Circulation September 26, 2017 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. Our featured discussion
today centers on new data from the Framingham Heart Study that
addresses the question of the prognosis of pre-hypertension among
individuals who never progressed to hypertension as well as the
role of early versus late onset pre-hypertension in this context.
Well, more soon, right after your summary of this week's journal.


                                               
The first original paper provides mechanistic insights on the
relationship between low and oscillatory wall shear stress,
together known as disturbed flow, and atherosclerotic arterial
remodeling and stiffness. Co-first authors doctors Kim and
Pokutta-Paskaleva, co-corresponding authors Dr. Brewster and Jo
from Georgia Institute of Technology in Emory University in
Atlanta, Georgia used a novel mirroring model of disturbed blood
flow to stimulate arterial stiffening through collagen deposition
in young mice. They discovered a critical role for Thrombospondin
1, or TSP1 in activating TGF beta and stimulating arterial
stiffening, all of which was significantly attenuated in the TSP1
knockout animal.


                                               
Blockade of TSP1 activation of TGF beta decreased the up
regulation of pro-fibrotic genes that contributed to arterial
stiffening. Furthermore, they show that TSP1 localized to regions
of disturbed flow in arteries from patients with peripheral
artery disease and these arteries had similar increases in
collagen gene expression. Thus, this work links TSP1 up
regulation to arterial stiffening and identifies TSP1 as an
important promoter of pathologic arterial remodeling in
peripheral artery disease.


                                               
The next study provides international insights on the degree to
which secondary prevention treatment goals are achieved in
clinical practice among patients with diabetes and cardiovascular
disease. First and corresponding author, Dr. Pagidipati from Duke
Clinical Research Institute at Duke University School of Medicine
in Durham, North Carolina, looked at 13,616 patients from 38
countries with diabetes and cardiovascular disease in the TECOS
trial. They found that only 30 percent of patients met all 5
secondary parameters of aspirin use, lipid control, blood
pressure control, angiotensin-converting enzyme-inhibitor, or
ARBUs, and non-smoking status.


                                               
Only 58 percent of individuals with diabetes and cardiovascular
disease attained blood pressure control. Furthermore, the degree
to which secondary prevention goals were met in this trial varied
by the world region and country. In summary, patients with
diabetes and cardiovascular disease are still being undertreated
globally with respect to secondary prevention, and especially
with regard to blood pressure control. These gaps in care provide
clear opportunities for improvement in this high risk population.


                                               
The next study is the first to directly compare data from an
electronic data research network to a large cardiovascular
disease cohort. First author Dr. Ahmed, corresponding author Dr.
Allen from Northwestern University in Chicago and colleagues
sought to evaluate the degree of agreement of electronic data
research networks compared with data collected by standardized
research approaches in a cohort study. To achieve this goal,
authors linked individual level data from the multi-ethnic study
of atherosclerosis, or MESA community based cohort with
Healthlink, a 2006 to 2012 database of electronic health records
from 6 Chicago health systems.


                                               
They identified areas of agreement and disagreement between blood
pressure, cardiovascular risk factor diagnosis, and
cardiovascular events between the two data sources. The
correlation was low for systolic blood pressure, compared with
MESA, Healthlink overestimated systolic blood pressure by 6.5mm
mercury. Conversely, there was a high correlation between body
mass index in MESA and Healthlink. Healthlink underestimated body
mass index by 0.3 kilograms per meters square.


                                               
Using ICD-9 codes and clinical data, the sensitivity and
specificity for Healthlink queries for hypertension were 82.4
percent and 59.4 percent. For obesity these figures were 73
percent for sensitivity and 89.8 percent for specificity and for
diabetes they were 79.8 percent for sensitivity and 93.3 percent
for specificity.


