Circulation November 12, 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, associate editor, director
of the Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr Carolyn Lam: Greg, we are going to have a great discussion
coming right up regarding intensive versus standard ambulatory
blood pressure control and its effects on cerebrovascular
outcomes in older people. It's the INFINITY trial, but that's all
I'm going to tell you for now because I want to hear all about
your picks for this week's journal first.


Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear
about that discussion regarding hypertension. My first paper
though is about titin and it comes from Dr Charles Murry from the
University of Washington. The giant sarcomere protein titin is
important in both heart health and disease as mutations in the
gene encoding for titin are the leading cause of familial dilated
cardiomyopathy. The uneven distribution of these mutations within
titin motivated the authors of this article to seek a more
complete understanding of this gene and the isoform it encodes in
cardiomyocyte sarcomere formation and function.


Dr Carolyn Lam: Cool. What did these investigators find?


Dr Greg Hundley: Using genetically engineered human induced
pluripotent stem cell derived cardiomyocytes, the authors
experimentally confirmed that the gene encoding for the giant
sarcomere protein titin includes an internal promoter and start
site. This internal start site encodes for the isoform Cronos,
which the authors demonstrate support some sarcomere formation in
these human induced pluripotent stem cell derived cardiomyocytes.


Dr Carolyn Lam: Oh, nicely summarized. What are the clinical
implications Greg?


Dr Greg Hundley: Well, Carolyn identification that Cronos titin,
a previously unstudied form of titin is necessary for normal
human cardiomyocyte function could be contributing to some of
these titinopathies that are relevant for some patients with
dilated cardiomyopathy.


Dr Carolyn Lam: Cool. Mine has to do with heart failure as well
and presents new results regarding heart failure and heart
failure related outcomes from the EXSCEL trial.


Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it
find?


Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest
glucagon-like peptide-1 receptor agonist or GLP-1 receptor
agonist trial reported to date where once weekly, exenatide had a
neutral effect on hospitalization for heart failure with no
differential treatment effect on major adverse cardiovascular
events or MACE, by baseline heart failure status. However, the
question remains, what about exenatide's effects on secondary
endpoints based on the heart failure status? This is from Dr Rob
Mentz and colleagues from Duke Clinical Research Institute who
aim to explore the effects of exenatide on secondary outcomes in
patients with and without baseline heart failure and test the
effects of exenatide on recurrent heart failure hospitalization
events.


Now they found that out of more than 14,750 EXSCEL participants,
16% had heart failure at baseline and when stratified by the
presence or absence of baseline heart failure, there was no
observed reduction in all cause death with exenatide in patients
with baseline heart failure. While the risk of mortality was
reduced with exenatide in the no heart failure group. And that
was a significant interaction P value of 0.031. Similar results
were observed for the combined outcome of all cause death or
heart failure hospitalizations.


Now regarding recurrent heart failure hospitalizations, 450
patients experienced at least one hospitalization for heart
failure, but there were 713 hospitalization heart failure events
in total. The effect estimate that included the recurrent events
was separately, statistically significant while the primary
analysis based on just first events was not.


In conclusion in EXSCEL, the use of exenatide in patients with or
without heart failure was well tolerated, but the benefits of
exenatide on reduction in all cause death and first heart failure
hospitalization were attenuated in patients with baseline heart
failure. Now this is accompanied by a great editorial by Bruce
Neil and Claire Arnett who caution against using post talk
subgroup analysis, but the interaction of exenatide tout with
baseline heart failure, it's interesting, although should be
treated with caution until confirmed by findings from another
trial.


Dr Greg Hundley: Very nice Carolyn, especially a nice issue
regarding heart failure and I'm going to steer a little bit away
from that and talk about atrial fibrillation duration and
CHA2DS2-VASc scores. Putting those two together and this article
comes from Rod Passman from Northwestern University. Studies of
patients with cardiovascular implantable electronic devices show
a relationship between atrial fibrillation duration and stroke
risk though the interaction with a CHA2DS2-VASc score is poorly
defined. The objective of their study was to evaluate rates of
stroke and systemic embolism in those patients with
cardiovascular implantable electronic devices as a function of
both the CHA2DS2-VASc2 score and A-fib duration.


Dr Carolyn Lam: Interesting. What did the authors do?


