Circulation July 09, 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 from the Pauley Heart
Center at VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
I'm so excited about our feature discussion today, Greg, because
it is about a familiar but very important problem of
hypertension, and we will be looking at trial results of a new
drug, a first in its class type of drug. And tackling a problem
that is particularly important perhaps in black patients with
hypertension. Well, more very soon. First, let's discuss some
papers, shall we? Do you have one?


Dr Greg
Hundley:            
My paper is from Joseph Burgoyne from King's College in London
and pertains to resveratrol. Now, resveratrol is a non-flavonoid
polyphenolic compound that has been found in the skin of several
fruits, with the most notable being grapes. The compound exhibits
beneficial effects, including the prevention of cardiovascular
neurologic diseases, cancer, metabolic syndrome, as well as it
promotes bone and eye health. And in this study, the
investigative team explains how resveratrol may mediate its
numerous beneficial effects including lowering of blood pressure
by direct thiol oxidation. Also, they demonstrate that
resveratrol can counter-intuitively induce direct protein
oxidation, a process that is enhanced under pro-oxidative
conditions associated with disease. The oxidation of cyclic GMP
dependent protein kinase 1 alpha, or PKG1 alpha, by resveratrol
lowers blood pressure in hypertensive mice.


Dr Carolyn
Lam:               
Okay. But what does that mean for us clinically, Greg?


Dr Greg
Hundley:            
Well, the results demonstrate how blood pressure can be lowered
by using resveratrol, and targeting cysteine 42, or PKG1 alpha,
may provide a new class of anti-hypertensive agents. In addition,
identifying additional proteins modified by resveratrol may
provide new targets for therapy to treat cardiovascular disease.
Carolyn, how about your first paper?


Dr Carolyn
Lam:               
We are going to look at the further results of the ODYSSEY
OUTCOMES trial. And as a reminder, ODYSSEY OUTCOMES was a
double-blind randomized comparison of the PCSK9 antibody
Alirocumab with placebo in almost 19,000 patients who had an
acute coronary syndrome 1-12 months previously and elevated at
the atherogenic lipoproteins despite intensive statin therapy.


                                               
And that trial found that Alirocumab reduced the risk of the
primary composite outcome of coronary heart disease, death,
ischemic stroke, myocardial infarction, or unstable angina
requiring hospital admissions. The current paper looked further
at the effects of Alirocumab on death.


Dr Greg
Hundley:            
So Carolyn, what did they find?


Dr Carolyn
Lam:               
Well, there are quite a number of findings here. The first, there
were fewer deaths in total that occurred with the PCSK9 inhibitor
Alirocumab versus placebo, and this resulted from a
non-significantly cardiovascular and non-cardiovascular deaths
with Alirocumab. The second finding was that in a pre-specified
analysis of more than 8,200 patients eligible for 3 or more years
of follow-up, Alirocumab reduced death.


                                               
And then, the third finding was that patients with non-fatal
cardiovascular events were at increased risk for both
cardiovascular and non-cardiovascular deaths, and a post-Hoc
analysis found that compared to patients with a lower LDL, those
with a baseline LDL above 100 had a greater absolute risk of
death, and a larger mortality benefit with Alirocumab. In the
Alirocumab group, all cause death declined with a lower achieved
LDL achieved at 4 months of treatment to a level of approximately
30.


                                               
So in summary, Alirocumab added to intensive statin therapy, has
the potential to reduce death after acute coronary syndrome,
particularly if treatment is maintained for 3 or more years, and
if baseline LDL is 100 or more, or if achieved LDL is low.


Dr Greg
Hundley:            
That's great, Carolyn. My next paper is going to talk a little
bit about endothelial cells. And what I think we're going to
learn is that not all endothelial cells are alike. This comes
from Dr Rajat Gupta from Brigham and Women's Hospital, and I
really thought this was an interesting article that used
single-cell RNA sequencing to make it possible to identify and
characterize cellular sub-populations.


Dr Greg
Hundley:            
The investigative team performed enzymatic dissociation of 4
whole mouse aortas, followed by single-cell sequencing of over
10,000 cells.


Dr Carolyn
Lam:               
Wow. What did they find?


Dr Greg
Hundley:            
Well using cluster analysis of gene expression from the aortic
cells, they identified 10 populations of cells representing each
of the main arterial cell types. There were fibroblasts, vascular
smooth muscle cells, endothelial cells, immune cells, including
monocytes, macrophages, and lymphocytes. And importantly, there
were 3 distinct endothelial cell sub-populations with differences
in them driven by major functional gene programs including
adhesion and lipid handling.


