Circulation December 6, 2016 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 feature discussion is
regarding the exciting results of the masked hypertension study
showing that clinical blood pressure underestimates ambulatory
blood pressure, but first here's your summary of this week's
issue.


 
 
The first study reviews the largest clinical experience so far
with pulmonary vein stenosis following ablation for atrial
fibrillation. First author Dr. Fender, corresponding author Dr.
Packer and colleagues from Mayo Clinic Rochester, Minnesota
evaluated the presentation of 124 patients with severe pulmonary
stenosis between 2000 and 2014 and examined the risk for
re-stenosis after intervention utilizing either balloon
angioplasty alone or balloon angioplasty with stenting. All 124
patients were identified as having severe pulmonary vein stenosis
by CT in 219 veins. 82% were symptomatic at diagnosis with the
most common symptoms being dyspnea, cough, fatigue and decreased
exercise tolerance. 92 veins were treated with balloon
angioplasty, 86 with stenting and 41 veins were not intervened
on. The acute procedural success rate was 94% and did not differ
by initial management. Overall, 42% of veins developed
re-stenosis, including 27% of veins treated with stenting and 57%
of veins treated with balloon angioplasty.


 
 
The three-year overall rate of re-stenosis was 37% with 49% of
balloon angioplasty treated veins compared to 25% of stented
veins developing re-stenosis. This was a difference that remained
significant even after adjusting for age, CHADS2 VASC score,
hypertension and time period of the study with an adjusted
[inaudible 00:02:30] ratio of 2.46 for risk of re-stenosis with
balloon angioplasty versus stenting. In summary, this study shows
that the risk for pulmonary vein re-stenosis is significant
following atrial fibrillation ablation. The diagnosis is
challenging due to non-specific symptoms and while there is no
difference in acute success by type of initial intervention,
stenting significantly reduces the risk of subsequent pulmonary
vein re-stenosis compared to balloon angioplasty.


 
 
The next paper shows that the index of microvascular resistance,
which is a novel invasive mreasure of coronary microvascular
function, has emerging clinical utility as a test for the
efficacy of myocardial re-perfusion in invasively managed
patients with acute ST elevation myocardial infarction. In this
study by first author Dr. [Carrick 00:03:30], corresponding
author Dr. Barry and colleagues from the University of Glasgow in
Scotland, index of microvascular resistance and coronary flow
reserve were measured in the culprit artery at the end of
percutaneous coronary intervention in 283 patients with ST
elevation myocardial infarction. Authors found that compared with
standard clinical measures of the efficacy of myocardial
re-perfusion, such as ischemic time, ST segment elevation and
angiographic blush grade, the index of microvascular resistance
was more consistently and strongly associated with myocardial
hemorrhage, microvascular obstruction, changes in left
ventricular ejection fraction and left ventricular end diastolic
volume at six months as well as all caused death of heart failure
during the median follow up of 845 days.


 
 
In fact, compared with an index of microvascular resistance
greater than 40, the combination of this index and coronary flow
reserve less than two did not have incremental prognostic value.
The take-home message is therefore that an index of microvascular
resistance above 40 represents a prognostically validated
reference test for failed myocardial re-perfusion at the end of
primary percutaneous coronary intervention. This study supports
further research into microvascular resistance based therapeutic
strategies in these patients.


 
 
The next study provides experimental data regarding molecular
mechanisms underlying calcific aortic valve disease. First
author, Dr. Haji, and corresponding authors Dr. Matthew and [Bose
00:05:24] from the Quebec Heart and Lung Institute in Canada
performed genomic profiling and in-depth functional assays in
human aortic valves. They demonstrated for the first time that
the promotor region of the long non-coding RNA H19 is
hypomethylated in patients with calcific aortic valve disease.
This hypomethylation in turn increases H19 expression in the
valve interstitial cells where it prevents Notch 1 transcription
by blocking or out-competing P53’s recruitment to the Notch 1
promotor. Thus, H19 appears to be the missing link connecting
Notch 1 to idiopathic calcific aortic valve disease. It may
therefore represent a novel target in calcific aortic valve
disease to decrease osteogenic activity in the aortic valve.


 
 
The next paper describes the largest cohort of mycotic abdominal
aortic aneurysms to date and is from Dr. [Sorelias 00:06:37] and
colleagues of Uppsala University in Sweden.  These authors
identified all patients treated for mycotic abdominal aortic
aneurysms in Sweden between 1994 and 2014. Among the 132
patients, they noted that the preferred operative technique
shifted from open repair to endovascular repair after 2001 with
the proportion treated with endovascular repair increasing from
0% in 1994 to 2000 to 60% in the 2008 to 2014 period. Survival at
three months was lower for open repair compared to endovascular
repair at 74% versus 96% respectively with a similar trend
present at one year. A propensity score adjusted analysis
confirmed the early better survival associated with endovascular
repair. During a median follow up of 36 months for open repair
and 41 months for endovascular repair. There was no difference in
long-term survival, infection-related complications or
re-operation. The take-home message is that endovascular repair
appears to be a durable surgical option for treatment of mycotic
abdominal aortic aneurysms.


