Circulation April 2, 2019 Issue

 Dr Carolyn
Lam:              
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to The Journal and its editors. I'm Dr Carolyn
Lam, associate editor from the National Heart Center, and Duke
National University of Singapore.


Dr Greg
Hundley:            
And I'm Greg Hundley, also associate editor in Richmond, Virginia
at VCU Health.


 Dr Carolyn
Lam:              
So, PCI or no PCI for chronic total occlusion. That is a
perennial question, and we have the results of the decision CTO
trial reported in this week's Journal. In fact, we're going to
discuss it right after our little chat here.


                                               
So, Greg, why don't you kick us off? What paper did you choose?


 Dr Greg
Hundley:           
Yeah, thanks so much Carolyn. My first paper is from Laura
Benschop from the Department of Obstetrics and Gynecology at
Erasmus Medical Center in Rotterdam, the Netherlands. It's going
to focus on placental growth factor as an indicator of maternal
cardiovascular risk after pregnancy.


                                               
So, as we all know, pregnancy is accompanied by extensive
maternal hemodynamic changes that allow for proper placental
implantation, growth, profusion, and fetal development and this
process requires a tight balance between pro-angiogenic factors
like placental growth factor, and anti-angiogenic factors like
soluble FMS like tyrosine kinase factors. So, in response to
stress, the syncytiotrophoblast will decrease the production of
placental growth factor and women with reduced placental growth
factor and increased FLT-1, are more at risk of a complicated
pregnancy. For example, like preeclampsia and spontaneous preterm
birth.


                                               
So, angiogenic placental growth factor concentrations can rise
during pregnancy, peaking at the end of the mid-pregnancy. And
low placental growth factor concentrations during pregnancy are
associated with pregnancy complications with recognized later
life cardiovascular risk. So here, the authors hypothesize that
low placental growth factor concentrations, especially in mid
pregnancy, identify not only a subset of women at risk for
pregnancy complications, but also women with greater
cardiovascular risk factor burden after pregnancy, regardless of
their outcome.


                                               
So, among 5,529 women, the authors computed gestational age
adjusted and mid-pregnancy placental growth factor concentrations
and pregnancy complications, like preeclampsia, small for
gestational age, spontaneous preterm birth, was obtained from
hospital registries.


 Dr Carolyn
Lam:              
Cool, and what did they find?


 Dr Greg
Hundley:           
So six years after pregnancy, the authors found that women with
mid pregnancy low placental growth factors, in the lowest
quartile, had larger aortic diameters, left atrial diameters, and
LV mass, and a higher systolic blood pressure by an average of
2.3 millimeters of mercury. High mid-pregnancy placental growth
factor concentrations were the opposite. They were associated
with smaller aortic diameters, smaller left atrial diameters,
lower LV mass by 3.9 grams, and lower systolic blood pressure.
And these differences persisted after exclusion of women with
complicated pregnancies.


                                               
So, the results suggest that a woman's response to the
cardiovascular changes of pregnancy, measured by
pre-mid-pregnancy placental growth factor levels could provide
insight into the path of physiological mechanisms leading to
future cardiovascular disease in multiparous women.


 Dr Carolyn
Lam:              
Wow. That is really interesting. Well, the paper I chose really
answers the question, are there racial differences in sudden
cardiac death, and why? And this is from corresponding author Dr
Guallar from Welch Center for Prevention, Epidemiology, and
Clinical Research in Johns Hopkins Bloomberg School of Public
Health and Colleagues.


                                               
What they did is they compared the lifetime cumulative risk of
sudden cardiac death among blacks and whites in the
atherosclerosis risk in community study, or ARIC. They evaluated
the risk factors that may explain racial differences in sudden
cardiac death risk in this general population.


                                               
What they found was that blacks had a much higher risk of sudden
cardiac death in comparison with whites, with a sex adjusted
hazards ratio of 2.12. Known factors explained 65% of the axis
risk of sudden cardiac death in blacks compared to whites. The
single most important factor explaining this difference was
income, followed by education, hypertension, and diabetes. These
racial differences were evident in both genders, but stronger in
women than men.


 Dr Greg
Hundley:           
Hmm. So are there implications, and are there potential
strategies that could help reduce this risk in African Americans?


 Dr Carolyn
Lam:              
Yeah, this is a really interesting study, and it really implies
that efforts to reduce the sudden cardiac risk in blacks should
perhaps focus on improving CPR outreach, medical care engagement
in response to cardiac arrest, the quality of treatment in
medical institutions in predominantly black neighborhoods, and
factors such as that. Because remember the single most important
factor explaining the difference was actually income and
education.