                                               
Comparison of aortic single-cell RNA sequence data sets from
normal and Western diet-fed mice suggested that these
sub-populations exist under both dietary conditions and have some
unified responses to diet alteration. Also, immunofluorescence
using single marker genes to identify endothelial cell
sub-populations showed that the VCAM1 positive population was
spatially located in regions of disturbed flow like the lesser
curve of the aorta.


Dr Carolyn
Lam:               
Okay. So bring it home for us, Greg. What does this mean
clinically?


Dr Greg
Hundley:            
Yeah exactly, Carolyn. So, characterizing functional
sub-populations may serve as a novel method for understanding
endothelial health in patients with vascular disease. And
although aortic endothelial cell sub-populations demonstrate some
unified responses to vascular disease relevant stimuli, like a
Western diet, functionally different sub-populations may
contribute differentially to vascular diseases, enabling
sub-population targeted therapies to perhaps be implemented in
the future.


Dr Carolyn
Lam:               
Cool. So Greg, cardiomyopathies have often been seen as genetic
in origin, but what about potentially modifiable causes? So, this
next paper that I picked looked at that, and it's from
corresponding author Dr Rosengren from Sahlgrenska University in
Gothenburg, Sweden, who with her colleagues, sought to
investigate a potential link between obesity in adolescence and
being diagnosed with cardiomyopathy in adulthood.


                                               
So, this was a nation-wide register-based prospective cohort
study of almost 1 million 690,000 adolescent men who were
enlisted for compulsory military service from 1969 to 2005. Now
at baseline, body mass index, blood pressure, and medical
disorders were registered, along with test results for fitness
and muscle strength. Cardiomyopathy diagnosis was then identified
from the National Hospital Register and Cause of Death Register.


                                               
So, they found that during a median follow-up of 27 years, 4,477
cases of cardiomyopathy were identified, of which 59% were
dilated, 15% were hypertrophic, and 11% were alcohol or
drug-induced. Increasing body mass index, or BMI, was strongly
associated with elevated risk of cardiomyopathy, especially
dilated cardiomyopathy, starting at levels considered normal,
meaning a BMI of 22.5 to less than 25 kilograms per squared
meters.


                                               
And this was even after adjusting for age, years, center, and
baseline comorbidities. There was a more than 8 fold increased
risk of cardiomyopathy at a body mass index of 35 and above,
compared with a BMI of between 18.5 and less than 20.


Dr Greg
Hundley:            
So, it sounds like BMI elevations and cardiomyopathies don't go
together. So, what are the clinical implications?


Dr Carolyn
Lam:               
This really shows that even mildly elevated body weight in late
adolescence may contribute to being diagnosed with cardiomyopathy
in adulthood. So, the already marked importance of weight control
in youth is really further strengthened by these findings, as
well as the greater evidence for obesity as a potential important
cause of adverse cardiac remodeling that is independent of
clinically evident ischemic heart disease.


Dr Greg
Hundley:            
Outstanding. So, BMI, not good.


Dr Carolyn
Lam:               
Nope, Greg. High BMI, not good. That was fun, Greg. So, shall we
move on to our feature discussion?


Dr Greg
Hundley:            
Absolutely.


Dr Carolyn
Lam:               
For our feature discussion today, we are talking about a familiar
problem, but just so very important, and that is hypertension.
And guess what? Our feature paper discusses a new first in class
centrally-acting renin-angiotensin system blocker that has such
remarkable initial results. I am so pleased to have with us the
corresponding author for the paper, Dr Keith Ferdinand from
Tulane University School of Medicine, as well as our Guest
Editor, Dr David Calhoun from University of Alabama and
Birmingham.


                                               
Keith, could you start by telling us a little bit about the kinds
of patients you see there in New Orleans that struggles with
hypertension control perhaps? And then, please tell us about
Firibastat.


Dr Keith
Ferdinand:         I'm in
New Orleans. In fact, I'm a native New Orleans. And as you know,
most of the south and southeast and part of the United States has
a high proportion of African American or US blacks. This
population has higher rates of hypertension, increased
prevalence, more severe hypertension, and more uncontrolled
hypertension.


                                               
We also note in the south that there tends to be an increase in
obesity, which is a powerful risk factor for all patients with
hypertension, regardless of race or ethnicity. And unfortunately,
the rates of obesity appear to be increasing. So based on the
fact that we have an increase in obesity, we have many patients
whose blood pressures are not controlled, and some of the
previous data have suggested less response to first step or
monotherapy with ACE inhibitors and angiotensin receptor
blockers, I initiated a trial with a first in its kind oral
active brain aminopeptidase A inhibitor.


Dr Carolyn
Lam:               
Wow. Could you tell us a little bit more about brain
aminopeptidase, and this new drug Firibastat?


