Circulation May 18, 2021 Issue

This week, please join author Uwe Tietge and Associate Editor
Anand Rohatgi as they discuss the article "High-Density
Lipoprotein Anti-Inflammatory Capacity and Incident
Cardiovascular Events"
(https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050808)


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:


And I'm Dr. Greg Hundley, associate editor, director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Well,
Carolyn, we've got a very interesting feature this week. It
involves another paper in the line of the story of HDL, and
looking at HDL and future cardiovascular events. But before we
get to that, how about we grab a cup of coffee and jump in and
review the other articles and the issue? And Carolyn, this week,
maybe I'll go first.


Dr. Carolyn Lam:


Go, I've got my coffee.


Dr. Greg Hundley:


Very good. So Carolyn, this paper comes to us from Dr. Huso
Hakala, from the University of Turku at Turku University
Hospital, and the study pertains to cognition and cardiovascular
disease. So Carolyn, as you know, cardiovascular risk factors
such as high blood pressure, adverse serum lipids, and elevated
body mass index, and midlife may harm cognitive performance. So
importantly, perhaps the presence of cardiovascular risk factors
since childhood, Carolyn, may impact cognition later in life. So
these authors studied the associations of the cardiovascular risk
factors from childhood to midlife, their accumulation and midlife
cognitive performance. They gathered their data beginning in 1980
from a population-based cohort of 3,596 children who are aged
three to 18 years that were repeatedly followed up for 31 years,
and they assess blood pressure, serum lipids, body mass index,
all in the follow-ups.


Dr. Carolyn Lam:


Wow. So accumulating risk, I suppose, Greg. So what did they
find?


Dr. Greg Hundley:


Great. Carolyn, glad you asked. So consistently high systolic
blood pressure or serum total cholesterol associated with worse
midlife episodic memory and associated learning, compared to
situations when blood pressure or cholesterol values were low.
Obesity since childhood associated with worse visual processing
and sustained attention compared to individuals or children that
had normal weight. And an inverse trend association was observed
for the cardiovascular risk factor accumulation with episodic
memory and associated learning with visual processing and
sustained attention and with reaction and movement time. So the
take home Carolyn, is that, maybe we should be launching
preventative strategies against some of these cardiovascular risk
factors beginning in childhood, because perhaps they could
benefit primordial promotion of cognitive health for those later
in adulthood, maybe like you and me.


Dr. Carolyn Lam:


Oh, wow. Thinking back on my blood pressure, cholesterol and
weight, I suppose, since childhood, yikes. Well, the next paper
Greg is an important analysis from DAPA-HF. Now as a reminder in
the DAPA-HF trial, the sodium glucose co-transporter two
inhibitor dapagliflozin was shown to reduce the risk of
cardiovascular death and a first episode of worsening heart
failure, in patients with heart failure with reduced ejection
fraction or HFpEF. In the current paper from Drs. Jhund and
colleagues from University of Glasgow, they described the
efficacy of dapagliflozin on the predefined secondary end point
of total heart failure hospitalizations. That's the first and
recurrent heart failure hospitalization and cardiovascular death.
And this is so important because we know that patients with HFrEF
are known to experience multiple episodes of heart failure during
the course of the disease.


Dr. Greg Hundley:


So Carolyn, what did they find?


Dr. Carolyn Lam:


Well, they did this analysis by two methods in the first, which
was the Lin, Wei, Ying and Yang or LWYY model the rate ratio for
the effect dapagliflozin on recurrent heart failure,
hospitalizations or cardiovascular death was 0.75.


Dr. Carolyn Lam:


And the second method, a joint frailty model, the rate ratio for
total heart failure hospitalizations was 0.71 while for
cardiovascular death, the hazard ratio was 0.81. The factors
associated with more hospitalizations were, being a men, having a
higher heart rate, NT-proBNP, New York Heart Association class
type 2 diabetes, and a longer duration of heart failure with less
hospitalization in those with higher systolic blood pressure and
higher ejection fraction. So in summary, dapagliflozin in reduced
the risk of total heart failure, hospitalizations and
cardiovascular death. In fact, if you compare it to the time to
first analysis, you can see that, that actually underestimated
the benefit of dapagliflozin in HFpEF.


Dr. Greg Hundley:


Very nice Carolyn, well, my next paper comes to us from the world
of basic science. And so Carolyn, neonatal mouse cardiomyocytes
undergo a metabolic switch from glycolysis to oxidative
phosphorylation, which results in a significant increase in
reactive oxygen species production that induces DNA damage. These
cellular changes contribute to cardiomyocytes cell cycle exit and
loss of the capacity for cardiac regeneration. Now the mechanisms
that regulate this metabolic switch and the increase in reactive
oxygen species production have been relatively unexplored.


Dr. Carolyn Lam:


Okay, Greg. So what did this current paper find?