 Dr Greg
Hundley:           
Oh, wow. Well, I'm going to switch gears a little bit here
Carolyn, and we're going to talk about pulmonary hypertension.
And this next paper is going to focus on pericytes. We'll learn a
little bit about what pericytes are. So, the paper is from
Vinicio de Jesus Perez, who's an assistant professor of medicine
and pulmonary critical care at Stanford University Medical Center
in California.


                                               
What are pericytes? So, pericytes are specialized perivascular
cells embedded in the basement membrane of blood vessels, where
in conjunction with neighboring and endothelial cells, they
support vessel maturation and stability. In the lung, pericytes
are mostly found associated with small precapillary arteries, the
capillaries, and then those post capillary venules. And it's
thought that pericytes are responsible for regulation of
vasomotor tone and structural support of these micro-vessels.
When the vessels become muscularized, pulmonary vascular
resistance increases, resulting in pulmonary artery hypertension.


                                               
So recent studies have focused on pericytes in addition to
pulmonary endothelial cells, smooth muscle cells, and fiberglass,
but not much is known about the contribution of pulmonary
pericytes to pulmonary arterial hypertension. Two genes are
involved in Wnt planar cell polarity pathway that is responsible
for coordinating complex cell movements during tissue
morphogenesis. So, in this group, they have produced prior
results that show that restoration of the Wnt planar cell
polarity in pulmonary arterial hypertension, pericytes could
partially restore recruitment to PNVECs and increase vessel
stability.


 Dr Carolyn
Lam:              
Interesting, and so that was their past research, and what did
the current paper show?


 Dr Greg
Hundley:           
Right. So Carolyn, what they found is that pulmonary
microvascular endothelial cells isolated from pulmonary arterial
hypertension patients, and endothelium from pulmonary arterial
hypertension tissue have reduced expression of Wnt-5a. Healthy
PMVECs produce and package Wnt-5a in the form of exosomes which
regulate pericyte recruitment, motility, and polarity.


                                               
And so, the overall implication is that promising therapeutic
strategies that help can restore the Wnt/PCP, or planar cell
polarity pathway, and endothelial pericyte communication could
help prevent micro-vessel loss in patients with pulmonary artery
hypertension.


 Dr Carolyn
Lam:              
Thanks, Greg. So, I'm going to take us to the cath lab for this
next paper. And it's the results of the CANTIC study, which aimed
to answer the question, does intravenous P2Y12 inhibitor
Cangrelor have a role in bridging the gap in platelet inhibition
in patients with STEMI undergoing primary PCI. And this is from
corresponding author Dr Angiolillo from the University of Florida
College of Medicine Jacksonville and Colleagues.


                                               
Now, CANTIC was a prospective randomized double-blind placebo
control parallel design investigation of the pharmacal dynamic
effects of Cangrelor versus placebo in patients undergoing
primary PCI, who were also treated with crushed Ticagrelor. So,
after diagnostic angiography, patients were randomized to a
blinded two-hour infusion of either Cangrelor or placebo. At the
same time, 180 milligrams of crushed Ticagrelor was administered
to both groups. Platelet reactivity was measured with Verify Now
P2Y12 point of care testing, and with vasodilator-stimulated
phosphoprotein, or VASP.


 Dr Greg
Hundley:           
So what did the trial show, Carolyn?


 Dr Carolyn
Lam:              
They found that addition of Cangrelor led to more prompt and
potent platelet inhibitory effects, compared with crushed
Ticagrelor alone in patients undergoing primary PCI. The
significant differences were observed as early as five minutes
post bolus administration, and persisted until the end of its
two-hour infusion.


                                               
Furthermore, after discontinuation of Cangrelor or the placebo
infusion, there were no differences in levels of platelet
reactivity between groups. And this importantly rules out a
drug/drug interaction when Cangrelor and Ticagrelor are
concomitantly administered. This lack of drug-drug interaction is
important, as it supports a more versatile use of Ticagrelor with
respect to timing of its administration in patients treated
concurrently with Cangrelor.


                                               
Overall, the results are reassuring and demonstrate reduced
platelet reactivity, and no high on treatment platelet reactivity
with Cangrelor in combination with Ticagrelor in primary PCI
patients. Of course, the implications of these pharmacal dynamic
findings really warrant investigation in an adequately powered
clinical trial.


                                               
And that brings us to the end of our summaries. Let's go to our
featured discussion.


                                               
So PCI, or no PCI for chronic total occlusion, that is a
perennial question isn't it? Especially nowadays when procedural
results for PCI and CTO have improved in recent years, and PCI
strategies have moved towards more complete revascularization.
Yet the evidence is clearly lagging behind for us to make
decisions on this. And that's why we're so happy that our
featured paper today is the DECISION-CTO trial from Korea, and so
happy to have the first author, Dr Seung-Whan Lee from ASA
Medical Center to tell us about this, as well as our associate
editor, Dr Manos Brilakis from UT Southwestern.


