Circulation December 13, 2022 Issue

This week, please join author Trisha Singh as she
discusses her article "Manganese-Enhanced Magnetic Resonance
Imaging in Takotsubo Syndrome."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass for the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Nam, 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.


Carolyn, very interesting feature discussion this week. Many
times we hear in magnetic resonance imaging the use of gadolinium
contrast. And remember, gadolinium is an extracellular agent. And
when we apply it in the heart, we look for infarcts, or areas of
the heart that are perhaps dead, or scarred over. This week's
feature discusses manganese as a contrast agent and it is an
intracellular contrast agent. And very interestingly, it
identifies calcium handling, so it's a marker of viability. And
these authors are going to apply manganese as well as gadolinium
in trying to understand mechanisms behind Takotsubo
cardiomyopathy.


But before we get to that, how about we grab a cup of coffee and
jump into some of the other articles in the issue?


Dr. Carolyn Lam:


Oh, I'd love to tell you about the other articles. But just have
to first say, I loved your description of the feature paper. It's
right up your alley and I can't wait to learn more.


But my first paper today I want to talk about pulse field
ablation. Now, what is that? Pulse field ablation, or PFA, is a
unique and novel technique to treat atrial fibrillation. It has a
unique safety profile largely related to its preferentially for
myocardial tissue ablation. And thus, sparing the esophagus and
thus, deemed to have a unique safety profile. Now, a pentaspline
catheter was the first such PFA system studied for AF ablation.
And in the initial trials the catheter was used for pulmonary
vein isolation and left atrial posterior wall ablation.


However, following its regulatory approval in Europe, in clinical
practice, physicians have ablated both these locations and
expanded lesions that could be in closer proximity to the
coronary arteries. Now, this is an unstudied important issue
since preclinical and maybe some clinical data have raised the
potential for coronary arterial spasm. Hence, the investigators
led by Dr. Vivek Reddy from Icahn School of Medicine at Mount
Sinai and colleagues studied the vasal spastic potential of PFA
lesion sets, both remote from and adjacent to coronary arteries.


Dr. Greg Hundley:


Wow, Carolyn, this is a really interesting question. So what did
they find?


Dr. Carolyn Lam:


In this retrospective analysis of a series of 25 patients
undergoing PFA for atrial fibrillation in whom coronary
angiography was performed pre, during and post ablation, they
found that during pulmonary vein isolation and left atrial
posterior wall ablation, coronary spasm did not occur. However,
cavotricuspid isthmus ablation provoked severe subtotal vasospasm
in five out of five consecutive patients. And this was relieved
by in coronary nitroglycerin. ST elevation was not observed. No
patient had severe spasm if first pretreated with parenteral
nitroglycerin, either intracoronary or intravenous.


And so in summary, coronary vasospasm was not provoked during PFA
at locations remote from the coronary arteries. But when the
energy is delivered adjacent to a coronary artery, like in
cavotricuspid isthmus ablation, PFA did provoke subclinical
vasospasm. And the phenomenon was attenuated by nitroglycerine
administered either post hoc to treat spasm or as prophylaxis.
And this is discussed in accompanying editorial, I like it,
“Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and
Sundeep and Saba.


Dr. Greg Hundley:


Very nice Carolyn. Very important research in this area using
that particular methodology.


Well Carolyn, my next study comes to us again from preclinical
science. And Carolyn, this study evaluated mechanisms responsible
for pulmonary hypertension.


So as background, pulmonary hypertension is associated with
increased expression of VEGFA and it's receptor VEGFR-2. But
whether and how activation of VEGFA signal participates in the
pathogenesis of pulmonary hypertension, that's unclear. And so
these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial
Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2
signal activation and VEGFR-2 Y949 dependent vascular leak in
lung samples from patients with pulmonary hypertension as well as
in mice exposed to hypoxia.


Dr. Carolyn Lam:


Another one of those excellent translational pieces, isn't it
Greg? So what did they find?


Dr. Greg Hundley:


Right Carolyn. So these authors found that pulmonary hypertension
led to excessive pulmonary vascular leak in both patients and
hypoxic mice. And this was owing to over activated VEGFA and
VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling
via a specific point mutation was sufficient to prevent pulmonary
vascular permeability and inhibit macrophage infiltration and
Rac1 activation in smooth muscle cells under hypoxia exposure.
This, in turn, led to alleviation of pulmonary hypertension
manifestations including muscularization of distal pulmonary
arterials, elevation of right ventricular systolic pressure and
right ventricular hypertrophy.


And so Carolyn, in summary, these results suggest that VEGFA,
VEGFR-2 Y949 dependent vascular permeability is an important
determinant in the pathogenesis of pulmonary hypertension and
might serve as an attractive therapeutic target pathway for this
disease.


