Circulation February 27, 2018 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal it's editors. I'm Dr. Carolyn
Lam, associate editor from the National Heart Center, and Duke
National University of Singapore. The new ACC/AHA hypertension
guidelines are hotly discussed. So much so that we have invited
perspectives of these new guidelines from around the world and
authors will be discussing this right here on Circulation on the
Run. Stay tuned, as it's coming right up after these summaries.


                                               
The first original paper this week is a translation study
suggesting that the parasympathetic system may be a novel
therapeutic target in pulmonary arterial hypertension.
Co-corresponding authors Dr. Handoko and de Man from University
Medical Center Amsterdam used heart rate recovery after maximal
cardiopulmonary exercise testing as a surrogate for
parasympathetic activity, and assessed white ventricular ejection
fraction in 112 patients with pulmonary arterial hypertension.
They found that patients with a lower right ventricular ejection
fraction had a significantly reduced heart rate recovery compared
to patients with a higher right ventricular ejection fraction.


                                               
Furthermore, they looked at tissues from the right ventricle of
11 patients undergoing heart-lung transplantation, and found that
there was increased expression of nicotinic receptors with no
difference in muscarinic receptor expression compared to
controls.


                                               
Finally, in a rat model of pulmonary hypertension, they showed
that chronic pharmacologic sympathetic stimulation by
pyridostigmine, which is an acetylcholinesterase inhibitor,
improved surviving right ventricular function and reduced
pulmonary vascular remodeling.


                                               
In summary, the study shows that right ventricular dysfunction is
associated with reduced systemic parasympathetic activity in
patients with pulmonary arterial hypertension, with an inadequate
adaptive response of the cholinergic system in the right
ventricle. Furthermore, enhancing the parasympathetic activity in
these patients may be a novel therapeutic strategy.


Dr. Carolyn
Lam:              
The next study unveils a new mechanism by which pericardial
adipose tissue coordinates immune cell activation and outcomes
following a myocardial infarction. First author Dr. Horckmans,
corresponding author Dr. Steffens, and colleagues from Institute
of Cardiovascular Prevention in Munich identified larger B-cell
clusters in epicardial adipose tissue of human patients with
coronary artery disease compared to controls without coronary
artery disease. Furthermore, they showed that infarcted mice had
larger pericardial clusters, and a 3-fold up regulator numbers of
GM-CSF producing B-cells within the pericardial adipose tissue,
but not in the spleen or lymph nodes. This was associated with
higher dendritic cell and T-cell counts in the pericardial
adipose tissue.


                                               
Further experiments show that activated dendritic cells migrated
from infarcts into the pericardial adipose tissue. Cytokines and
growth factors released locally within the pericardial adipose
tissue as well as systemically promoted immune cell proliferation
and emergency granulopoiesis after myocardial infarction.


                                               
Finally, the enhanced fibrosis and worsened ejection fraction in
mice was limited by removal of the pericardial adipose tissue.


                                               
In summary, these pre-clinical data suggest that pericardial
adipose tissue may be a central compartment for innate and
adaptive immune responses, which regulate post-myocardial
infarction healing.


Dr. Carolyn
Lam:              
The next study reports for the first time in a large,
comprehensive national cohort study, the incidence of atrial
fibrillation in children and young adults with congenital heart
disease. First and corresponding author Dr. Mandalenakis and
colleagues from University of Gothenburg in Sweden used data from
the Swedish Patient and Cause of Death registers to identify all
patients with a diagnosis of congenital heart disease who were
born between 1970 and 1993. Each patient with congenital heart
disease was matched by birth year, sex, and county with ten
controls from Sweden. Follow-up data were collected until 2011.


                                               
The authors found that the risk of atrial fibrillation in
children and young adults with congenital heart disease was 22
times higher than that in matched controls. Up to the age of 42
years, one in 12 patients with congenital heart disease had
developed atrial fibrillation and one in 10 patients with
congenital heart disease with atrial fibrillation had developed
heart failure. In particular, patients with the most complex
congenital malformations, conotruncal defects, had the highest
risk to develop atrial fibrillation. These patients should be
considered for targeted monitoring.


Dr. Carolyn
Lam:              
The next study provides a novel and simple risk score for
right-sided heart failure in adults undergoing Left Ventricular
Assist Device implantation with the current mainstream devices.
First and corresponding author Dr. Solomon and colleagues from
University Medical Center Rotterdam studied almost 3000 adults
who underwent continuous flow Left Ventricular Assist Device
implantation in the largest EU registry of mechanical circulatory
support devices. They derived and validated a right-sided heart
failure prediction model that out-performed several published
scores and well-known hemodynamic and echocardiographic
individual markers of right-sided heart failure.


                                               
This prediction model included the following risk factors: need
for three or more inotropic agents, inter-agency registry from
mechanically-assisted circulatory support class one through
three, severe right ventricular dysfunction on semi-quantitative
echo cardiography, ratio of right atrial to pulmonary capillary
wedge pressure of more than 0.54, and a hemoglobin level of less
than 10 grams per deciliter.


