Dec 5, 2016
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.