                                               
Finally compared with adjudicated events in MESA, the concordance
rates for myocardial infarction, stroke, and heart failure were
at 41.7 percent, 61.5 percent, and 62.5 percent, respectively.
These findings therefore illustrate the limitations and strengths
of electronic data repositories compared with information
collected by traditional standardized epidemiologic approaches
for the ascertainment of cardiovascular risk factors and events.


                                               
The next paper helps physicians and patients to make an informed
decision about whether or not to stop low dose aspirin use. First
and corresponding author Dr. Sundstrom from Uppsala University in
Sweden and colleagues investigated whether long term low dose
aspirin discontinuation increased the risk of cardiovascular
events in a cohort study of more than 600,000 users of low dose
aspirin for primary or secondary prevention in the Swedish
prescription register between 2005 and 2009.


                                               
They found that patients who discontinued aspirin had a 37
percent higher rate of cardiovascular events than those who
continued, corresponding to an additional cardiovascular event
observed per year in one out of every 74 patients who
discontinued aspirin. The risk increased shortly after
discontinuation and did not appear to diminish over time. Thus,
in long term users, discontinuation of low dose aspirin in the
absence of major surgery or bleeding seemed to be associated with
a more than 30 percent increased risk of cardiovascular events,
thus adherence to low dose aspirin treatment in the absence of
major surgery or bleeding may be an important treatment goal.


                                               
The final study raises the possibility of using Histone
Methyltransferase Inhibitors for the treatment of heart failure.
Dr. Papait from Humanitas Clinical and Research Center in Italy
and colleagues focused on G9A, a histone methyltransferase that
defines a repressive epigenetic signature. Using normal and
stressed cardiomyocytes from a conditional cardiac specific G9A
knockout mouse, and a specific G9A inhibitor, they showed that
the histone methyltransferase G9A was important in defining the
epigenetic landscape that maintained the transcription program of
the cardiomyocyte. It was also important for the regulation of
gene expression reprogramming during cardiac hypertrophy.


                                               
Furthermore, impaired G9A function promoted cardiac dysfunction.
Thus, these findings suggest that G9A may represent a therapeutic
target for early stages of cardiac hypertrophy.


                                               
That wraps it up for your summaries, now for our feature
discussion.


                                               
For today's feature discussion, we're talking about the very
important topic of the prognosis of prehypertension without
progression to hypertension. Now, we've always known that mild
blood pressure elevations that we call prehypertension are
associated with cardiovascular risk. However, this risk could be
attributable to the fact that these patients with prehypertension
eventually progress to overt hypertension. But, what happens to
the patients with prehypertension who do not progress to
hypertension, and what is the role of early versus late onset
prehypertension?


                                               
Well, we have some answers today and I am so pleased to have the
first and corresponding author with us, Dr.  Teemu Niiranen,
from Boston University's Framingham Heart Study. Welcome, Teemu.


Dr. Teemu Niiranen:       Thank you
very much, great to be here.


Dr. Carolyn
Lam:              
And to help us along in this discussion, we have a familiar
voice. Dr. Wanpen Vongpatanasin, associate editor from UT
Southwestern. Welcome back, Wanpen.


Dr. Wanpen Vongpatanasin:      
Thank you Carolyn. Happy to be here.


Dr. Carolyn
Lam:              
Teemu, you know, I sort of set the background that you so nicely
articulated in this research letter, but could you tell us a
little bit more of what you were looking at, how you did it, and
what you found?


Dr. Teemu Niiranaen:     My boss, Dr. Vasan,
was also a coauthor in this paper, he already showed some 15
years ago that prehypertension carries greater cardiovascular
risk than perfectly normal blood pressure. However, it's pretty
much unclear what happens to people who are prehypertension but
never go on to develop hypertension because even the name
suggests that if you have prehypertension you will get
hypertension. We also looked at what effect does the age of
developing prehypertension and hypertension have in this context.