                                               
So Dr Lee, could you tell us about the DECISION-CTO trial?


Dr Seung-Whan Lee:       Yeah, in
our trial our multicenter, randomized, noninferiority trial,
PCI-eligible patients were assigned to receive either one of two
strategies; PCI or no PCI or CTO. We did the option for PCI of
the other. The primary endpoint as you know the composite outcome
of deaths, myocardial infraction, stroke, or any
revascularization. As related to quality of life was assessed up
to three years. However, because of the slow recruitment, the
trial was stopped before completion. We started 208 planned
enrollments. For six years 834 patients there were randomly
assigned to the CTO PCI versus no CTO PCI strategy.


                                               
Among the patients assigned to the no CTO PCI strategy, nearly 20
percent of patient cross over to the CTO PCI. That is our big
limitation, as you know. Anyways, the primary end point was
assessed per year, and then, finally, we founded the per year
risk of the major adverse cardiac events there’s no difference in
contributor composite outcome, MI, revascularization, and stroke.


                                               
However, in our trial, in some detail, in CTO PCI was success
rate around 91 percent. However, complication is very low, .6
percent of patient is complication. Very surprisingly the coheir
is up to the three, and no difference between CTO PCI versus no
CTO PCI.  


                                               
I think our main message is our patient is a relatively low-risk
population, including the syntax score 20 and the score 22%. The
majority of patient preserved LV function and single-vessel
disease 25%. The relative low risk population CTO PCI versus no
CTO PCI clinical outcome is no difference of the per year from
the two groups.


                                               
I think that our trial is make the reposition with the medical
law in the CTO patient. That’s my summary.


Dr Carolyn
Lam:               
Thank you. Manos, could you maybe paint the background and let us
know why this was so important for us to publish in Circulation?
Why is it so difficult to do these trials?


 Dr Manos
Brilakis:          
This is the largest study on CTO PCI so congratulations on
getting this accomplished. I know it was many years and a lot of
effort.


                                               
I think a couple of things on the background. As Dr Lee said as
well, CTO PCI success rates have been improved, and now at
experienced centers you can get 85 to 90 percent success fairly
consistently.


                                               
The complication rates are low. .5 to 3 percent is the average
rate. We do have a tool right now. The procedure is mature, and
it's time test in the randomized trials.


                                               
The question has always been for CTO PCI, "How does it help?"
Does it improve symptoms? Does it improve the heart outcomes?
Myocardial Infarction?  This is what DECISION CTO was trying
to answer.


                                               
Couple of I think limitations that we should take into account
when interpreting the results. The first one is that these were
notations with an isolated CTO, but a significant proportion had
also multi-vessel disease. They were enrolled before treating the
other vessels, which were subsequently treated.


                                               
Sometimes it's hard to know how much the residual ischemia or
symptoms would be present after the other lesions were treated.
That's one thing.


                                               
The second is that there was a significant crossover for about 1
in 5 patients that randomized to medical therapy immediately
crossed over to the CTO PCI group. And that always uses the power
and creates difficulty in interpreting the results.


                                               
In my mind, the question still remains, in low risk populations
it's possible that CTO PCI doesn't improve symptoms, but the ones
that were expected to improve, the heart outcomes dec-MI, would
be the high-risk patients with significant ischemia. Ideally,
studies in the future should actually look specifically at
patients who have high ischemia, significant symptoms when
looking at heart outcomes.


 Dr Carolyn
Lam:              
Dr Lee, I think you did mention as well in your manuscript that a
viability test was not mandatory for patient enrollment. I mean,
clearly it was such as work of labor enrolling such patients. If
you put even more criteria it would have been impossible, I
suppose. Do you have some thoughts there on maybe future studies?


Dr Seung-Whan Lee:       Yeah, as
you know, the currently ongoing CTO PCI process medical treatment
is nobel CTO and ischemia CTO is assessed at the reduction of the
ischemia burden in CTO PCI. I think there maybe two studies that
give us some answer for the low level of the CTO PCI for the
reduction of the ischemia.


                                               
So, I think the larger ischemic burden the patient is maybe high
risk to make the however we don’t know exactly the cut off…
ischemic burden in CTO patient. Usually instable angina any
kind…coronary disease…3 years circulation showed more than 10
percent of ischemic burden is really predictive of future cardiac
event. However, we don't know exactly the can be applied to CTO
patient. We don't know exactly.


