Circulation September 24, 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 Gregory Hundley:       I'm Greg
Hundley, also associate editor from the Pauley Heart Center at
VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
Greg, what do you think is the association between preeclampsia
and hypertensive diseases of pregnancy and cardiovascular disease
and future? Well, we're going to find out in a large U.K.
pregnancy cohort of linked electronic health records, the CALIBER
Study, but that's a feature discussion that's coming right up.


                                               
I think we need to start by discussing this week's hot issue. For
the first paper, we know that the incidents of acute
cardiovascular complications are highly dependent on the time of
day. Greg, have you ever wondered what mechanisms drive the
rhythmicity of ischemic vascular events?


Dr Gregory Hundley:       You know
what, Carolyn, I had a dream about that and I think that somehow
maybe it might be something to do with leukocytes.


Dr Carolyn
Lam:               
Good guess, Greg. Well, Dr Christoph Scheiermann and his
colleagues from University of Geneva looked at this and they
examined the role of rhythmic leukocyte adhesions and what those
play in different vascular beds. They did this by evaluating
leukocyte recruitment in vivo with real time, multichannel
fluorescence intravital microscopy of a TNF alpha induced acute
inflammation Murine model.


                                               
Now, they also used ablation of sympathetic nerves or adrenergic
receptors to assess their relevance for these rhythmic leukocyte
adhesions. Basically what they found was that leukocytes adhere
to arteries and veins following a circadian rhythm in mice, with
adhesion peaking in the arteries in the morning and in the veins
at night.


                                               
These peaks in leukocyte adhesion at different times in the two
vascular beds were associated with increased vascular
inflammation and shortened times to local basal occlusive events
occurring out of phase between the arteries and the veins. The
differences in cell adhesion molecules and leukocyte adhesions
were ablated when disrupting the sympathetic nerves, thus
demonstrating their critical role in this process and the
importance of beta2-adrenergic receptor signaling. Neat, huh?


Dr Gregory Hundley:       Really
neat. It's interesting how that ties together sympathetic nerve
activity and leukocyte adhesion.


Dr Carolyn
Lam:               
You got a paper?


Dr Gregory Hundley:       I've got
a paper to discuss and it's from Dr John Cooke at the Houston
Methodist Research Institute. It's involving nuclear
S-nitrosylation and how that defines an optimal zone for inducing
pluripotency, the ability to generate induced pluripotent stem
cells or I.P.S.C's from somatic cells as it enhanced the field of
regenerative medicine.


                                               
It has facilitated studies of development in differentiation,
promoted insights into pathobiology, and generated a novel
platform for drug discovery and testing. In fact, work in this
area has been sufficient to induce nuclear reprogramming to
pluripotency and galvanized our whole scientific community.
Recently in 2012, this work was recognized by the Nobel Prize for
physiology or medicine.


Dr Carolyn
Lam:               
Wow. What did this week's paper show in this area?


Dr Gregory Hundley:       Well,
Carolyn, in this study, the team identified an optimal zone. They
call it the Goldilocks zone of innate immune activation for
nuclear reprogramming to pluripotency. The authors believe that
this Goldilocks zone for nuclear reprogramming may have broad
relevance for epigenetic control, for regenerative processes, and
for the pathobiology of cancer and even other diseases.


                                               
Consequently, the results from this study may help to develop
methods that identify whether a patient or tissue is in an
optimal zone of inflammatory signaling to improve surgical and
medical therapies. In addition, they may provide a method to
detect early inflammatory signaling and DNA accessibility and
thereby reverse these processes to guide cancer prevention.


Dr Carolyn
Lam:               
Oh wow, Greg. It sounds like a real landmark paper. Everyone,
you've got to pick that one up. As with this next paper, it is
the first randomized trial comparing internal cardioversion by
commanded shock and external cardioversion in patients with ICD's
who present in atrial arrhythmias.