                                               
We used a case cohort setting in the Framingham Heart Study in
the way that we only looked at 5 1/2 thousand decedents. These
were people who had already passed away. Then we categorized
those decedents into 5 categories, people who never got
prehypertension or hypertension, people who developed
prehypertension late in life, who never developed hypertension,
and people who developed early onset prehypertension but never
developed hypertension, and then people who went on to develop
late or early onset hypertension. We used a cutoff of 55 years as
the definition of early onset versus late onset.


                                               
Then, in a case cohort setting, we estimated case versus
controls, adjusted case versus control odds ratios, for the 4
prehypertension/hypertension categories versus those who died
without ever developing prehypertension.


Dr. Carolyn
Lam:              
Teemu, could I just stop you here before you share the intriguing
results. I just wanted to remark that it's so amazing how the
Framingham Heart Study really enables analysis like this, simply
because of the long follow up and just the great detail and the
standardization of blood pressure measurements and so on. I mean,
as I said, I worked at the Framingham Heart Center, and we were
trained to do this in a standardized fashion.


                                               
Define prehypertension and hypertension, just in case, and then
please tell us your results.


Dr. Teemu Niiranaen:     Prehypertension was
120 to 135 systolic blood pressure, and a diastolic blood
pressure of 80 to 89 millimeters mercury, and then hypertension
was 140 over 90 millimeters mercury, or antihypertensive
medication, and yes, your correct that the Framingham Heart Study
provides a very unique setting. Especially for defining early
versus late onset hypertension because we can define the age of
hypertension or prehypertension or prehypertension onset
objectively because these people have been followed up, they have
attended so many exams, especially the original cohorts.


                                               
But, to the results, so we observed that basically people who
develop prehypertension, either early and especially late in
life, but did not ever develop hypertension, their risk, or odds
of dying of cardiovascular disease versus non-cardiovascular
disease was pretty much similar to those who never develop
prehypertension or hypertension, while conversely the people who
went on to develop either late or especially early onset
hypertension, or developed early onset hypertension they had
considerably greater risk of cardiovascular death versus those
who developed either prehypertension or hypertension. That's our
main result. I won't go into conclusions yet.


Dr. Carolyn
Lam:              
Okay, but maybe at this point, I could ask Wanpen to share some
thoughts. I mean, this is very striking findings. Curious what
you think the clinical implications were, and especially as we
discussed among the editors.


Dr. Wanpen Vongpatanasin:       It
is very important study that, as Teemu outlined it, to look at
the fate of people with prehypertension and I think that's the
first time we had this kind of data to show whether the earlier
versus late prehypertension and even hypertension itself. I don't
think people have looked at in the large number in terms of
outcome people who have early versus late onset hypertension. I
found the result to be fascinating.


Dr. Carolyn
Lam:              
Yeah, what does this mean though when we see a patient with this
sort of borderline hypertension, you know, falling in the
prehypertension range. We don't know whether they're going to
develop hypertension. What do you think the clinical implications
are? Teemu?


Dr. Teemu Niiranaen:     Unfortunately a lot
of the people who develop prehypertension as the name suggests
they go on to develop hypertension, but there is still a
considerably great part that never develop hypertension, and our
study shows basically that if you are able as a doctor or a
patient to prevent progression to hypertension you are much
better off and this really hasn't been previously shown, so it
just should motivate patients and also doctors to strive to, if
they see a prehypertensive individual, try to through lifestyle
and other interventions try to prevent the progression to
hypertension.


Dr. Carolyn
Lam:              
Yeah, I think that was one of the take home messages for sure.
Were there any other plans for future work you think that needs
to be done?


Dr. Teemu Niiranaen:     There's the
everlasting problem with observational studies, so definitely it
would be great if our results could be taken into clinical trials
or anything to test whether interventions, A, that preventing the
progression from prehypertension to hypertension could then
impact cardiovascular outcomes.


Dr. Carolyn
Lam:              
Indeed, and if I may comment, I've always wondered about ethnic
differences when it comes to this. The one thing that Framingham,
you know, it's difficult to see from there, is what happens in
other ethnicities other than white ethnicities, isn't it? Still,
very striking findings. Wanpen did you have any other comments or
questions from Teemu?