 Dr Manos
Brilakis:          
Can I ask Dr Lee a question regarding the study and his
interpretation as well. Now the study was borrowed for hard end
points dec MI. What his is perception, based on the DECISION CTO,
and, of course, everything else in the literature and the CTO
study with symptomatic benefit...Dr Lee, what is your conclusion
about, or your kind of thoughts about, the effect of CTO PCI on
improving symptoms, which is a more accepted indication for the
procedure right now?


Dr Seung-Whan Lee:       As you
know, the university trials symptom assessment was done after the
no CTO PCI. However, our trial is a pragmatic trial, initial
approach to the CTO vessel and the vessels that is patient.


                                               
At this moment, I think the other vessel, other no CTO vessel
intervention and OMT may improve the patient symptom and then CTO
vessel is the intervention including the CI patient
completely…improve the symptom status. However, analysis showed
up to the 3 year, maybe no difference between two groups in the
CTO PCI versus medical treatment.


                                               
Our trials of the CTO PCI symptom, we don't exactly the role of
the after no CTO PCI. We don't know exactly the CTO based symptom
assessment was not done, because of the symptom assessment was
done before the intervention.


                                               
I think that our trials are more practical, because of the
initial…multivessel… CTO. Our trials, maybe, completely
vascularization including CTO and no CTO vessel revascularization
without the CTO intervention. Sometimes the patient to complain
of symptom multivessel with the CTO I think we can wait if we
continue the patient symptom…


                                               
However, in this trial showed CTO specific intervention trial,
because of the symptom assessment was done after no CTO vessel
intervention. There is some improvement of the… receptor
treatment satisfaction of the angina stability. I think that the
CTO intervention is maybe reserved for the symptom control after
the medical treatment failure of patient.


                                               
I fully agree the symptom control is possible with the CTO PCI.


 Dr Manos
Brilakis:          
Wonderful. Thank you. I think that's a critical differentiation
that the DECISION CTO is not specific for CTO, but it's
multi-vessel disease plus CTO. Thanks for clarifying. That's very
important for the leaders and the entire community to understand
that part.


                                               
One more question, if it's okay. I know that in Asian countries
bypass patients are relatively less. I think in the U.S. 50
percent. Any comment on that? I know people get less bypass in
Asia than they do in the United States. How may that affect the
interpretation of the DECISION CTO?


Dr Seung-Whan Lee:       Initially,
I introduced my studies to our patients syntax score under 20. As
you know, the U.S. Registry shows the syntax score more than I
think the 20, and the tester score around 46. Quite different in
population, because the risk factor is quite different. U.S.
patient is hypertension and diabetic are more prevalent than the
Asian patient. Bypass surgery is 40 percent in Asian patients.
Bypass surgery is around 102 percent in CTO registry. Quite big
difference of the base rank, risk factor, and morbidity.


                                               
I cannot apply to U.S. population exactly the same ... Not same
situation. We cannot apply directly to the U.S. population. I
fully agree with your suggestion, though. Lowest population is
maybe ... Our trial is maybe lowest population. We agree.


 Dr Carolyn
Lam:              
I'm just learning so much listening to both of your
interventionists. What do you think are the take-home messages
from this? Maybe, could I start with Dr Lee, and then give Manos
the last word?


Dr Seung-Whan Lee:       CTO PCI
critical outcome, it should be tested as a large random trial.
Maybe Manos already mentioned about the high-risk population,
because our population is the lowest population. However, in some
large random trial with a high-risk population we have consider
some random trial because they are not easy.


                                               
Maybe not easy to test in high-risk population. However, you must
do that, because of the two established CTO PCI law in the
current practice.


 Dr Carolyn
Lam:              
Manos?


 Dr Manos
Brilakis:          
Yeah, I would agree with that. I think the main conclusion
regarding the field of CTO PCI is that still right now, the key
indication remains symptom improvement. We do have the trials at
this point showing that you do CTO PCI in terms of improving
mortality. However, CTO PCI is a tool. It's a revascularization
tool. Patients who have severe, complex, coronary disease,
multi-vessel disease, may be best served with bypass in the first
place. Those who have multi-vessel disease that's less complex
and don't have significant symptoms after fixing the non-CTO
lesions, then they may not benefit from CTO PCI as well. But
those who have CTO lesions and have significant symptoms, this is
the population for which I think there is general agreement, and
I the decision that CTO is good with that, that those patients
could benefit from CTO intervention.


 Dr Carolyn
Lam:              
Thank you so much for sharing your insights.


                                               
Thank you, listeners, for joining us today. You've been listening
to Circulation on the Run. Don't forget to tune in again next
week.


                                               
This program is copyright American Heart Association 2019.