 
 
The final study provides insights into the molecular mechanisms
by which aldosterone triggers inflammation and highlights the
particular role of NLRP3 inflammasome, which is a pivotal immune
sensor that recognizes endogenous danger signals and triggers
sterile inflammation. Authors Dr. Bruden [Esimento 00:08:32], Dr.
[Tostes 00:08:33] and colleagues from the University of Sao Paulo
in Brazil analyzed vascular function and inflammatory profiles of
wild-type NLRP3 knockout, caspase-1 knockout and interleukin-1
receptor knockout mice, all treated with vehicle or aldosterone
while receiving 1% saline. They found that mice lacking the
interleukin-1 beta receptor or lacking inflammasome components
such as NLRP3 and caspase-1 were protected from
aldosterone-induced vascular damage. In-vitro, aldosterone
stimulated NLRP3-dependent interleukin-1 beta secretion by bone
marrow derived macrophages. Chimeric mice reconstituted with
NLRP3 deficient hematopoietic cells showed that NLRP3 in immune
cells mediated the aldosterone-induced vascular damage.


 
 
In addition, aldosterone increased the expressions of NLRP3,
caspase-1 and mature interleukin-1 beta in human peripheral blood
mononuclear cells. Finally, hypertensive patients exhibited
increased activity of NLRP3 inflammasome. Together these data
demonstrate that NLRP3 inflammasome via activation of
interleukin-1 receptor is critically involved in the deleterious
vascular effects of aldosterone, thus NLRP3 is a potential target
for therapeutic interventions in conditions with high aldosterone
levels.


 
 
That wraps it up for our summaries. Now for our feature
discussion.


 
 
On today’s podcast we are going to be discussing the very
important issue of masked hypertension. This is an issue that
gets a lot less attention than I think compared to white coat
hypertension. I’m so pleased to have the first and corresponding
author of the masked hypertension study, Dr. Joseph Schwartz,
from Stony Brook University and Columbia University in New York.
Welcome to the show, Joe.


 
Dr. J. Schwartz:
My pleasure. I’m delighted to join you.


 
Dr. Carolyn Lam:
We have a regular on the show today as well, Dr. Wanpen
Vongpatanasin, associate editor from UT Southwestern. Welcome
back Wanpen.


 
Dr. Wanpen V.:
Thank you so much. Happy to be here.


 
Dr. Carolyn Lam:
Joe, I want to start by addressing the common misperception that
ambulatory blood pressure is usually lower than clinical blood
pressure. That seems to make a lot of sense to us clinically
because, for example, I always use ambulatory blood pressure to
diagnose white coat hypertension and so the assumption there is
that my clinically measured blood pressure is higher than what
I’m going to be finding if this patient measures the blood
pressure on an ambulatory 24-hour basis. It’s also from the
cutoffs that we use. For example, ambulatory blood pressure we
use a 24-hour cutoff of 130/80 to make the diagnosis whereas with
clinical blood pressure we use a cutoff of 140/90 so all of this
kind of reinforces that ambulatory blood pressure is usually
lower. Your study, though, tells us otherwise so please fill us
in here.


 
 Dr. J. Schwartz:
You're right that in the doctor's office there are a certain set
of people who probably get anxious when they're around a doctor
and with that anxiety may cause a temporary increase in their
blood pressure, a temporary elevation, and that's the basis of
where we think white coat hypertension comes from. That's a very
widespread belief among doctors and it's even been in previous
guidelines, there have been statements to that effect. When I
talk to people out in the general public and tell them I'm doing
a study comparing blood pressure out in the real world compared
to blood pressure in the doctor's office, all of them tell me,
"Well, usually when I'm in a doctor's office that's a relatively
calm period for me unless there's really something wrong with me
and out in the everyday world I have to face a variety of
stressors. I have deadlines. I have places I need to get to.
Sometimes I have people yelling at me. Sometimes I'm just in a
hurry."


 
 
All these things elevate your blood pressure out in the real
world and so when we were trying to recruit people for the study,
and we were very agnostic in recruiting them, telling them that
we were interested in the differences in blood pressures between
the doctor's office and the ambulatory blood pressure and they
might go in either direction. When I told them about the fact
that their ambulatory blood pressure or real world blood pressure
might be higher than in the doctor's office, the vast majority of
people nodded affirmatively and said, "It wouldn't surprise me at
all."


