Circulation November 9, 2021 Issue

Please join author Maria Nunes and Associate Editor
Ntobeko Ntusi as they discuss the article “Incidence and
Predictors of Progression to Chaga Cardiomyopathy: Long-Term
Follow-Up of Trypanosoma cruzi-Seropositive
Individuals.”


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, this feature this week, we're going to talk about Chagas
disease and we have some really important long-term, really for
the first time, observational data and a cohort that's been
followed in Brazil. And it's just a wonderful discussion from a
team that's been working very hard in this area over an extended
period of time. But before we get to that, how about we grab a
cup of coffee and get started on some of the other articles in
this issue? Would you like to go first?


Dr. Carolyn
Lam:            


I would. And with your coffee, I would like to tell you about
non-combustible nicotine or tobacco products. Fancy a smoke with
your coffee? Well, you know that those are novel forms of
nicotine consumption composed of things like nicotine vaping
products that vaporize the nicotine-containing fluids and heated
tobacco products that really heat the tobacco products without
combustion. Now, these have recently gained popularity because
they're portrayed as being safer modes of smoking compared with
the traditional combustible cigarettes. However, their
associations with subsequent cardiovascular disease risks are
still unclear. So Greg, here's today's quiz. Gosh, I miss our
quizzes. What do you think? Are they safer or are they not?


Dr. Greg
Hundley:          


Oh, Carolyn, you're catching me on this and I never know which
way to go, but I'm going to guess not. How about you tell us?


Dr. Carolyn
Lam:            


Well, the paper will tell us, and this is from co-corresponding
authors Dr. Lee from Seoul National University Bundang Hospital
and Dr. Park from Seoul National University College of Medicine
and their colleagues. And they basically studied more than
5,000,000 adult men who underwent health screening examinations
during both a first and second phase of health screening periods
from the Korean National Health Insurance Service Database
spanning 2014 to 2018. Initial combustible cigarette smokers who
subsequently quit that cigarette smoking and converted to a
non-combustible nicotine or tobacco product use was associated
with a lower incident cardiovascular disease risk compared to
those who continue the combustible cigarette use. However,
compared with combustible cigarette quitting without using these
non-combustible substitutes, those who ceased smoking but
continued with the non-combustible products was associated with a
higher cardiovascular disease risk. So the take home message is
although the non-combustible nicotine or tobacco products may be
associated with a lower cardiovascular disease risk compared with
continued combustible cigarette smoking, those who quit without
using these substitutes may benefit the most in reducing the risk
of developing future cardiovascular disease events. And this is
discussed in a wonderful editorial by Dr. Auer, Diethelm and
Berthet.


Dr. Greg
Hundley:          


Very nice, Carolyn. Great presentation and really new information
in this space. Well, my paper comes from the world of preclinical
science and it involves long noncoding RNAs. And Carolyn, they
are important regulators of biological processes involved in
vascular tissue homeostasis and cardiovascular disease
development. And so, the current study, led by Professor Lars
Maegdefessel from Karolinska Institute, assessed the functional
contribution of the long noncoding RNAs myocardial infarction
associated transcripts and their relationship to atherosclerosis
and carotid artery disease.


Dr. Carolyn
Lam:            


Hmm, interesting. They are the rage, these lncRNAs. So what did
they find, Greg?


Dr. Greg
Hundley:          


Right, Carolyn. So long noncoding RNAs possess key regulatory
functions directly interacting and mediating expression and
functionality of proteins, other RNAs, as well as DNA. Next, the
long noncoding RNA myocardial infarction associated transcript
plays a key role during atherosclerotic plaque development and
lesion destabilization. Its expression becomes highly increased
in high risk patients with vulnerable plaques. And so, Carolyn,
the take home therapeutic targeting of the long noncoding RNA
myocardial infarction associated transcript, using antisense
oligonucleotides, well that offers novel treatment options for
patients with advanced atherosclerosis in the carotid arteries
that are at risk of stroke.


Dr. Carolyn
Lam:            


Oh, very interesting. So from the preclinical world back to the
clinical world with an important clinical trial. Now, we know
that percutaneous closure of the left atrial appendage is an
alternative to chronic oral anticoagulation to reduce stroke risk
in patients with nonvalvular atrial fibrillation. The Amplatzer
Amulet Left Atrial Appendage Occluder IDE trial, called the
Amulet IDE trial, was designed to evaluate the safety and
effectiveness of the dual seal mechanism of the Amulet left
atrial appendage occluder compared with the WATCHMAN device. And
here, 1,878 patients with nonvalvular atrial fibrillation at
increased risk of stroke were randomly assigned to undergo
percutaneous implantation of a left atrial appendage occluder
with the Amulet occluder or a WATCHMAN device. And the primary
end points included safety, which was a composite of
procedure-related complications all cause death or major bleeding
at 12 months, and effectiveness, which was a composite of
ischemic stroke or systemic embolism at 18 months. They also
looked at the rate of left atrial appendage occlusion at 45 days.
And this paper is from Dr. Lakkireddy and colleagues from Kansas
City Heart Rhythm Institute.