Dr. Carolyn Lam:


Aw, thanks Greg for explaining that so well.


The next paper talks about transcatheter aortic valve replacement
of TAVR, recognizing that it is a well established treatment now
for high and intermediate risk patients with severe symptomatic
aortic stenosis. However, the question asked here is what makes
some, but not all patients improve their left ventricular
ejection fraction following TAVR associated after load reduction?


Now, hypothesizing that circulating microRNAs may play a role
here, the authors led by corresponding authors, Dr. Hosen and
Jansen from University of Bonn and their colleagues profiled the
differential expression of microRNAs in circulating extracellular
vesicles in patients after TAVR. And in particular, the novel
role of circulating microRNA 1225p in cardiomyocytes.


Dr. Greg Hundley:


Oh wow. So Carolyn, important study. So what did they find?


Dr. Carolyn Lam:


Well, first aortic stenosis increases circulating microRNA 1225p,
which correlated with a lack of improvement of the EF in patients
after TAVR. Extracellular vesicles harbored microRNA 1225p and
facilitated its startling into the cardiomyocytes. Vesicular
shuttling of this particular microRNA was regulated by a direct
interaction with a multifunctional RNA binding protein called
heterogeneous nuclear ribonucleoprotein U in a sequence specific
manner. Extracellular vesicles containing the specific microRNA
post transcriptionally repressed BCL2 an anti-apoptotic gene,
which is central to cell viability and apoptosis.


So in summary, Greg, an increase in extracellular vesicle
microRNA 1225p in patients with aortic stenosis represents a
novel mechanism for the deterioration of cardiac function in
patients following TAVR. And pharmacological manipulation of this
axis may improve ejection fraction and cardiac function in
patients with aortic stenosis by improving the viability of
cardiomyocytes, which opens the door to a potential therapeutic
approach in patients with limited EF improvement following TAVR.


Dr. Greg Hundley:


Oh Carolyn, beautiful, beautiful description of that wonderful
preclinical science.


Well, let's reach into the mail bag and see what else is in the
issue. And first, there's a research letter by Professor van
Raalte entitled “Kidney Hemodynamic Effects of Angiotensin
Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition
Alone and in Their Combination: A Crossover Randomized Trial in
People with Type 2 Diabetes.”


And Carolyn, there's also an In Depth piece from Dr. Marx
entitled “GLP1 Receptor Agonist for the Reduction of
Atherosclerotic Cardiovascular Risk in Patients with Type 2
Diabetes.”


Dr. Carolyn Lam:


Very, very nice papers, those two. There's also an exchange of
letters between Drs. Hou and Sedej regarding the article, “Fine
Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to
Promote Health and Longevity.” As well as a Perspective by Dr.
Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More
Precision in Aortic Care.”


Now, let's go onto the feature discussion of all things MRI,
shall we?


Dr. Greg Hundley:


You bet. More on manganese.


Welcome listeners to this very interesting feature discussion on
December 13th. And we have with us Dr. Trisha Singh from the
University of Edinburgh in Edinburgh, Scotland.


Welcome, Trisha. This is a fascinating study incorporating
manganese cardiovascular magnetic resonance to study some of the
mechanistic underpinnings of hypokinesis left ventricular
hypokinesis in patients with Takotsubo syndrome. So maybe just
describe for us some of the background information that went into
the preparation of your study, and what was the hypothesis that
you wanted to address?


Dr. Trisha Singh:


Yes, of course. So we know with patients with Takotsubo syndrome,
it predominantly affects middle aged women, patients present with
a degree of left ventricular dysfunction, which is transient.
And, unfortunately, it can be quite difficult to diagnose because
it can phenotypically present very similar to an acute coronary
syndrome. We know from previous studies that these patients do
have ongoing symptoms despite normalization of their LV function.
And actually their outcomes are not as benign as previously
thought.


In terms of manganese enhanced MRI imaging, we at Edinburgh
University have imaged patients with other cardiac conditions
such as hypertrophic cardiomyopathy, and dilated cardiomyopathy.
And have established that it can be used as a surrogate marker of
myocardial calcium uptake and handling. So we were very
interested to see whether or not patients with acute Takotsubo
syndrome have got a myocardial calcium dysfunction and more
importantly whether or not this translates into long-term
dysfunction and perhaps could explain their symptoms and worse
prognosis in long-term.


Dr. Greg Hundley:


Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is
manganese different? You mentioned it's a nice marker for calcium
handling. Is this widely used clinically? What kind of contrast
does it provide?