 
Dr. Carolyn Lam:
Could you define masked hypertension compared to white coat
hypertension and tell us a little bit about the population you
studied.


 
Dr. J. Schwartz:
Sure. First with the definition. I'm going to say something a
little bit different from something you said before. You
mentioned cutoffs that we typically used for ambulatory blood
pressure of 130/80 and those are the cutoffs that are used if you
compute an average blood pressure over the entire 24 hours. What
many people do, and what we did for this study, was compare the
average blood pressure when people were awake to their blood
pressure in the doctor's office because obviously in the doctor's
office everybody is awake. The typical cutoffs there are 135/85,
recommended by numerous guidelines in this country and with our
international collaborators. The definition of masked
hypertension is having a blood pressure in the clinic setting
that's below 140/90 but having an ambulatory blood pressure where
either the systolic blood pressure is above 135 or the diastolic
is above 85 millimeters of mercury.


 
 
In terms of the sample, for years I've had a particular strategy
for trying to recruit participants. I do worksite-based studies
and so I identify large organizations that will allow me to
recruit their employees and then what we did for this study is go
to individual departments, both here at Stony Brook University,
at Columbia University, at a residential veterans' home that's
affiliated with Stony Brook University and then also at a local
private hedge fund management company. We would go to these
sites, I talk to the head of a department and tell them a little
bit about masked hypertension and what the study was about and
ask them if they would be willing to have their employees
participate in the study. Once I had the okay from the department
head then we would conduct public health screenings, blood
pressure screenings. My staff and I would go into the department
for multiple days and invite anybody who was interested to have
their blood pressure taken on site and while we were taking those
blood pressures carefully.


 
 
The proper way to take those is to take three readings and leave
a minute or two interval between them and rather than just have
silence then between the readings we would tell them a little bit
about our study. At the end of the study if they didn't have
extremely high blood pressure and were not taking blood pressure
medication we would ask them if they might be interested in
participating in the study that we just described. That's how we
identified potential participants and about 2/3 of the people
that we talked to who looked eligible indeed chose to
participate.


 
 
 
 
 
 
 
 
 
Dr. J. Schwartz:
The one other thing I might mention that I think we mentioned, I
hope we mentioned as a limitation of the study, is that everybody
in the study had health insurance and at least until recently
there were very large portions of the population that didn't have
health insurance, everybody by virtue of their employment by the
organizations that participated in the study, did have
employer-based health insurance.


 
Dr. Carolyn Lam:
Thanks for clarifying the population so well. Could you just give
us the top line of your findings. How big a difference did you
find, which direction and that intriguing effect of age?


 
Dr. J. Schwartz:
Sure. The first thing we found is that on average the systolic
blood pressure is seven millimeters mercury higher out in
everyday life than it is in the clinic setting where we take our
clinic readings. I should mention that unlike most studies, and
all studies at the time that we began our study, we brought
people in three separate times to take the clinic blood pressure.
Up until that, almost all of the studies of ambulatory blood
pressure monitoring only had clinic blood pressures from a single
visit. I think we have a very reliable measure of the clinic
blood pressure as well as reliable measure of ambulatory blood
pressure. We see a seven millimeter difference in the systolic
blood pressure and a 2 millimeter difference, again the
ambulatory being higher for diastolic blood pressure.


 
 
What's more remarkable is if you think about what's a sizable
difference. If you think if we perhaps somewhat arbitrarily say
10 millimeters of systolic blood pressure is a large difference.
More than 35% of the population has an ambulatory blood pressure
that is more than 10 millimeters higher than their clinic blood
pressure whereas only 3% of our sample had that large a
difference in the opposite direction, what many people would call
a white coat effect. It's more than a 10 to 1 difference in
numbers of people who have elevated ambulatory versus elevated
clinic.


 
 
You asked me to mention something about the age difference. When
you look at how that difference in systolic blood pressure varies
by age, it's quite a bit larger for people who are younger. If
you're under 30 the difference is, on average, 10 millimeters
rather than seven millimeters and if you go up as you approach 60
years of age or so the difference becomes relatively small,
perhaps in the neighborhood of two millimeters. We don't have
enough people because it's a working population over 65 to say
very much about what would happen. In fairness to prior research,
which often is on older populations and particularly hypertensive
populations, the studies that have historically shown that
ambulatory blood pressure tends to be lower than clinic blood
pressure are in these older populations and populations that have
elevated blood pressure to start with.