Dr. Greg Hundley:


Right, Carolyn, so Dr. Ahmed Mahmoud from University of
Wisconsin-Madison, they found that malonate, a competitive
inhibitor of succinate dehydrogenase, promotes adult
cardiomyocyte proliferation, revascularization of the infarct
zone and myocardial regeneration following infarction. They also
found that SDH inhibition by malonate is consistent with a
metabolic shift from oxidative phosphorylation to glucose
metabolism in the adult heart. So Carolyn, the clinical
implications include the observation that transient inhibition of
SDH may represent an important metabolic target to promote adult
heart regeneration, following myocardial infarction.


Dr. Carolyn Lam:


Cool. Thanks Greg. Well, I've got another basic science paper.
Let me try to tell you about la ribonucleoprotein domain family
member seven. And I'm going to call that LARP7. Again, it's la
ribonucleoprotein domain family members seven. Now LARP7 is a
master regulator that governs the DNA damage response. The
authors today, Dr. Zhang, from Xin Hua Hospital and Shanghai Jiao
Tong University and colleagues aim to study its role in heart
failure, pathogenesis by assessing LARP7 expression in human
heart failure and in non-human primate and mouse heart failure
models.


Dr. Greg Hundley:


Great, Carolyn. So what did they find?


Dr. Carolyn Lam:


LARP7 was essential for mitochondrial biogenesis energy
production and cardiac function by modulating silent mating type
information regulation to homolog-1, which is cert one, cert one
homeostasis and activity. Now, reduction in LARP7 and diseased
hearts due to activation of ataxia-telangiectasia mutated protein
pathway contributed to the heart failure pathogenesis and
conversely restoring LARP7 in the injured heart conferred
myocardial protection. So in some, these results identified that
this LARP pathway is a target or rather is a potential target for
therapeutic intervention in heart failure.


Dr. Greg Hundley:


Great, Carolyn. One of the things I love about our journal is
really the translational basic science that really could have
future implications for how we manage patients with
cardiovascular disease. So I, to follow, have another basic
science article, and it comes to us from Dr. Florian Weinberger
from the University Medical Center in Hamburg-Eppendorf. So
Carolyn, human engineered heart tissue transplantation represents
a potential regenerative strategy for our heart failure patients
and has been successful in preclinical models. Clinical
application requires upscaling, adaptation to good manufacturing
practices and determination of the effective dose. So these
authors performed studies in which cardiomyocytes were
differentiated from three different human induced pluripotent
STEM cell lines, including one reprogrammed under these GMP
conditions. Protocols for human induced pluripotent STEM cell
expansion, cardiomyocyte differentiation and engineered heart
tissue generation were adapted to substances available in good
manufacturing process quality. Engineered heart tissue geometry
was modified and repair efficacy was evaluated at three doses in
a cryo-injury Guinea pig model, human scale patches were
epicardialy transplanted onto healthy hearts in pigs to assess
the technical feasibility of this entire process.


Dr. Carolyn Lam:


Wow. And what did they find?


Dr. Greg Hundley:


Right, Carolyn? I mean, this is just so exciting, the
practicality of how you implement some of these new strategies
that we work on in the lab. So Carolyn, they found that human
engineered heart tissue patch transplantation resulted in a
partial re-muscularization of the injured heart and improved left
ventricular function in a dose dependent manner in a Guinea pig
injury model and human scale patches were successfully
transplanted in pigs in a proof of principle study. So an
exciting new front for engineered cardiac tissue transplantation.
I mean, this is a really exciting article.


Dr. Carolyn Lam:


Wow, well, indeed. Thanks, Greg. Well, other than those wonderful
papers in today's issue, we have an exchange of letters between
Drs. Morgan and Lopes regarding initial invasive versus
conservative management of stable ischemic heart disease patients
with a history of heart failure of left ventricular dysfunction
and that's insights from the ischemia trial. Tracy Hampton does
her wonderful review from the literature and it covers new
research published in nature medicine, which indicates the impact
of a Mediterranean diet on cardio-metabolic disease risks, which
may be affected by an individual's gut microbes and goes all the
way to network correcting therapeutic candidate for heart valve
disease, which was published in science and even a newly
discovered genetic arrhythmia syndrome, which was described in
science translational medicine. That's a perspective piece by Dr.
Kuwabara on the Japanese national plan for promotion of measures
against cerebral vascular and cardiovascular disease.


Dr. Greg Hundley:


Great, Carolyn. Well, you've heard of mission accomplished. Well,
Dr. Brooke has an On My Mind piece entitled mission
unaccomplished, the optimal hyper, any hypertensive therapy. And
then finally, Dr. Glembotski has a Research Letter entitled
optimizing AAV9 for studies of cardiac chamber specific gene
regulation. Well, Carolyn, what a great issue and integrating all
the wonderful world of basic science in a translational fashion.
Now, how about we get on and move toward our feature discussion?