                                               
These findings offer a step towards improving prediction of the
risk of right-sided heart failure to target future optimal
strategies aiming at early and intension right-sided heart
failure management for the highest risk subgroups of patients
undergoing Left Ventricular Assist Device implantation.


Dr. Carolyn
Lam:              
Now, sharing a patient-level clinical trial data has been widely
endorsed, but just how extensively have these data been used for
cardio metabolic diseases? The final study this week attempts to
answer this question. First and corresponding author Dr.
Vaduganathan and colleagues from Brigima Women's Hospital
extracted data from clinicalstudydatarequest.com, a large,
multi-sponsored data sharing platform hosting individual
patient-level data from completed studies sponsored by 13
pharmaceutical companies.


                                               
They found that the median time from study completion to data
availability was more than six years. Most data requesters of
cardio metabolic clinical trial data were from academic centers
in North America and Western Europe, and half the proposals were
unfunded. Only 15% of these trials had been accessed by
investigators thus far, and few findings have reached
publication. Most requests for shared data access focused on new
hypothesis generating questions rather than validation of the
original study findings. These data may allow anticipation of
barriers to effective system implementation and shared data
consumption in cardiology.


                                               
Well, that wraps it up for our summaries this week. Now for our
feature discussion.


Dr. Carolyn
Lam:              
We are having a truly global conversation today on a really
global problem. That is hypertension. From Canada, we've got Dr.
Ernesto Schiffrin from McGill University, from Europe we've got
Dr. Giuseppe Mancia from university of Milano, from the United
States we have Dr. Wonpen Vongpatanasin from UT Southwestern, our
dear associate editor and regular voice on this podcast, and then
of course from Asia, that's me. You know what we're talking
about? It is the global impact of the 2017 ACC/AHA hypertension
guidelines. So many novel aspects about these guidelines,
including new definitions of hypertension and it's stages, new
thresholds and goals of treatment, consideration of the global
risks and treatment decisions, addition of classes of
recommendations and levels of evidence. So much to talk about,
and let's start right now.


                                               
Wanpen, you were the brainchild of suggesting these global
perspectives. Perhaps say a few words about the ACC/AHA new
guidelines first.


Dr. Wonpen Vongpatanasin:      
Yeah, so I think that this is the guidelines that actually
incorporating the more recent evidence and trials, particularly
SPRINT, and applying this into the threshold and the blood
pressure goal across the board. There's three comprehensive
guidelines, and obviously ... The first time, the threshold was
lower across the board, and that leads to a lot of discussion and
concern and trying to see how we're implementing this or is it
appropriate to all the population? Particularly not just in the
US and around the world. I guess that leads to us reaching out to
many hypertension leaders across the globe and really get very
interesting and very insightful feedback from the global experts,
two of which is on podcast today. I'm really thankful and excited
to have some more in depth insight from them.


Dr. Carolyn
Lam:              
Yeah, exactly. The buzz has really been worldwide, I can see that
even from where I'm sitting here in Asia. But maybe Ernesto, I'm
just gonna jump straight to the core questions. How are these
guidelines different from the hypertension Canada guidelines, and
frankly do you think that the ACC American guidelines are going
to impact hypertension care in Canada?


Dr. Ernesto Schiffrin:      Well, there
are quite a few differences. The definition of hypertension
remains the classical one in Canada. We have different thresholds
and goals, and interestingly, the hypertension Canada guidelines
have adopted a SPRINT-based recommendation for high
cardiovascular risk patients in contrast to the AHA/ACC
hypertension guideline. Although it has intensified the goals for
treatment, it has lowered ... Has introduced as you mentioned a
category of elevated blood pressure, a new definition of
hypertension equal to or above 130 over 80 in contrast to ours
equal to or above 140 over 90. It has not really introduced a
SPRINT-based recommendation. As well, I think that one of the
major questions remains the measurement of blood pressure. In
Canada, we have adopted the AOBP, the Automated Office Blood
Pressure measurement, at least for high risk, SPRINT like
individuals. In the AHA/ACC hypertension guidelines, there is
emphasis on standardized blood pressure measurement, but the
SPRINT-like measurement of blood pressure has not been adopted.


Dr. Carolyn
Lam:              
Very interesting. In Canada, with the AOBP, how do you translate
that? I suppose you estimate it as lower than what would
otherwise be labeled?


Dr. Ernesto Schiffrin:      That is
indeed a problem, because the evidence for the relationship
between the AOBP carried out in the absence of a health care
professional and the standardized oscillometric measurement, or
the osculatory manual measurement, is unclear. The evidence is
weak. So we have not really provided a guideline or
recommendation with respect to these differences.


                                               
In contrast, AHA/ACC provides at least a pragmatic expert-based
recommendation on what the differences are between office blood
pressure and out-of-office blood pressure measurement. But, as I
mentioned, there is no recommendation regarding the SPRINT-like
measurement of blood pressure, and that's important because there
may be major differences in the order of ten or even 15
millimeters of [inaudible 00:13:32] systolic blood pressure.
However, as I see it, the committee for the ACC/AHA hypertension
guideline has adopted a prudent and pragmatic approach, and
actually simplified thresholds and goals to 130 over 80, and in
my view this is a prudent approach.