Dr. Greg
Hundley:          


Well Carolyn, these devices, they are really being heavily tested
in patients with atrial fibrillation. So what did they find?


Dr. Carolyn
Lam:            


The Amulet occluder was non-inferior with respect to safety and
effectiveness compared to the WATCHMAN device, and superior with
respect to left atrial appendage occlusion; however,
procedure-related complications were higher with the Amulet
occluder, largely related, perhaps, to more frequent pericardial
effusion and device embolization. And the authors noted that the
procedure-related complications decreased with operator
experience; however, I think all of this still needs to be
further investigated. Well, those were really nice original
papers, but let's also discuss what else there is in today's
issue. There is an exchange of letters between Drs. Mueller and
Allen regarding the article “Diagnostic Performance of High
Sensitivity Cardiac Troponin T Strategies and Clinical Variables
in a Multisite U.S. Cohort.” There's a perspective piece by Dr.
Olson, “Toward CRISPR Therapies for Cardiomyopathies.”


Dr. Greg
Hundley:          


And Carolyn, I've got a research letter from Professor Layland
entitled “Colchicine in Patients with Acute Coronary Syndromes:
Two Year Follow Up of the Australian COPS Randomized Clinical
Trial.” Well, what a great set of papers that we've discussed.
Now, let's get on to that feature discussion and learn a little
bit more about the longitudinal history and progression of
cardiovascular disease and patients with Chagas disease.


Dr. Carolyn
Lam:            


Yay. Let's go, Greg.


Dr. Greg
Hundley:          


Well, listeners, we are here for our feature discussion today and
a very exciting one we have, pertaining to Chagas disease. And we
have with us today Dr. Maria Nunes from Belo Horizonte, Brazil,
and also one of our Associate Editors, Dr. Ntobeko Ntusi from
Cape Town, South Africa. Welcome to you both. And Maria, we'll
start with you. Could you describe for us some of the background
information pertaining to your study and what was the hypothesis
that you wanted to address?


Dr. Maria
Nunes:            


Yes, thank you for these opportunities. My main hypothesis is
that Chagas disease is the major cause of dilated cardiomyopathy
in endemic areas. So we selected patients without cardiomyopathy
at baseline to see if the Trypanosoma cruzi seropositivity is a
predictor of further developing of cardiomyopathy.


Dr. Greg
Hundley:          


Very nice. And so tell us, how did you construct this study? What
was your design? And then also, maybe describe for us how you
selected the participants for this study.


Dr. Maria
Nunes:            


We selected the participants from two blood donor centers. One in
Sao Paulo and one in Montes Claros, which is north of Minas
Gerais State. We select blood donors because it's the way that we
have Chagas disease’s screening tests. And in asymptomatic
patients, usually at the hospital, patients comes to us with
heart failure or a kind of symptoms related to Chagas disease.
Our main goals in this study is to select healthy participants
based on the screen test of Trypanosoma cruzi. So the population
was blood donors selected from two centers.


Dr. Greg
Hundley:          


Very good. And then again, your study design. So did you follow
these two groups of individuals longitudinally over time, and for
how long?


Dr. Maria
Nunes:            


Yes, we have different visits of this study with the patients
initially was selected at first in 1996 and 2002. At this time,
they don't have cardiovascular exams. And our study actually is
starting 2008 to 2010, and we select all these patients with all
comprehensive cardiovascular evaluation with the clinical
examination, echocardiogram and electrocardiogram, and then just
the baseline for our patient population. And we follow them 10
years on average until 2018, 2019.


Dr. Greg
Hundley:          


Very nice. So it sounded like from individuals in two regions of
Brazil, identified those through screening of the blood, and I
guess these were blood donors, and then performed a series of
cardiovascular exams 2008 to 2010 and followed them for the next
10 years. And you're going to tell us about the results that
occurred 2018 to 2019. And so what were those results?


Dr. Maria
Nunes:            


We found that Trypanosoma cruzi seropositive is a risk factor for
developing cardiomyopathy. Nowadays, this is still a risk factor,
seropositive without cardiomyopathy at baseline has two times
higher risk of developing cardiomyopathy compared to the
seronegative controls. And we have also detected that the
parasite load or the level of parasite in the blood expressed by
antibodies against Trypanosoma cruzi is an important risk factor
for disease progression. That means some patients have Chagas
disease, but the level of antibodies is not too high. These
patients go well. And other hand, the patients with high level
antibodies means the parasite load may be higher too. This is the
high risk of disease progression to cardiomyopathy or of dying
too.