Dr. Trisha Singh:


So manganese was actually one of the first contrast agents to be
used with magnetic resonance imaging. It kind of came about in
the 1970s and 1980s. And previous animal models have looked at
how it is essentially an intracellular contrast agent. And what I
mean by that is manganese is a calcium analog and therefore, in
cells where they are viable and there's intact cell function,
they will be taken up through a voltage gated calcium channels.
So, for example, in the heart. So the theory is that manganese,
when you've got normal viability, manganese is taken up into the
myocardium via voltage gate calcium channels. And several studies
have shown that if you then have disease myocardium, these
tissues do not take up the manganese as normal tissue would.


And the main difference between manganese and gadolinium is they
are both paramagnetic, which is why they're helpful and useful in
MRI. But gadolinium, as a compound, is too big and it cannot
cross an intact cell membrane and therefore, gadolinium is more
extracellular. And as, we know, accumulates in tissues where
there is increased edema, or water content. So gadolinium, for
all intents and purposes, is incredibly useful contrast agent,
certainly what we use predominantly at the moment in clinical
practice, but it is extracellular. So the theory behind manganese
is that it is an intracellular contrast agent as opposed to
gadolinium. And where gadolinium accumulates in disease tissue,
manganese accumulates in viable tissue. So they behave almost
kind of in contrast to each other.


And currently, manganese is not used in clinical practice. I
think the only clinical compound contrast agent utilizing
manganese was mangafodipir, otherwise known as Teslascan, which I
believe came off the market in 2012 and that was predominantly
used for imaging liver metastasis.


Dr. Greg Hundley:


Well Trisha, thank you for clarifying for us the difference
between manganese, the intracellular contrast agent, and
gadolinium, the extracellular contrast agent, that's so widely
used clinically.


Well, with that description, can you describe for us now, your
study population and your study design?


Dr. Trisha Singh:


Perfect. So the study population was we aimed to recruit 20
patients with acute Takotsubo syndrome. The diagnosis of
Takotsubo syndrome was based on a clinical diagnosis, so all our
patients underwent a baseline echocardiography and invasive
coronary angiography.


Now, for us, the coronary angiography was quite important because
we wanted to ensure we ruled out anyone with an acute myocardial
infarction, which can often be tricky in this cohort of patients.


So after recruiting 20 patients during the acute phase of
Takotsubo, they all underwent a baseline gadolinium enhanced MRI
scan followed by a manganese enhanced MRI scan. And these were
done at least 48 hours a part. And then about three months
roughly after the acute index, they were all invited to
participate in a second manganese enhanced MRI scan.


Dr. Greg Hundley:


Very good. So two exams separated longitudinally over time. What
were your study results?


Dr. Trisha Singh:


Our results demonstrated that during the acute phase as one would
expect, patients had a degree of left ventricular dysfunction.
The majority of our patients had afibrillar Takotsubo, so had
afibrillar ballooning with preservation of the basal segments.
With this, we also noted that in the areas that were affected by
Takotsubo, so kind of the mid ventricular wall and the apex that
all patients had significantly elevated native T1 and associated
T2 as well. And as we expected there was reduced uptake of
manganese and therefore kind of reduced calcium uptake in the
myocardium in the area affected by Takotsubo syndrome.


Interesting, what we also noticed was that all these patients had
significantly elevated LV mass, which has been described in
previous Takotsubo papers, certainly by Professor Dawson. And
when you measured the left ventricular wall thickness, the LV
wall thickness is elevated in the affected and actually not even
in the non-affected areas, which I suspect explains why in the
acute phase people almost doubles up which kind I guess fit with
kind of acute myocardial edema and intense water content.


And then, three months later when these patients returned for
their follow-up scan, a lot of the acute changes had resolved. So
native T2 values had improved and gone back to baseline. Native
T1 and post contrast T1 values had remained elevated compared to
the control population. And what we found was that manganese
uptake, though it had improved, it still remained abnormal and
reduced compared to the control population, which is a finding
that we weren't expecting to find.


Dr. Greg Hundley:


Very interesting. So acutely we've got extracellular water there,
elevation of myocardial T2, and also impaired manganese uptake.
So intracellular abnormalities with calcium handling. Then later,
so three months later, we have restoration of myocardial T2 so
the extra water content is absent, but we have impaired manganese
uptake indicating an abnormality with calcium handling. So how do
we put this all together mechanistically? What does this tell us
about the pathophysiology of Takotsubo syndrome?


Dr. Trisha Singh:


For one thing, I think we can say that there is, as described
before, there is obviously intense myocardial edema present in
patients with acute Takotsubo. And I think the significant
elevation in T2 and LV mass kind of all fits together. Actually
interestingly, as native T2 improves in their follow-up scans,
the LV mass actually all return back to normal baseline. So I
think the acute edema does resolve.