Dr Greg Hundley: They had 21,768 non-anticoagulated
cardiovascular implanted electronic device patients from the
Optum electronic health record, de-identified database from 2007
to 2017 and they link those to the Medtronic CareLink TM database
of CIEDs capable of continuous AF monitoring. Now the age
averaged about 69 years and 63% were men and they found that
increasing a fib duration, and of course increasing CHA2DS2-VASc2
score were both significantly associated with annualized risk of
stroke and systemic embolism. These rates were low however, in
those individuals with CHA2DS2-VASc2 scores of zero to one,
regardless of the device detected a fib duration.


Dr Carolyn Lam: Ah. Were there any particular threshold values
that seemed important?


Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk
crossed an actionable threshold defined as greater than 1% per
year in those with CHA2DS2-VASc2 score patients of two or more
with greater than 23 and a half hours of a fib or those patients
with CHA2DS2-VASc2 scores of three or four with greater than six
minutes of a fib duration or finally in those individuals with
CHA2DS2-VASc2 scores greater than five even if they had no atrial
fibrillation.


Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions
here. Thanks Greg. I'm going to tell you what else is in this
issue. There's also a research letter by Dr Rosenmeier entitled,
“Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac
Muscle Mass Through an Interleukin 6 Receptor Dependent
Mechanism.” And this is a cardiac analysis of a double blind
randomized controlled trial in abdominal obese humans. We have an
on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to
Explore the Role of Genetic Heterogeneity in Conferring
Phenotypic Variability.” And this discusses among other things,
the role of induced pluripotent stem cells and functional studies
of bioengineered HFpEF patient derived cardiac micro tissues that
could potentially enable several important questions to be
answered for the first time. There's an ECG challenge as well by
Dr Naru Kanya, and it's really interesting. It's a hiccup
artifact. If you haven't heard about that, you should take a
look. And finally cardiology news by Dr Kuhn and it's entitled,
“Nourishing Native American Communities by Increasing Access to
Traditional Food.” A very interesting paper right there.


Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten
provides a perspective piece regarding emerging affinity reagents
for high throughput proteomics, sort of an emerging field,
everyone doing proteomic studies, we have to pay a special
attention to the reagents that are being used. And then Andrew
DeFilippis from University of Louisville as well as Johns Hopkins
reviews important concepts related to the definition of MI.


Dr Carolyn Lam: Is this pertaining to that fourth universal
definition of MI?


Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this
white paper, the authors review the epidemiology, risk factor
associations and diagnostic tools that may assist in
differentiating between non-ischemic myocardial injury, type 1 MI
and type 2 MI. And then finally from Suowen Xu from the
University of Rochester, there's a letter discussing the CCN
family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are
mechano-sensitive proteins that are differentially regulated by
sheer stress, the frictional force exerted by blood flow in our
vessels. Well Carolyn, that's a great issue. How about we move on
to our feature article?


Dr Carolyn Lam: Let's go Greg.


For our feature discussion today we are talking about intensive
versus standard ambulatory blood pressure control and that effect
on cerebral vascular outcomes in older people or the INFINITY
trial. Very, very important stuff and I'm so pleased to be with
the corresponding author, Dr William White from Calhoun
Cardiology Center in University of Connecticut School of
Medicine. Dr White, thank you so much for being here. Could you
maybe set up already the background of what you were thinking
when you started this trial? Especially given the results that we
know from SPRINT and SPRINT mind. Could you perhaps comment on
how this INFINITY trial is different?


Dr William White: We started work in this area about 15 years ago
and we initially were interested in interactions among vascular
risk factors including ambulatory blood pressure, lipids and
other sort of thrombotic factors and so forth with the
development of small vessel disease in the brain that led to
these fairly classic images on MRI called white matter
hyperintensity lesions. And we learned from a prospective cohort
study that we started about 15 years ago, that there was a very
strong relationship between ambulatory blood pressure and the
development and progression of these white matter hyperintensity
lesions on MRI, but not very nice relationship with the clinical
blood pressures measured in the standard office practice.