Dr. Carolyn Lam:


Yep. HDL, here we come.


Dr. Greg Hundley:


Well, listeners, we are onto our feature discussion today and
we're very excited to have with us today, professor Uwe Tietge
from Stockholm, Sweden, and our own associate editor Anand
Rohatgi from UT Southwestern. Welcome gentlemen. And Uwe, could
you describe for us the hypothesis that you wanted to test and
tell us a little bit about your study design?


Dr. Uwe Tietge


Okay. So thank you very much for inviting me and for having the
opportunity to discuss this article with you today. So we've been
for a long time interested in HDL function, and we have developed
an HDL anti-inflammatory see, and we have tested it in some
cross-sectional studies. And we have seen in this cross-sectional
work, for example, in the acute mi or diabetes, are associated
with significant reductions in HDL anti-inflammatory function. So
we felt that the next important step would be to study this
prospectively in the general population. So this is why we made
use of the prevent cohort, which is a prospective general
population study with white participants from Groningen, which is
a city in the North of the Netherlands. Prevent stands for
prevention of menial and stage disease, and prevent has a total
number of participants of 8,592.


Dr. Uwe Tietge


So we first excluded all that had already experienced mi
intrusion. And then we took all subjects, was the first
cardiovascular disease events during follow up and matched
controls for sex, age, smoking, and importantly also for HDL
cholesterol levels. And we felt that such a design would allow us
to truly identify changes in HDL function, independent of HDL
cholesterol levels. So then finally we ended up with 340 match
case control pairs.


Dr. Greg Hundley:


Uwe, sounds like a very interesting hypothesis. So what was your
methodology and how did you perform your analysis? And then also
describe for us, what did you find?


Dr. Uwe Tietge


The key method that we used was our essay determining the atrial
anti-inflammatory capacity and the main outcome measured was
incident cardiovascular disease. And in our case, that was deaths
from cardiovascular disease, hospitalization from mi, PDCA,
ischemic heart disease, or CABG. We did not have stroke in our
study. So with respect to HDL function, we isolate HDL by means
of PEG precipitation. And this is an established method that is
widely used in larger cohort studies. We then take a primary
industry that cells, humans, and we pre incubate them for 30
minutes with the individual engineer preparations. Then the
agents removed and TNF alpha is added for another five hours. And
after these five hours, we isolate RNA and determine BK1 and mRNA
levels by quantitative real time PCR. Then we calculate the
results relative to the [inaudible 00:16:09] or without the edit
HDL. So when the empties data, we use statistical analysis to
determine the perspective association in, based on HDL
anti-inflammatory function and the outcome measure incident CVD.


Dr. Uwe Tietge


So to summarize the main findings of the study. So first of all,
the anti inflammatory activity of HDL baselines intrusion in this
study was significantly higher in controls than in cases. Next,
the HDL anti-inflammatory activity was not correlated with any
other CBD related biomarkers. Importantly also know it was HDL
cholesterol at 8.1, but also not, for example, with
triglycerides, or isolated CRP, and also not with [inaudible
00:16:58] capacity, which is another function metric of HDL.


Dr. Uwe Tietge


The further finding was that in conditional logistic regression
analysis, we found that baseline HDL anti-inflammatory activity
was significantly associated with future CV events, even in a
fully adjusted model. Then finally, when we were adding this
function of HDL to the premium, this form, or when we were
replacing anti-inflammatory capacity in the score that improved
risk prediction and interestingly adding cholesterol reflux and
other HDL function, as said before, resulted in a further
improvement.


Dr. Uwe Tietge


So the general conclusion was that of the HDL functional measures
in the case of our actual study, this is the HDL
anti-inflammatory activity has the potential to provide clinic
information independent of conventional use biomark.


Dr. Greg Hundley:


Very nice who made. So we always think of HDL is the good
cholesterol. And sounds like you're describing a whole nother
process by which HDL could be beneficial. Well, Anand turning to
you now. I know you see many papers come across your desk. What
drew your attention to this particular manuscript and how does
this new HDL anti-inflammatory capacity or activity impact the
remaining science that we have that focuses on other beneficial
effects of HDL?


Dr. Anand Rohatgi:


Thank you, Greg. And I would like to first start by thanking Dr.
Tika to submitting his article to circulation and thinking about
us for his studies. I will say when this came across my desk, I
became extremely excited as HDL function is an area that is near
and dear to my heart as well. And Dr. Tika is an international
expert in this area. So we are quite excited. The reason why this
really picked our attention at circulation is that this was
really the first and large demonstration that this novel marker
on anti-inflammatory capacity was linked to the incidents of
cardiovascular events, so that it wasn't just the range and
people who already had disease, but at baseline, in people who
are otherwise healthy, it could predict those who would go on to
be at higher risk of atherosclerotic events. So in this case,
what we saw was a truly unique and novel cardiovascular marker.