                                               
Dr Lüker and colleagues from University Hospital Cologne
randomized 230 consecutive patients with ICD's undergoing
elective cardioversion for atrial arrhythmias at 13 centers and
they randomized them to either internal or external
cardioversion. The primary safety endpoint was a composite of
lead or device malfunction and conversion of the atrial
arrhythmia to sinus rhythm was the primary efficacy endpoint.
Myocardial damage was studied by measuring troponin release in
both groups.


Dr Gregory Hundley:       I really
like where this study's going. What did they find?


Dr Carolyn
Lam:               
They found that external cardioversion was superior for the
restoration of sinus rhythm, with shock efficacy of 93% in the
external cardioversion group compared to 65% in the internal
cardioversion group. There were three cases of preexisting silent
lead malfunction that were unmasked by the internal shock
resulting in lead failure. Troponin release did not differ
between the groups.


                                               
In summary, these findings suggest that external cardioversion
may be considered as the first line approach to electrical
cardioversion in patients with ICD's and atrial fibrillation.
Because silent lead malfunction may be present in some ICD
patients, internal cardioversion may be considered in select
patients to detect it and with no difference in adverse events
associated with internal or external shocks. That's a good sign
but needs to be evaluated in larger randomized trials.


Dr Gregory Hundley:       Oh, very
nice, Carolyn. Well, my next paper is entitled the Androgenic
Effects on Ventricular Repolarization and it's a translational
study from the International Pharmacovigilance Database to
iPSC-cardiomyocytes. The corresponding author is Dr Joe-Elie
Salem from Vanderbilt University Medical Center.


                                               
Male hypogonadism arising from a range of ideologies, including
androgen deprivation therapies and other things, has been
reported as a risk factor for acquired long QT syndrome, as well
as torsade de pointes. The authors searched the International
Pharmacovigilance Database, VigiBase, for men and they had
6,560,000 plus individual case safety reports presenting with
long QT syndrome, torsade de pointes, or sudden death associated
with androgen deprivation therapies.


                                               
In cardiomyocytes derived from induced pluripotent STEM cells
from men, they also studied the electrophysiological effects of
androgen deprivation and dihydro testosterone.


Dr Carolyn
Lam:               
That's super interesting. What did they find, Greg?


Dr Gregory Hundley:       It's one
of these combinations of a clinical study as well as basic
science. Of the 10 androgen deprivation therapies examined, seven
had disproportional association reporting odds ratios of one four
to four seven with long QT syndrome, torsade de pointes, and
sudden death. The minimum medium times to sudden death were from
0.25, a quarter of a day, to 92 days respectively. The androgen
receptor antagonist, enzalutamide was associated with more deaths
than any other androgen deprivation therapy used for prostate
cancer.


                                               
In the basic science experiment, in induced pluripotent STEM
cells acute and chronic enzalutamide at 25 micromolar, a.
Significantly prolonged action potential durations, b. Generated
after depolarizations and activity, c. Inhibited delayed
rectifier potassium currents, and d. Chronically enhanced late
sodium currents.


                                               
Interestingly, dihydrotestosterone at 30 nanomolar reversed the
enzalutamide electrophysiologic effects on these induced
pluripotent STEM cells.


Dr Carolyn
Lam:               
Again, really interesting approach from this Pharmacovigilance
Database as well as bench work and clinical work, but what do we
do with this information?


Dr Gregory Hundley:       Couple of
key points, Carolyn. One, men receiving androgen deprivation
therapy are at increased risk for drug induced QT prolongation
and torsade de pointes. Two, in men developing acquired long QT
syndrome or torsade de pointes, a diagnostic workup might include
evaluation of testosterone blood levels, androgen deprivation
therapy intake, and evaluation for endocrine conditions
associated with hypogonadism. Three, in men treated with androgen
deprivation therapy for example, for prostate cancer, other risk
factors for torsade de pointes should be sought and corrected to
avoid any accumulation of risk. And finally number four, in men
treated with androgen deprivation therapy, the role of
electrocardiographic monitoring to detect QT prolongation really
requires an additional study.