We decided to pursue a clinical trial, a randomized clinical
trial in which we would evaluate different levels of ambulatory
blood pressure versus the development of the small vessel disease
as imaged by MRI, but very importantly we also wanted to link it
to functional outcomes because this was in older people,
typically in their late seventies, eighties and even nineties in
which cognitive impairment begins to develop. There's problem
with mobility, bladder function and things of that nature. And
since our funder was always the National Institute of Aging of
the NIH, there's a great deal of interest in more than just the
vascular risk factors and even the cerebral vascular disease that
we would detect on the MRI. That was the background of why the
study got developed the way it did.


Dr Carolyn Lam: That's so interesting. You've already pointed out
ways that this was very different from SPRINT OR SPRINT MIND in
looking at ambulatory instead of clinic blood pressure and I
suppose in the population you selected, out of curiosity, you
mentioned that your prior work showed a relationship between
white matter hyperintensity on MRI and perhaps future dementia.
In which direction? And is there any basis to suspect low, too
low blood pressure may also be bad in these older people who
already have microvascular brain disease?


Dr William White: Absolutely. Very important point. When we look
at our prospective cohort which was about a 100 older people, we
followed for four years without any intervention. This was just a
mixture of normal tensive and hypertensive individuals. Some on
meds, some not on meds. But we did show that when you got too low
or if you stay too low during those four years with a systolic
blood pressure of under 115 on a 24-hour blood pressure monitor,
it seemed like there was an almost like U shaped relationship
with progression of white matter disease. Below 115 there was
more accrual of white matter disease. Above 150 there was a
systolic blood pressure, there was also a greater accrual, but in
between about 125 and 145 we weren't really sure if there was
going to be a difference. And that there was the target is that
everybody's talking about for clinical measurement, so we decided
to pursue that in this study to determine if we could figure out
whether or not there was a sweet spot for the desk blood pressure
without getting into trouble with hypotensive symptoms.


Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely.
Now I get it that you chose the targets that you did, which just
for everyone, just a reminder, it was a 24 hour mean systolic
blood pressure by ambulatory blood pressure control and the two
targets were 130 millimeters mercury and less versus 145
millimeters mercury and less. With that, could you please tell us
the results?


Dr William White: Right. We called the 130 or less systolic
group, the intensive treatment group and the 145, the standard
group. We focused on the primary endpoint was changes in mobility
parameters in conjunction with changes in white matter
hyperintensity lesion growth. And after a period of about three
to four months of randomization, post randomization, we achieved
a 24-hour systolic blood pressure about 128 millimeters of
mercury in the intensive treatment group and 144 in the standard
group. And we maintained a pretty good separation in blood
pressure, ambulatory blood pressure throughout the three years of
treatment. Now the changes in gait speed, which was one of our
primary parameters for mobility actually turned out not to be
different between the treatment groups. That is intensive versus
standard. However, the changes in the accrual of light matter
hyperintensity volume was smaller in the intensive treatment
group of a 0.29% versus a 0.48% in the standard treatment group.
That was significant at a P value of 0.03.


We actually also had a pre-specified sensitivity analysis, sort
of a per protocol analysis that allowed us to look at people who
stayed in their sort of assigned treatment groups based on blood
pressure throughout the three years of the trial. And in that
circumstance, there was actually a stronger separation because
these are people who stayed clearly at 130 or less than about 145
throughout the three years and now the differences were
approximately 0.23% in the intensive group and 0.58% in the
standard group. And now the P value is smaller, .0028.


I think we proved in the study that maintaining a systolic blood
pressure on the ambulatory recorder over 24 hours of 130 or less
benefited patients by reducing the accrual of white matter
hyperintensity lesions by about 40% relatively speaking compared
to a standard ambulatory blood pressure value of a 145. One of
course caveat is that after that happened within three years, but
we did not see the expected benefit on mobility or on most of the
cognitive parameters either. And while we were a little bit
surprised about that, when we went back and analyzed our
situation with where people started from as far as this
particular cohort of patients, they might've been a little on the
healthy side compared to some other studies. A very educated
group, very compliant with everything that they did. And probably
three years was just not long enough to show the result of this
white matter hyperintensity benefit on some of the functional
outcomes.


Dr Carolyn Lam: That's really interesting and I'm glad you sort
of tackled head on that sort of apparent dissociation between the
clinical end points and the MRI end point. Could I also ask,
wouldn't those findings also be consistent with SPRINT and SPRINT
MIND?