                                               
Will it impact Canada? I think in Canada, most physicians follow
the hypertension Canada guidelines, and they are recommended as
best practice by governments across the country, provincial and
federal. I think that physicians will be aware, but will still
carry out their practice following the hypertension Canada
guidelines.


Dr. Carolyn
Lam:              
I like that. Aware but perhaps not so practice-changing in
Canada. Let's shift to Europe though. Giuseppe, do you agree with
that? How do you think these American guidelines may impact
physicians in Europe?


Dr. Giuseppe Mancia:    The American guidelines
have been received with interest, lots of interest. But also
there has been some criticism. For example, the question of the
SPRINT [inaudible 00:14:55], you read the question of how blood
pressure was measured as professor Schiffrin mentioned. It was
measured at least in large number professions, why they were
[inaudible 00:15:10], I'm not sure. This means that values have
lower worth than those obtained by conventional office blood
pressure measurement. How much room is still debated, but it
could be 10, 15 millimeter mercury, which means that you could
compare these SPRINT-like values to conventional office blood
pressure values. Probably the SPRINT values are not much lower
than 140 millimeters to the mercury systolic.


                                               
Then there is the question that can SPRINT mutually [inaudible
00:15:50] at the start. Most of them with two hypertensive
charts. So if it's difficult to decide the bounds of threshold to
treatment, lower these pressures to the high-low of blood
pressure range, less than 140 millimeters mercury systolic when
you have patients already treated, because their original blood
pressure was probably higher than 140 millimeters of mercury.
This [inaudible 00:16:15], however there are other data
suggesting that, at least in high-risk individuals, one might
indeed start treatment when blood pressure is in the 140
millimeter of mercury. You'll see what the European guidelines
will recommend ... They are going to be published in June ... But
perhaps this fraction of the population will be a candidate for
treatment.


                                               
One last point, however, collecting the data from SPRINT is what
you wish for in this regard, is that there should be a definite
reduction in the threshold blood pressure for treatment in the
elderly. In Europe, this was about 160 millimeters mercury based
on randomized trials but probably in the future it will be about
140 millimeters mercury. So a large fraction of the elderly
population will be involved in [inaudible 00:17:14].


Dr. Carolyn
Lam:              
You know a question I always get though, is what about the side
effects? We talk about the benefits of lowering it further, but
what about the side effects. I don't know, does anyone have any
thoughts on that?


Dr. Ernesto Schiffrin:      I would say
that, when you look at SPRINT, although there were increased side
effects in the intensive treatment group, actually side effects
were relatively rare. Some of them were important, such as acute
renal failure and hyperkinemia, and so on, and other electrolyte
abnormalities and syncope. But they were rare, and when we are
recommending intensified treatment for the elderly, for example,
which is SPRINT based in the hypertension Canada guidelines, we
do say that this approach should be a gentle and progressive one,
very aware that particularly in the elderly orthostatic
hypertension may occur. One has to be very careful about this
intensification of treatment, but yet we believe that if using
automated office blood pressure measurement unobserved, you are
able to reach lower blood pressures and they are well tolerated
around or below 120 systolic, this will benefit these patients as
shown in the SPRINT trial.


Dr. Carolyn
Lam:              
Yeah, indeed. That's very nicely put, and just brings up the gaps
that we still need to answer, like the way blood pressure is
measured, standardization. We may be accounting more about risk
versus benefits, patient subgroups. Wanpen, have I missed out
anything else? What is the other buzz that you've heard?


Dr. Wonpen Vongpatanasin:       I
think that we really need to do a better job in measuring blood
pressure in basic clinical practice, particularly in the US where
we allow only 20 minutes to see your follow-up patient. I don't
think that it will be possible to do an AOBP in the US, but I
think one thing that makes the issue a little bit murkier is the
SPRINT group. I actually just had an abstract presentation at the
last HA meeting, that said only half of that site measure in the
intended way on AOBP.


                                               
Actually, at UT Southwestern we also SPRINT site and we actually
did not use AOBP, and when that stratified the treatment side by
using AOBP versus non-AOBP, the outcomes was still the benefit of
intensive blood pressure reduction for what it's worth. I think
that the AOBP story is still controversial, but I think that I
agree that we hardly have patient, sit down quietly, for five
minutes before we do the measurement. I think that's first and
foremost, we need to be able to do that, and do at least two
measurements. We'd be lucky if we'd get one measurement after
sitting down immediately, that's what we usually get in clinical
practice. I definitely agree with Dr. Schifferin that when we ...
Particularly the elderly, we have to be careful about orthostatic
hypertension. Particular in the SPRINT trial, they actually
exclude anyone who had standing systolic blood pressure less than
110. These people who are high risk of having [inaudible
00:20:35] never get into those trials to begin with.


Dr. Carolyn
Lam:              
I can't thank you enough, everyone, for joining me in this chat
around the world. It has been a learning conversation for me, as
I'm sure it has been for our listeners as well.


                                               
Listeners out there, you've been listening to Circulation on the
Run. Thank you for joining us today.