And as you said, interestingly, despite all of these patients,
their LV function completely recover. And despite that their
myocardial calcium uptake, or handling remain normal. And I think
that's not been demonstrated before. And I think it just points
to that there is obviously, still something going on in the
myocardium and it's not behaving completely normally despite
completely normal kind of gross LV function. And potentially,
this might point in the direction of why these patients have
ongoing symptoms. So, certainly, from our observational cohort
group, about 70% of patients had ongoing symptoms and this was
predominantly breathlessness and palpitations. And potentially,
might be related to why patients have worse outcomes compared to
the general population.


Dr. Greg Hundley:


Very nice. And Trisha, can you describe, was there a therapeutic
intervention between the acute and then the three month later
measurements? Were these patients administered any type of
medical therapy and were there differences in what those
therapies may have been between different patients in your study?


Dr. Trisha Singh:


So predominantly, most of the patient population that were
started on some combination of heart treatment due to the
baseline LV dysfunction. And this kind of was a combination of
most of them were on Ramipril, a few of them were also on
spironolactone or eplerenone. And then, every single one was on
furosemide. And interestingly, I mean I appreciate, I think the
population group was quite small, so it's very difficult to
compare those that were on kind of full heart failure treatment
versus those who were just on beta blocker and ramipril therapy.
But even in that cohort there was a split of about, I think
predominantly, I think 17, 16 patients were on kind just beta
blockers and ramipril as opposed to beta blocker, ramipril,
spironolactone. And there was no difference kind of in the
recovery in manganese uptake in that cohort. But, again, the
numbers are quite small, so I think it's difficult to extrapolate
any kind of true meaning in that.


Of course, we know there's a lack of randomized control trial
data looking at how to best treat patients with acute Takotsubo
syndrome and certainly, what treatment may prevent these patients
from having a recurrence of Takotsubo. And I know some of the
TACA registry data has looked at actually despite the fact
patients of being on beta blocker, or ramipril therapy, they
still go having recurrence of Takotsubo and certainly of our
cohort, one of our patients went on having a recurrent episode of
Takotsubo within a year of her index event and she was on
aspirin, beta blocker, spironolactone as well.


Dr. Greg Hundley:


Very nice.


And then lastly, when you made these measurements looking at the
manganese uptake or lack thereof, were these in the regions of
myocardium where you mentioned many had apical LV wall motion
abnormalities, were they in those regions or did you also measure
regions remote to where the wall motion abnormality occurred?


Dr. Trisha Singh:


Of course. So we took measurements in the affected regions of the
heart that kind of demonstrated spironolactone syndrome. And we
also took measurements in kind of, so to speak, the remote
segments of the heart.


Now, for the remote segments of the heart, we could only measure
native T1 and post contrast T1 at 30 minutes and to measure
manganese uptake well, unfortunately, what we have to do is take
a measurement over time, so we'd do every two and a half minutes
for 30 minutes after the manganese contrast. So we weren't able
to calculate manganese uptake in the remote regions. But what we
could do was measure the native T1 in the remote region, and then
the post contrast T1 and see how it differed with the region of
interest in the affected portion of the heart, so to speak.


Dr. Greg Hundley:


Very good.


Well, Trisha, with this really exciting research and very nice
methodology, what do you see as the next study to be performed in
patients with Takotsubo?


Dr. Trisha Singh:


So I think, in terms of manganese enhanced imaging, I think it'd
be really interesting to re-scan these patients at one year or at
two years. And the question there is whether or not their
manganese uptake ever recovers really. I know we previously
talked about this and thought about whether or not these patients
who go onto developing Takotsubo syndrome might actually have a
kind of an underlying cardiomyopathy that puts them at risk of
developing Takotsubo with stress. So it'd be interesting to see
whether or not actually their calcium uptake ever recovers in the
long-term, or whether actually they have more of a chronic heart
failure type like picture.


And I think another area of interest would be to see potentially
using manganese imaging as a noninvasive measure of kind of
myocardial calcium activity and to see whether or there's any
changes with therapy over the course of months to years or so.


Dr. Greg Hundley:


Very nice.


Well listeners, we want to thank Dr. Trisha Singh from University
of Edinburgh in Edinburgh, Scotland for bringing us this really
interesting article in patients with Takotsubo syndrome
demonstrating that there is a marked perturbation of myocardial
manganese uptake, which is most evident in the acute phase of
Takotsubo presentation, but also persists for at least three
months despite apparent restoration of normal left ventricular
ejection fraction and resolution of myocardial edema. All of this
suggesting that abnormal myocardial calcium handling may be
implicated in the pathophysiology of Takotsubo syndrome.


Well, on behalf of Carolyn and myself, we want to wish you a
great week. And we will catch you next week on the run.


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 ajjournals.org.