Dr William White: In many ways our results were consistent with
SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course,
just let me mention the differences between the two studies. Of
course, SPRINT was very large but there are sub-studies were not
as large as the parent study. The MRI study had about 300 plus
patients randomized into it, but the measurement of blood
pressure was done in the standard clinical fashion and used that
digital device that was able to take measurements without
somebody present in the exam room. Though they were a bit lower
than what I would have seen on an ambulatory monitor during the
day time. And their goals were 120 systolic versus 140, whereas
ours were an ambulatory systolic of 135 and 145.


But the results were actually comparable because they showed a
benefit with regards to lesser accrual of white matter
hyperintensity volume in the intensive group versus this banner
treatment group. But they also showed no differences after 3.4
years in the incidence of dementia. And they also showed in a
separate study, no differences in gait speed in the population
who are in intensive versus standard treatment. One would say
that results were really actually comparable despite the age
differences and the blood pressure measurement differences. And I
think both studies really point to the fact that lower systolic
blood pressures in older people should be our target because it's
safer actually then than maintaining people in the 140s.


Dr Carolyn Lam: Maybe the follow-up period was not long enough.
Could it be possible too that maybe blood pressure control should
start earlier in life. Could that be it? And then also, could you
give us an idea of the kinds of changes, the magnitude of the
change on MRI that you see for those of us that don't think about
this all the time, is this a big change considered for your
cohort or is it a little change?


Dr William White: I think it's true that these people started out
around 81 years old in this trial and so by the time they got to
that age and had systolic hypertension for probably as many as 20
years, that some of the damage that was done was obviously
permanent and we don't really know how long it took for that to
accrue. What we did know is that with three years of intensive
treatment, we benefited patients by reducing the continued growth
or confluency of these small vessel lesions in the brain. Now the
range in the amount of damage varies from about half a percent of
the overall brain volume to about 5%, so a 10-fold magnitude
difference in our cohort.


And as a result of that, certainly somebody who's got about two
to 3% of their brain occupied by better hyperintensity lesions or
damage is going to have a great deal more functional disability
than somebody who's .5%. I think we have to look at the outliers
as well as the mean and median changes that we saw. The mean
changes are not huge. The difference between 0.2 and 0.6% for
example, in our protocol analysis, 0.4% to me it's clinically
relevant because I know that that means that there are some
people who went up by a percent or two over the years versus the
standard versus the intensive treatment group. That's a big
difference in an individual over that period of time.


Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my
brain.


Dr William White: Yeah. Plus it's also where it's located because
the lesions are typically around the ventricles of the brain and
it's exactly where neurons are going sort of posteriorly to
anteriorly to transmit information. For example, from the visual
center to the sort of spatial motor cortex. And when those are
interrupted, even if it's in one or 2% of the tissue, it can
cause substantial difficulties for people. And it's for both the
flow of cognitive information as well as this flow of a mobility
and balance. I think that it is very relevant, but the gray
matter is affected much less by this compared to the white
matter. But there are still studies that show that gray matter
sort of follows in line with that so that of course also enhances
thought processes and cognitive function as well.


Dr Carolyn Lam: Wow. I love the way you explained that. Very
important question would of course be the safety and tolerability
of this more intensive approach. Any comments there?


Dr William White: Our sponsor, the National Institute of Aging
did recruit a data safety monitoring board that was independent
from the study for all the years. Impressively over the course of
this trial, even though there wasn't a large sample, it was a 199
people, we saw a significant benefit in the intensive group for
cardiovascular events, so there were less admissions for heart
failure. There were less myocardial infarctions, there was less
strokes. All these kinds of things that we worry about in our
patients as they get older with vascular disease was reduced by
about 75% in the intensive treatment arm versus the standard arm.
As far as the events that we were concerned about, such as falls
and syncope and presyncope and things of that nature, they were
virtually identical in the intensive treatment group and `the
standard treatment group. When you take that into consideration,
along with the fact that you're reducing the accrual of small
vessel disease in the brain, it's clear that this population,
even though they're older, would benefit from a lower systolic
blood pressure.


Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That
was a beautiful summary. That is the take home message right
there.


Listeners, I'm sure you agree with me. Thank you so much for
joining us this week, and don't forget to tune in again next
week.


This program is copyright American Heart Association 2019.