Dr Carolyn
Lam:               
Cool, Greg. What else in the journal did you find cool?


Dr Gregory Hundley:       Yeah,
this is great, Carolyn. We're going to start now with sort of a
new format where we go through all the other wonderful
information. We're just going to trade back and forth.


                                               
The first one I'm going to tell you about is a letter from James
Tisdale who is from the College of Pharmacy at Purdue University,
and he demonstrates in a small randomized controlled trial that
transdermal testosterone attenuates drug induced QT lengthening
in older men. Really kind of links back to that study I just told
you about.


Dr Carolyn
Lam:               
Nice. Well, I want to highlight an on my mind paper and it's
entitled, Chronic Severe Aortic Regurgitation, Should we Lower
Operating Thresholds? This is from Dr Desai at Cleveland Clinic
and he considers newer EchoMRI methods to assess the severity of
aortic regurgitation and determine suitability for valve
intervention. It's a large study and just a really nice read of a
short on my mind paper.


Dr Gregory Hundley:      
Excellent. Well, you know we also highlight excellent reviews in
circulation and the one I'm going to discuss briefly is from
Schuyler Jones from Duke and he revisits the role of primary
aspirin for primary prevention of cardiovascular disease.


                                               
He talks about the indications, that there are really few
indications for aspirin in those with diabetes mellitus,
community dwelling elderly individuals, and patients without
diabetes who are at intermediate risk for atherosclerotic events.
Also, he discusses the role of aspirin and reviews very nicely
the role of aspirin in primary prevention including the optimal
drug formulations, different dosing schedules, weight-based dose
selection, and the interplay between sex and treatment response.
It's a great review.


Dr Carolyn
Lam:               
Ah, and then from a nice in-depth review we also have a
perspective, a nice short read. This one is from Dr Simari from
Kansas who discusses diversity in clinical trials and you know,
his title is actually a question, when will clinical trials
finally reflect diversity? Really lovely paper. He points out
that to increase the diversity of enrollment, we need to consider
expanding the diversity of investigators. So, a nice piece there,
too. Thanks, Greg. That was a super chat. Shall we go on to our
feature discussion now?


Dr Gregory Hundley:      
Absolutely. Welcome everyone to discussion of our featured
article focusing on hypertensive disorders in pregnancy, and then
the subsequent long-term outcomes related to that. For our author
discussion, we have Fergus McCarthy from Ireland and the Irish
Center for Fetal and Neonatal Translational Research at Cork.
Then, we also have our associate editor, Sharon Reimold.


                                               
Fergus, could you tell us a little bit about what was your
thinking behind starting this study? What type of questions were
you trying to answer? And then after that, tell us a little bit
about the study design.


Dr Fergus McCarthy:       I'm an
obstetrician by trade and we have this funny paradox where a lot
of us know that pregnancy is not just about the nine-month
periods that a woman is pregnant and then ultimately delivers,
that what happens in pregnancy can influence long-term maternal
health. But despite this, we have this paradox whereby a woman
becomes pregnant, the pregnancy may be complicated by hyper
pressure in pregnancy, the woman delivers her baby, goes home and
often doesn't see a healthcare practitioner for possibly another
10, 20 years.


                                               
Even though we know if a pregnancy is affected by high blood
pressure, we don't really do a huge amount about it and we deal
with this funny situation. We know that high blood pressure in
pregnancy affects two to 8% of pregnancies, depending on the
population studied. What we wanted to do was examine specifically
the impact of hypertension or high blood pressure in pregnancy on
long-term maternal health.


                                               
But importantly, what we also wanted to try and determine was is
there any factor that may be modifiable that may be ultimately
able to improve or reduce the long-term morbidity associated with
having hyper pressure in pregnancy? So, if you have high blood
pressure in pregnancy, is that it or is there anything that we
maybe could make women aware of that may ultimately improve their
long-term health?


                                               
Also as I said, despite research documented in the association
between preeclampsia, which is high blood pressure in pregnancy
and major cardiovascular disorders later in life, but we felt
also that there was a lot of limitations with the evidence that's
there.