Dr. Wanpen Vongpatanasin:      
Well, I think that one thing also that's interesting to me is
even the people who had early onset prehypertension, although the
number of CHD deaths were not significant, but the odds still 28
percent higher than the control that will never have
prehypertension so, I think that that the signal is there but
perhaps because the number of people who had prehypertension but
never really progress to prehypertension is relatively small. It
could be underpowered to see the significance and I think that
from this study, it tells me that the exposure to blood pressure
to our life, I think is the blood pressure lowered on the
cardiovascular system, I think that's the one that really
determine the cardiovascular outcome the most. I think that we
should not discount that this is not a truly benign phenomenon, I
think hopefully they'll be some more data from the Framingham
group or other group.


                                               
Also, I think that this study also very important to show that
early onset hypertension actually have the worst prognosis, and
often time when people come to see a doctor when they're 30 and
40 years old, they don't really want to take medicine, and the
physician often time are reluctant to prescribe the drug, and I
think that this study say that we probably need to be a little
bit more serious about it, because they actually have the most
cardiovascular events.


Dr. Carolyn
Lam:              
What excellent points, and you know what? At this point I just
want to highlight that beautiful figure that you have in your
research letter, Teemu. I think it says it all. It highlights
that point estimate for the prehypertension groups is not exactly
1. If anything, it is above 1, right? For the odds of poor
outcomes, so I do take Wanpen's point as well. Beautiful figures,
and I also actually want to use that to ask you a different
question Teemu. You have 1 figure, because this is a research
letter that only allows 1 figure and 800 words, and you've put so
much important information into that space. I'd love for you to
share that experience with our listeners too, of a research
letter versus a full paper. Why did you choose to submit yours as
a research letter, and how was that?


Dr. Teemu Niiranaen:     One of the important
take home messages from this was the differences between early
onset versus late onset hypertension that we'd been also recently
publishing on, so we wanted to delve more in depth on this
prognosis of prehypertension versus hypertension so we don't have
to be repetitive too much. We decided to focus on this very small
topic most intensively, therefore we decided that maybe a
research letter would be the most effective way so we could
communicate all the really novel stuff that we have in just one
figure. Well, it has 3 panels, but it still counts as 1 figure.


                                               
I just wanted to point out that maybe the early onset
prehypertension, yeah the confidence intervals are somewhat wide,
but the panels sees for coronary heart disease versus
non-cardiovascular disease deaths, so that's maybe a bit more
underpowered than the back panel B, so the CHD deaths are part of
the CBD deaths, so with CBD deaths, the early onset
prehypertension, the odds ration was 1.09, but still of course
the confidence intervals reach up to 1.49. Just to clarify the
difference between panel B and panel C, so B's better powered.


Dr. Carolyn
Lam:              
It's a very nice figure, and indeed, I think it works very, very
well as a research letter, and I think the fact that we're
discussing it right now shows that length doesn't dictate
importance. Wanpen you had a few comments about that. What do you
think of a research letter format?


Dr. Wanpen Vongpatanasin:      
Yes, I think this research letter is a really important part of
articles in Circulation. I think that all the others should be
aware that we're trying to enter at submission if it's suitable,
just like this one. It actually show up in the pub med exactly
like the full article and gets cited as much and sometimes much
more than a regular article because it capture the essence of one
more focused problem and the figures and table allow to show only
one or two at a time, so they really capture the essence or the
guts of the article and the reader can go through that quickly
and grasp the concept and learn within flipping through a few
pages.


                                               
I think we should have many more interesting research letter like
this.


Dr. Carolyn
Lam:              
Congratulations again Teemu for a beautiful paper, a very
important one. Thank you Wanpen for shepherding this one.


                                               
And thank you listeners for joining us today. Don't forget to
tune in again next week.