Dr. Anand Rohatgi:


It was a significant translational study working in effort on the
part of Dr. Tika and his research team to be able to do this, and
so many participants, this is not an easy undertaking. So to be
able to do this and show the results that they were able to show
is really remarkable, which is really why it elevated to our
interest at circulation. A couple of things in terms of the
implications in science are that when they recorded this study,
they intriguinly we found that there were really no other
stablished risk factors, cholesterol levels, or other markers
that are associated with this novel anti-inflammatory capacity,
it really wasn't associated with high sensitivity CRP, a global
marker of inflammation. And it wasn't associated with the only
other HDL function that had been shown to be linked to
cardiovascular events, cholesterol influx.


Dr. Anand Rohatgi:


So really what we have here is a truly novel marker that stands
on its own. And it's not confounded by the usual things of
obesity or other cardiovascular risk factors, and is clearly
imparting different information than a global marker, like CRP.
I'll extend that these observations to one or two concepts, when
it comes to inflammation, there are a couple of things to think
about. One is the timing of the inflammatory cascade. A lot of
markers are studied at the time where people are in an acute
disease state and pro-inflammatory already, and so that can
actually have an effect itself on the markers. In this case, by
self-report, the participants did not have any acute illness. And
so the relationship we see here between anti-inflammatory
capacity and cardiovascular events is presumably in the context
of a healthy, low inflammatory state. So I think that's
important. The other thing that's important, I think for our
audience to know is that the inflammation can have tissue
specific effects.


Dr. Anand Rohatgi:


So when you think of global markers like CRP or interleukin 6,
those are flagged systemic levels of inflammation in your body,
and they are also predictive. But when it comes to
atherosclerosis, we think about specific tissue types, the
endothelium, macrophages, dipocytes. And in this case, what this
marker represents is specific activity at the level of the
endothelium, which is a key player in the atherosclerotic
process. So it really gives us new and novel insights into that
process. And it highlights the potential to find maybe
therapeutic targets that can be more precise in targeting the
atherosclerotic process and improving outcomes. So those were
some of the main things that we saw that were exciting.


Dr. Greg Hundley:


Very nice. Uwe, as an international expert. What do you see as
the next study that needs to be performed that will perhaps use
this new market?


Dr. Uwe Tietge


I think what we need here first would be validation in another
cohort and ideally a cohort that involves different ethnicities
because our participants were predominantly white. So in terms of
generalization, I think this is the next step that we would need.
In terms of making this essay applicable to clinical settings in
the daily routine, so to speak, we need to simplify it. And this
is another issue that we are currently working on, trying to have
an easier essay that gives us quicker readouts and ideally, maybe
not using primary industry, but something that is better
standardizable. And I mean, when you think about next steps, then
also identification of a certain biomarker, comes to mind. So
something that would reflect the dimension, the activity
component of the age that reflects its functioning. And can be
used in daily routine and is applicable. It lies to take all the
types of essays.


Dr. Greg Hundley:


Very good. Anand, do you have anything to add to that?


Dr. Anand Rohatgi:


Well, I agree completely. I think when you always see a novel
marker, you want replication and validation, and I think
extending this to other nonwhite cohorts is important. The
prevent cohort with 70% men, and also add average out there were
probably higher than contemporary populations, at least in the
United States. So it'd be nice to see an extension of these
observations and cohorts that reflect that diversity.
Interestingly, cholesterol wheat blocks the other HDL functions
that's been associated with events is not linked through vascular
events, it's mostly linked to coronary events. So it would be
really interesting to find out how the anti-inflammatory capacity
relates to events related to other vascular beds outside of the
coronary tree. And then I guess a question that I had for
professor Tika is, do you think there might be certain groups of
people either by disease or demographic that this might be more
powerful formative? Or do you think you would have the same kind
of information across the board?


Dr. Uwe Tietge


Yeah, that's a relevant question of course. When we divided our
population by participant level characteristics, we saw that
there are sex differences. So the predictive capacity seems to be
a bit better in females are significantly better than females,
which is in male. And also in participants with lower BMI, with
ahigher BMI. And the third parameter was in participants with was
lower for this one was higher this month. So yes, I expect that
some parameters can play a role here and it would be very wise to
explore these connections.


Dr. Greg Hundley:


Very good. Well listeners, what an excellent discussion. And we
want to thank Dr. Uwe Tika and his team from Stockholm, Sweden,
and also our associate editor, Dr. Anand Rohatgi for bringing to
us this new research regarding this marker of anti-inflammatory
capacity involving HDL, that demonstrates an inverse association
with cardiovascular events.


Dr. Greg Hundley:


On behalf of both Carolyn and myself. We want to wish you a great
week and we will catch you next week on the run.


Dr. Greg Hundley:


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