                                               
Firstly, a lot of the evidence is focused on more composite
endpoints and secondly, over the past several decades, the
pattern of initial presentation of cardiovascular disease has
changed significantly. And thirdly, a lot of the studies that are
out there have been unable to adjust for post-pregnancy factors
such as hypertension. We wanted to see whether that was a
significant factor. But that's the thought process behind why we
undertook this study.


                                               
Then we had a great opportunity with the collaboration with the
Fire Institute in London and University College London, whereby
we were able to use a database which is called CALIBER. What
CALIBER stands for is cardiovascular research using linked
bespoke studies and electronic health records, bit of a mouthful.
But what CALIBER is, is basically it's a combination of the GP
database in the U.K., which is called the Clinical Practice
Research Database, hospital episodes, statistics, and the Office
for National Statistics cause specific mortality records. What
that does is basically it combines a lot of pregnancy data with
long-term really well phenotyped cardiovascular disease.


                                               
In particular, what CALIBER is very strong for is they have
phenotypes, 12 cardiovascular phenotypes, in an extremely strong
robust way. So, we were able therefore to examine the impact of
pregnancy using the GP database, using the CPRD with these 12
cardiovascular phenotypes as our outcomes.


Dr Gregory Hundley:       Tell us a
little bit about your study population and what were some of the
results of your study?


Dr Fergus McCarthy:       What we
did was we used electronic health records from a period of 1997
to 2016 and we looked at a U.K. population core of about 1.3
million women. The mean age of delivery of these women was about
28 years of age and they had about just under 2 million, 1.9
million completed pregnancies.


                                               
Over the 20-year study period, we were able to observe just over
18,000 cardiovascular disorders, 65% of which had occurred in
women under the age of 40. Again, this was quite surprising
because using cardiovascular disease, you think a much older
group, and when we looked at the pregnancies that were affected
by hypertension in pregnancy, we were able to see that compared
to women without hypertension in pregnancy, women who had one or
more pregnancies affected by preeclampsia had increased hazard
ratio for stroke, atherosclerotic events, heart failure, atrial
fibrillation, cardiovascular death, and for chronic hypertension.


                                               
What was particularly interesting was that the differences in the
cumulative incidence curves that we were able to see. According
to preeclampsia, we were able to see these differences within one
year of the first index pregnancy. So again, this was quite
fascinating from our point of view because I think prior to this
study, maybe we thought that it was happening a bit earlier than
we thought in women's lives, but actually, to see something so
soon occur after pregnancy was quite interesting.


                                               
The other thing that, and one of our motivations to do this was
to say, okay, well is there anything we can do about it? Is there
anything that might be modifiable here? What we were able to do
within our study was we were able to examine, is this just
because women are leaving hospitals with high blood pressure and
this high blood pressure is not being treated? What we were able
to do was we were able to adjust into our models this concept of
having postpartum hypertension. If we were able to adjust for the
mediating effect of post-pregnancy hypertension, we observed a
35% reduction in the point estimates of the hazards ratio for any
cardiovascular disease event.


                                               
One of the things I think that this study shows is that it is
critically important that women have appropriate medical
follow-up after their pregnancy. It's a very difficult period.
People have young babies, they may be going home to more children
at home, and often the neglected person in this situation is the
mother. What we're saying is that actually even if we could focus
on that one factor which is post-pregnancy adequate control of
hypertension, we may be able to reduce the hazards ratio of
developing a cardiovascular disease by approximately 35% is what
the study is suggesting.


Dr Gregory Hundley:       Really
interesting results, Fergus. Sharon, I wanted to turn to you a
little bit. How do the results of this study change for us the
way we might practice in terms of managing this patient
population?


Dr Sharon
Reimold:         This
study, I think, is very interesting because of the large
population and the significant number of unfortunately adverse
outcomes and the ability to compare those with and without
preeclampsia and hypertension. I think that we end up with two or
three different issues or ways that we think about dealing with
them.