Dr Keith
Ferdinand:         Most
people don't know anything about this molecule, because this is
something that was discovered by some French physiologists. They
approached me to design the clinical trial here in the United
States. And what it does is, it blocks the conversion of
angiotensin II to angiotensin III in the brain. Angiotensin III
is actually the active component of the renin-angiotensin system
centrally, and if you block angiotensin III production, it has a
triple therapy effect.


                                               
One is that it causes the diuresis. It decreases sympathetic
tone, and it stimulates the carotid artery, such that you have,
again, a decrease in sympathetic tone. Now, why choose it for
patients who are obese, and why want to include a large
proportion of non-Hispanic blacks here in the United States?
Well, the reasons are that when you look at some of the bench
research using rats, it appears to have a more beneficial effect
in DOCA-salt rats, which is a model for salt-resistant
hypertension.


                                               
Salt-resistant hypertension is more common in blacks, more common
in patients with obesity, and may indeed be one of the reasons
why monotherapy or first-step with conventional renin-angiotensin
system agents, specifically ACE inhibitors and ARBs, have not
been as effective in the past.


Dr Carolyn
Lam:               
Gosh. That is so interesting, and it's really making me think
about my patients too here in Asia, where we have a lot of
salt-sensitive hypertension. Now, could you please tell us about
the trial you did, and what you found?


Dr Keith
Ferdinand:         We
looked at a cohort of patients. All of the patients were
overweight and obese. They were washed out for 2 weeks, and had a
systolic blood pressure of 145-170, and a diastolic of less than
105. We wanted to get at least 50% self-identified blacks or
Hispanics, and I suspect that any patient who meets this
phenotype, and that would include Asians, or even Whites, may
respond similarly.


                                               
We then placed them in an open label format, and I can discuss
why we used an open label, with monotherapy with Firibastat.
After 2 weeks, we then titrated the dose level from 250 twice
daily to 500 twice daily if needed, and we had a low dose
thiazide and hydrochlorothiazide 25 mg addition, if needed, for
escape, if patients had a blood pressure greater than 160/100.


                                               
The other thing that was interesting and unique about this
particular trial is that we used the automatic office blood
pressure, where the blood pressure was taken 6 times. The first
time was discarded, and then averaged, without a particular
doctor or a nurse being there to do the blood pressure. We felt
that this was a valid means of getting blood pressure loaded. It
tends to mimic, to a large extent, what you see in 24 hour
inventory daytime systolic blood pressure.


                                               
So, this was a valid means of measuring blood pressure loads.
This was a relatively high risk patients. And these were patients
whom, previously, probably would not have responded as well to
monotherapy with ACE inhibitors or ARBs.


Dr Carolyn
Lam:               
That's really clear, and clever design. I would love to hear a
little bit more about why the open label, and of course, the
results.


Dr Keith
Ferdinand:         Well,
that's one of the criticisms of this study, but actually, we
presented to the FDA when we were discussing designing this
trial, perhaps doing a placebo control trial. And we were told by
the FDA that if you use a valid means of measuring blood pressure
load, so that would be ambulatory blood pressure, or automated
office blood pressure, that a placebo would not be necessary,
because those means of checking blood pressure load would be
considered a true valid means of finding a blood pressure effect.


                                               
The other thing is, dealing with minority patients, and really
dealing with patients in general, for blood pressure, if they
have substantial hypertension, the message has been out there
that this is a killer and cause of cardiovascular disease. It
would probably have been very difficult to enroll the patients,
you've got 254 patients in a national study. It would have been
very difficult to enroll these patients, who would have known
easily that they had substantial elevation of blood pressure, and
we said, "You know, 50% chance you're going to get a sugar pill
that has no effect."


Dr Carolyn
Lam:               
Right. Right. Very nice. The results?


Dr Keith
Ferdinand:         Well,
the results were a robust 9.7 mm reduction in systolic blood
pressure. At day 56, the p-value was less than 0.0001. And when
you do a sub-group analysis of patients who were in the study, it
was effective for persons who are under 65, or over 65, male or
female. All patients were overweight, and the patients who were
obese, with a BMI of 30 or above, had a trend towards even a
better blood pressure effect, which again, is not seen with first
step with conventional ACE and ARBs.


                                               
We also did an analysis based on black and non-black, and there
was no difference, again with the trend towards the black
patients actually doing fairly well. So, the take home from the
particular study was this is the first in its kind, new approach
to central Ras blockage with aminopeptidase A inhibitor, that was
effective in a population which was overweight and obese, with
over 50% minority, and showed substantial blood pressure
reduction using a valid means of checking blood pressure, the
automated blood pressure in the clinic.


