. Also, I liked the paper that examine the
different cutoffs that for example, the paper has a project in
blood pressure that recommend by the American Heart at different
levels of 1,500 milligrams a day was just the usual American diet
about 3.5 grams a day, and in some subgroups even more. We can
get pretty good idea and what it's translate into a blood
pressure reduction.


Dr. Wanpen Vongpatanasin:


The thing that I particularly like is there's no threshold. I
think that's fascinating and I think that's really important. The
data, at least part of, I think, inertia in the public too, at
least for me as a physician, I saw many remarks saying, "Oh, if
it's part of the problem we had before, without these type of
techniques, we usually give a general blanket. Sodium
restriction, lower blood pressure by a few millimeters. Why do we
even bother? But here you can see a dose response relationship
without plateau. It really tells us that the more you eat, the
more you're going to get into this kind of problem. I think this
is really important and perhaps we'll push the certain population
that address and consume a lot of salt to rethink about it.


Dr. Carolyn Lam:


Wanpen that was just really, really nicely put. I know that Marco
was just nodding and appreciating as well. I know you had some
questions from Marco too. Would you like to ask them?


Dr. Wanpen Vongpatanasin:


Yes. Based on the information from your study, would you give a
recommendation a little bit differently, or how would you ...
you've changed your view in terms of preexisting guidelines from
European or from the United States?


Dr. Marco Vinceti:


I think that our results are really strengthening the most recent
guidelines from both the U.S. and in Europe. I'm talking about
the American Health Association guideline of limiting sodium
intake below or at least at 1.5 gram per day, about the national
recent sodium dietary allowance reference values of coming not
beyond the 2.3 gram, and the European Food Safety Authority it's
not just a recommendation, it's a risk assessment of indicating 2
gram per day the ideal intake of sodium. I would say the AHA was
absolutely right in pointing out the opportunity to reduce to 1.5
gram and even lower, I would say. It's not a general assessment
that we're one of the sodium and the Human Health Association.
It's not a general risk assessment of sodium, but we know that
hypertension, high blood pressure is a major, probably the major
driver of all cardiovascular diseases. In our opinion, keeping
this threshold, let's say, and even attempting to go below, we
know how difficult it is in public health. That is absolutely
correct.


Dr. Carolyn Lam:


I completely agree. That's the amazing public health message of
this very important paper. As you said, it supports the
guidelines, but it also suggests, I mean, should we just be
saying, go as low as you can? We don't see a threshold so that's
really, really fascinating.


Dr. Carolyn Lam:


Oh, may I ask maybe, cheekily, I recall, you mentioned Marco,
that you had a lot of press about this paper and the publication
and circulation. We would love to hear about that. Could you
share with the viewers?


Dr. Marco Vinceti:


I can tell you that this is not to use or to ask, to be able to
publish in such a top journal and you are not only the according
to Web of Science, number one journal in the world in the
cardiovascular community, let's say, but everybody. Even in the
journal of medicine. I mean, I'm a public health physician, and
anybody in my world, in Italy, and of course, not only Italy, I'm
talking about my country, well knows this journal and what is
publishing in such a journal is like some kind of an endorsement
of what you are telling.


Dr. Marco Vinceti:


We received a lot of attention not only in my medical school, in
my university, but also for the local press. From the national
press a lot of people call me and ask for interview and even from
the media. This is something that, particularly in this period of
what everybody, I'm a public health physician is talking about
COVID-19 and this is the emergency of course. Having the capacity
to look at usual traditional disease but so important, that
probably haven't received enough attention during the last
months, I think is very important because I hope we are not
forgetting that these are the major health issues, even in this
period that is so difficult for an effect of disease for the
COVID-19 outbreak.


Dr. Carolyn Lam:


Thank you so much Marco. I mean, I wish the whole audience could
see the smiles you have put on all of our faces. Really, the
credit all goes to you and your team for fantastic work done. We
are privileged to have published this very important paper in
circulation. And so thank you very, very much once again, to both
of you for being on the show and to the audience for listening in
today.


Dr. Carolyn Lam:


From Greg and I, you've been listening to Circulation on the Run.
Thank you for joining us today.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2021.