                                               
First of all, just as Fergus alluded to is we need to make sure
that we take hypertension seriously in pregnancy and since it's a
small, but significant number of women leave the hospital and
will remain hypertensive, we need to assure that they are getting
care. The other thing that I think is important in this group,
but you would never be able to capture in the current study is my
approach is also to think about, well, what other risk factors
does this woman have other than just high blood pressure? Is she
at risk to be a diabetic? Does she smoke? Is she getting enough
exercise? What other things can we do to modify their long-term
risks?


                                               
This points out a method to identify those patients pretty
easily. Are they hypertensive early post-pregnancy, and then it's
up to the medical community to really develop strong guidelines
and training that emphasizes using prevention in the outpatient
setting.


                                               
The two things I found very interesting about this work, first of
all, the rapid separation of these curves. I know that they had
some very young women that gave birth and then some obviously
women of what I guess would be termed advanced maternal age. But
we do think of a woman who has a child at 30 maybe being at
higher risk when she's 50 or 60, but the risk is much earlier,
and patients are really not aware of this.


                                               
Then, the ultimate thing is how do we identify these women early
in their pregnancy or before they're pregnant, so we can help
avoid these complications altogether? I guess the take home
message is if somebody has hypertension or they're going home
hypertensive, they need early follow-up and we need to be
aggressive about their treatment.


Dr Gregory Hundley:       Both of
you have emphasized the point that this paper makes of early
identification of hypertension. In the paper, it talks about
hypertensive disorders of pregnancy. I think many of us
understand about preeclampsia or eclampsia and relatively high
blood pressures, HELLP syndrome, et cetera. Are there other
issues that we need, like what blood pressure ranges are we
thinking about?


                                               
If I'm picking up a chart of a woman in their early forties, late
thirties what should I be looking back for retrospectively in
terms of blood pressure levels? Do I follow the new guidelines
and I'm looking for blood pressures above 120 systolic? Can
either of you give us some guidance on what to look for, how I
would set up a program, what the timing would be, when I need
women to come back? Just practical things like that.


Dr Sharon
Reimold:         I
believe that is still in the obstetric world that the older
guidelines are really what are used and whether those shift over
time to lower thresholds for the diagnosis of hypertension is not
clear, but usually it's 140 over 90. You want to try to get the
patient history and differentiate between those people that
perhaps were hypertensive prior to their pregnancy, people who
had isolated short-term hypertension during their pregnancy, and
those people who then left pregnancy remaining hypertensive. But
I'll ask Fergus since he deals with this a lot more than I do
with the pregnancies, what they use as the cutoff in the U.K.


Dr Fergus McCarthy:       In
general, we had the CHIPS Study, which was published several
years ago. That advocated, certainly during pregnancy, that a
tighter control of blood pressure was associated with an improved
pregnancy and improved maternal outcome. That type of control
generally aimed for a systolic blood pressure of under 135. In
general, when we are managing our patients, that's usually what
we're aiming for, to keep the systolic blood pressure under 135.


                                               
I think the other thing that is becoming apparent from a lot of
the work that's been done is that it's maybe not just about the
pre-eclamptic woman, which is generally the woman with
hypertension and proteinuria that gestation and hypertension,
which often is nonproteinuric by definition, is also playing a
significant part.


                                               
Certainly, when you look at populations where I previously worked
in the U.K. and London, women with chronic hypertension,
pregnancy is becoming a huge issue, both with increasing obesity
and certain ethnic groups, and with advanced maternal age women
coming into pregnancy with chronic hypertension is really
becoming a major issue for us, as well, and is associated with a
much worse pregnancy outcome. But to answer the question, that's
usually where we're aiming for and we're trying to, where
possible, run as tight a control of blood pressure as possible.


Dr Gregory Hundley:       Thank you
very much, and we look forward to talking and discussing with you
with Carolyn next week.


Dr Carolyn
Lam:               
This program is copyright American Heart Association 2019.