Dr. Greg
Hundley:          


Very nice. And were there any subgroups of patients where you
found these relationships to be particularly more striking? So
for example, the elderly, or was there a discrepancy based on
sex, men versus women?


Dr. Maria
Nunes:            


Yes, other studies has already shown that the male gender is a
risk factors in Chagas disease. Usually they progress more, they
have more severe clinical presentation, usually die at the age
between 30 and 50 years old, the most productive years of the
life. That's why Chagas is so important here in Brazil and
Argentina, in Latin America countries because people die at early
ages.


Dr. Greg
Hundley:          


And your results confirmed what was previously known in that
regard.


Dr. Maria
Nunez:            


Yes, patients with developing cardiomyopathy with heart failure
has a high mortality rate. And then even patients with
cardiomyopathy detected by exams like based on ECG or echo, they
asymptomatic, but they progress more for dying or to develop
cardiomyopathy compared to seronegative with similar risk effects
for cardiovascular disease, such as hypertension, diabetes,
smoking.


Dr. Greg
Hundley:          


Very good. Well Ntobeko, you see many papers come across your
desk as an Associate Editor for Circulation, and what attracted
you to this paper and the results that Maria has described?


Dr. Ntobeko
Ntusi:         


Thank you, Greg. I was attracted to this paper because it's an
important natural history study of Chagas disease. But secondly,
it's also one of the largest contemporaneous cohorts of Chagas
disease which provides important insights and advances in our
knowledge with regard to this clinical entity. And for me, there
were three things that stood out. The first one was an important
description of the outcomes of Chagas cardiomyopathy. The second
was the contemporaneous description of the epidemiology in a
well-characterized cohort. And the third and novel contribution
was the description of the determinants of disease progression.
So I thought overall, the really important contribution to the
field.


Dr. Greg
Hundley:          


Very good. And for those that might not live in the endemic area,
but might occasionally encounter someone with Chagas disease,
what results from this paper can we use to help manage patients
in this situation?


Dr. Ntobeko
Ntusi:         


Thanks, Greg. So this was a study which had a number of really
positives. Firstly, it's a large study, it was non acute
[inaudible 00:16:42] design and it used PCR for diagnosis. And
unlike many other studies, also ascertained antibody levels and
had very good clinical characterization, which included
electrocardiographic, echocardiographic assessment, including
serum assessment of proBNP and CK-MB. And all really important
take home messages are for me. The first one is understanding
that the relationship of your antibody levels and baseline LV
function to mortality. In other words, are finding that in those
with existing LV structural abnormalities, or higher levels of
antibody titers, mortality was higher. The second important
contribution is a description of the incidence of Trypanosoma
cruzi, and this was highest as one would expect in the
seropositive donors and much lower in seronegative donors. The
third important contribution relates to our improved
understanding of the determinants of disease progression, which
were related to the Trypanosoma cruzi antibody levels.


In other words, the higher your antibody titers, the quicker you
progressed to manifest the cardiomyopathic phenotype. And then
lastly, the predictors of mortality, which were related to your
PCR being positive, as well as your antibody titers. Important is
this contribution is there are a number of important caveats. The
first is that the study is limited by the huge amount of loss to
follow up, which as you can imagine, adds a number of biases to
our conclusions. The second is that the observations may of
course be confounded by comorbidity in particular because these
patients are older and had higher comorbidity. The third is that
we assume that the PCR positivity and antibody titers actually
correlate with parasite pattern, but in fact, we know that is not
always the case. And then lastly, for people who read this paper
from non-endemic parts of the world, the result may not be
clearly generalizable to those parts of the world.


Dr. Greg
Hundley:          


Very nice. Well, we've had a great discussion, listeners. From
Maria and Ntobeko sort of presenting the paper and then what are
some of the take home messages. So now I'd like to go back to
both of them and Maria, first you and then Ntobeko. Maria, what
do you think is the next study to really be performed in this
sphere of research?


Dr. Maria
Nunes:            


We may should stratify patients with Chagas disease. Those who
have high antibodies titers should refer to a kind of treatment
or benznidazole treatment. We should intervene in this subgroup.


Dr. Greg
Hundley:          


Very good. And Ntobeko, anything to add?


Dr. Ntobeko
Ntusi:         


Yes, Greg, I think that there are two important next steps. The
first one is that I think we need other large designed
prospective studies that will validate the observations by Dr.
Nunes and colleagues. And then the second key step for me would
be the design of randomized controlled trials to test therapeutic
agents with antitrypanosomal activity to demonstrate their
ability to retard or completely block disease progression, which
would be a nice way to complete the story.


Dr. Greg
Hundley:          


Very nice. Well listeners, we've had a great discussion today and
we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from
South Africa for bringing these really informative results
pertaining to Chagas disease, and highlighting the natural
history and showing an association between these high titer
values and poor cardiovascular outcomes.


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, 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.