 
 
My speculation there, and you haven't asked me to mention it but
I will, is that older people and those with hypertension have a
reason to be more nervous or more anxious when they go to the
doctor than people who are not taking medication and probably
don't even know that they have hypertension. People who are just
being screened perhaps during a routine physical for the
possibility of hypertension, because the doctors take a blood
pressure reading every time you go in, they're doing that in
order to see whether you might have hypertension, but most people
who are going in for what we call a well patient visit are not
nervous about their blood pressure being high.


 
Dr. Carolyn Lam:
I have to say, the take-home message for me when I read this was,
I am not paying enough attention to masked hypertension and then
another thing was, maybe I need to think about more white coat
hypertension in the older and masked hypertension in the younger.
Wanpen, do you think it's as simple as that? What were your
take-home messages?


 
Dr. Wanpen V.:
I think this is a very important study that examines this in a
systematic way. I'm not surprised that Joe found as much masked
hypertension here. I think that he's absolutely right. We looked
at this in Dallas Heart Study as well recently and we found that
in the population-based sample in Dallas almost 20% of people
have masked hypertension and white coat we found only like 3% and
the average in the Dallas Heart Study was very close to those
samples, about mid-40s. I think that's a very important finding
in that the people with masked hypertension would not be
suspected otherwise to have problems. Also, in the Dallas Heart
Study they used home readings but Dr. Schwartz used ambulatory
blood pressure monitoring. Unless extra out of office monitoring
is being done we will totally miss these people who are more
likely to have target organ damage from high blood pressure. I
think that's absolutely important.


 
Dr. Carolyn Lam:
Actually, Wanpen you brought up something I was going to bring up
as well. Where does home blood pressure fit in with this? Do you
think it's home blood pressure versus ambulatory blood pressure?


 
Dr. Wanpen V.:
The US Preventive Services Task Force has issued a little bit of
recommendations recently that we need to either use ambulatory
blood pressure monitoring or home blood pressure monitoring to
confirm diagnosis of hypertension in the office. If someone shows
up with elevated blood pressure in the office either home blood
pressure or ambulatory blood pressure needs to be done. If we
just followed that guidelines we're still going to miss people
with masked hypertension because by definition they don't have
elevated blood pressure in the office. I think that from these
findings and Dr. Schwartz' study I think to catch these people we
really need to pay attention to people with pre-hypertension type
of blood pressure because it seems like those are the group that
has the most probability to have elevated ambulatory blood
pressure so anyone with borderline blood pressure in the clinic,
those are the ones who the doctor needs to tell the patient to
monitor blood pressure at home or order ambulatory blood pressure
themselves if that's available in their facility.


 
Dr. Carolyn Lam:
Wanpen, I fully agree. What an important message. Joe, I'd like
to give you the final word but I'd love to hear how you have
maybe taken this into your own practice.


 
Dr. J. Schwartz:
I think we mostly focused on and indeed the paper mostly focuses
on the difference between clinic blood pressure and ambulatory
blood pressure. When we talk about the young people, the young
people have a bigger difference but those differences are for the
most part all in the normal range. You might see a 10- or a
12-point difference but it might be that the ambulatory is 124
and the clinic is 112 and no doctor is going to worry about that
very much. There are really always two things that we're trying
to look at simultaneously: The first is what is that difference
between the ambulatory and the clinic, but the second is for whom
does the clinic stay under the threshold for diagnosis of
hypertension but the ambulatory is over? That's the diagnosis of
masked hypertension.


 
 
We haven't said it today so I'll say it: Of those people who had
normal clinic blood pressures averaged across three repeated
visits, 15.7% of them had elevated ambulatory blood pressure and
would have been diagnosed as having hypertension based on their
average daytime ambulatory blood pressure reading. That's one
message.


 
 
The last message is unfortunately there is almost no research yet
telling us what we should do in terms of treating people with
masked hypertension. We are now at the point where we can
identify these people and we're also at the point where we now
know that there are a lot of such people and we don't even have
any research to base guidelines on for deciding what we should do
with them. The most obvious thing is to recommend lifestyle
changes. If they're overweight we could suggest that they lose
weight. We could suggest that they exercise more. We might think
about treating some of those people, especially if their
ambulatory blood pressure is well above 140/90. There are no
statements out in the literature by any of the organizations, and
in fact there's no research examining whether there's a benefit
or not a benefit to perhaps putting some of those people on
medications. I think that's a big question that future research
needs to address.


 
Dr. Carolyn Lam:
Joe, thank you so much. I think your last statements just really
emphasize how important this paper is. It increases awareness and
it's going to open the door to much more needed research in this
area. Thank you so much. Thank you Joe and Wanpen for being on
the show today.


 
 
Thank you listeners for joining us. Don't forget to join us next
week for even more news and exciting discussions.