Dr Carolyn
Lam                 
Keith, congratulations. A very important study. David, could I
bring you in here? What were your thoughts as you were managing
this paper, and what do you think are the future steps here?


Dr David
Calhoun:           
Looking at the submission, I was obviously excited about the
results and the potential implications. I think, like Keith, in
treating a lot of resistant or obesity-related hypertension,
we're frustrated that control rates are not better, that the
initial response to monotherapy is not better, and that's
particularly true of Ras blockers. I think many of us are
investigating the initial use of Ras blockers for a variety of
reasons related to outcome benefit and reduction in incident and
diabetes.


                                               
So, I know I like to start with such an agent. I'm particularly
excited that there may be, firstly, a new opportunity to block
the Ras system, and potentially comparable or even better in the
most difficult patients to treat. That is, the African American
and the Hispanic patients, who often have very severe
hypertension. So, my initial reading was I was very excited to
see the potential, and that was brought out by the reviews as
well. They shared my excitement. So, I'm looking forward to Keith
advancing this compound.


Dr Carolyn
Lam:               
Indeed. Keith, I'm sure everyone's thinking now, wow, remarkable
results. What's the drawbacks? How well-tolerated was this drug?


Dr Keith
Ferdinand:         One of
the drawbacks is that the structure of Firibastat included a
sulfhydryl group. And we saw with early studies with captopril,
which also has a sulfhydryl group, some skin rash, and we saw
those similar changes with some of the patients in this
particular study. At least 2 of them were suggested to
potentially have erythema multiforme, although this was not
proven. This was an investigator initiated adverse event.


                                               
So, I don't know if we're going to be able to structure a similar
type of aminopeptidase inhibitor without a sulfhydryl group. The
other thing is that in its presence formulation, it's given twice
daily. We know optimally you'd like to have a long-acting agent
that can be given once daily. And I don't think we need a placebo
control trial, but we may need to do a trial where patients are
on 2 or more medications, and then, you add the Firibastat versus
adding placebo. But, I don't think at this particular point, we
need to get some of these more difficult to treat patients, and
just place them on placebo, and watch and see what happens.


                                               
We know what happens. The blood pressure goes up. Many of them
may have acute heart failure, or progression of renal failure.
And I just don't think it's necessary. And the FDA doesn't think
it's necessary to prove that hypothesis.


Dr Carolyn
Lam:               
David, what do you think about that? Do we need a placebo control
trial? And that use of ambulatory blood pressure, that's novel
aspects of this trial too.


Dr David
Calhoun:           
I think use of placebo comparison has been for the traditional or
conventional approach. I think most investigators, most
clinicians, sort of anticipate seeing the placebo corrected
effect. So, I think the results would have been, or will be
potentially, more compelling if that's done. But, I can also
appreciate Keith's contention, and it sounds like the FDA, that
in this day and age, with use of automated office blood pressure
measurements tend to minimize that white coat effect, and
particularly true of ambulatory monitoring, that it may be that
not using a placebo comparison maybe is compelling as well.


Dr Carolyn
Lam:               
Indeed. I really enjoy actually just digging deep into the study
like this. Keith, if I could just ask for some final words from
you, learning lessons, or even what have you got planned next.


Dr Keith
Ferdinand:         The
first lesson is, we need to continue to pay attention to
hypertension. It's kind of been placed on the back burner with
more interest now in diabetes and sugar, a lot of interest in
lipids because of some of the new agents. But if you look across
the globe, Asians, blacks, whites, regardless of race or
ethnicity or geography, hypertension is the most potent
cardiovascular risk factor, and I think we need to continue to
address that.


                                               
In terms of this particular agent, I believe that we will have to
have some sort of placebo arm, but again, I think it's going to
be built on a conventional medication, and then randomized with
Firibastat versus placebo on top of conventional medications. In
a more severe or a more difficult to treat hypertension, I'm just
not really convinced that we need to do a purely placebo arm.


Dr Carolyn
Lam:               
Great, Keith. And David, how about yourself? Any take home
messages?


Dr David
Calhoun:           
I think when there's a new in-class compound, I think that's
always exciting, particularly when it has the initial results,
preliminary results, that Keith is reporting. As many agents as
there are out there to treat hypertension, we still are not doing
as well as we should be. I think it can only help to have
additional classes of agents as therapeutic options, and I think
that's particularly true with minority patients, who are, as
Keith has indicated, are at the biggest need in terms of
controlling blood pressure. Keith, these initial results are very
exciting, and I look forward to future studies.


Dr Carolyn
Lam:               
Completely sharing your enthusiasm here. Thank you so much,
Keith, for publishing this remarkable paper with us at
Circulation. Thank you, David, for helping us manage it.


                                               
And thank you, audience, 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.