Circulation April 10, 2018 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation On The Run, your weekly podcast summary
and backstage pass to the journal and its editors. I am Dr.
Caroline Lam, Associate Editor from the National Heart Center and
Duke National University of Singapore.


                                               
Can we reverse the cardiac effects of sedentary aging? Well if
you're curious, you have to read the feature paper in this week's
journal, as well as listen to the upcoming discussion of a trial
that addresses this issue. All coming right up, after these
summaries.


                                               
Desmond mutations are known to cause skeletal and cardiac muscle
disease, and also recently has been described in patients with
inherited arrhythmogenic right ventricular cardiomyopathy or
dysplasia. In today's first original paper, however, authors
identified a novel Desmond mutation in a large Spanish family
with inherited left ventricular arrhythmogenic cardiomyopathy or
dysplasia, and a high incidence of, at first, cardiac events.


                                               
First in corresponding author, Dr. Bermudez Jimenez from Granada,
Spain, describe for the first time the largest family to date
with a single Desmond mutation with a phenotype of left dominant
arrhythmogenic dysplasia in the absence of skeletal myopathy
symptoms and atrioventricular conduction disorders and supported
by strong clinical and functional data. In a series of elegant
experiments using explanted cardiac tissues and mesenchymal stem
cell derived cardio myocyte from the family members, the author
showed that the pathogenic mechanism probably corresponds to
alteration in Desmond dimer and oligomer assembly and its
connection with membrane proteins within the intercalated discs,
thus Desmond mutations should be suspected in patients presenting
with a cardiomyopathy characterized by mild left ventricular
systolic dysfunction and/or dilatation, fibrosis, ventricular
arrhythmias and a family history of sudden death.


                                               
The next study is the first large scale report examining the
incremental risk of surgical aortic root enlargement in patients
undergoing aortic valve replacement.


                                               
First author Dr. Rocha, corresponding author Ouzounian from
University of Toronto and their colleagues sought to evaluate the
early outcomes of patients undergoing aortic valve replacement
with or without surgical aortic root enlargement.


                                               
Now aortic root enlargement allows for larger prosthesis
implantation and maybe an important adjunct to surgical aortic
valve replacement in the transcatheter valve in valve era.


                                               
Among more than 7,000 patients undergoing aortic valve
replacement at a single institution from 1990 to 2014, the
authors observed no incremental risk in post-operative mortality
or adverse events following surgical enlargement of the aortic
root as compared to aortic valve replacement alone. They
therefore concluded that surgical aortic root enlargement appears
to be a safe adjunct to surgical aortic valve replacement in the
modern era.


                                               
The next study suggests that in patients with acute coronary
syndrome and an LDL cholesterol above 50 milligrams per
deciliters, health care providers should consider adding
ezetimibe to statins, particularly in two patient subgroups.


                                               
First in corresponding author Dr. Giugliano from the TIMI study
group at Harvard Medical School in Boston, Massachusetts and his
colleague explored outcomes stratified by diabetes in the
"improve it" trial where patients with a recent acute coronary
syndrome were randomized to ezetimibe versus placebo on top of
backgrounds in the statin.


                                               
They found that patients with diabetes derived significantly
greater relative and absolute benefit with the addition of
ezetimibe relative to patients without diabetes. This enhanced
benefit was driven by reductions in acute ischemic events
including myocardial infarction and ischemic stroke in diabetics,
while non-diabetic patients who were more than 75 years of age or
who had a high risk score also significantly benefited from the
addition of Ezetimibe to Simvastatin.


                                               
These benefits of Ezetimibe were achieved without an increase in
safety events compared to placebo. Thus, the two patient
subgroups of acute coronary system who are likely to achieve
greater benefits with the addition of ezitimibe include: one,
patients with diabetes, and two, patients without diabetes who
have a high risk score.


                                               
The final study provides insight into sudden cardiac arrests in
the young and the potential contribution of standard
cardiovascular risk factors to this risk, even in the young.


                                               
First author, Dr. Reshmy Jayaraman, corresponding author Dr.
Chugh from Cedars-Sinai Medical Center in California and their
colleagues, prospectively ascertained 3,775 individuals who
suffered sudden cardiac arrest between the ages of 5 and 34 years
in the Portland, Oregon Metropolitan area and who were also
followed up for 13 years. They found that 5% of cases occurred in
young residents between the age of 5 and 34 years.


                                               
Among the young, there was an unexpectedly high prevalence of
classical cardiovascular risk factors, such as obesity, diabetes,
hypertension, hyperlipidemia and smoking. In fact, one or more
risk factor was observed in 58% of cases, with obesity being the
most common.


                                               
Less than a third had warning symptoms prior to their lethal
event and sports activity was a trigger in only 14% of young
cases. Thus, standard cardiovascular risk factors, especially
obesity, may play a larger role in sudden cardiac arrests in the
young than previously recognized. This suggests the potential
role of public health approaches that screen for cardiovascular
risk factors at earlier ages.


                                               
And that wraps it up for our summaries, now for our feature
discussion.


                                               
Oh boy, today's featured discussion is gonna make everyone
listening fall in love with exercise and seriously get off your
chair right now as you listen to this discussion.


                                               
It's about how exercising may reverse cardiac aging and I am so
delighted to have with me none other than the corresponding
author, Dr. Ben Levine from the institute of exercise and
environmental medicine at Texas Health Presbyterian and UT
Southwestern, as well as Dr. Jarett Berry, and he's our dear
associate editor from UT Southwestern.


                                               
Ben, I have been dying to have you on this show, so welcome and
please, tell us what you did.


Dr. Ben
Levine:                
Thank you very much, it's a pleasure to be here Carolyn, thanks
for inviting me to talk about it. As you know, our lab has been
particularly interested in the components of aging that are
related to senescent versus those that are related to senescence
activity.


                                               
Perhaps the most dramatic reason that we're interested in this,
I'm just gonna give you a little bit of background, if you don't
mind, comes from one of the most important studies ever done in
our field, that was done in Dallas in the mid-1960s. It's called
the Dallas Bedrest and Training Study.


                                               
At that time, my mentors, G Blomqvist, Jerry Mitchell, Bengt
Saltin, took five young men, put them to bed for three weeks and
then trained them for two months and virtually everything we know
about the adaptive capacity of the circulation to exercise starts
without study.


                                               
I was only ten years old, so I really had nothing to do with it,
but 1996, 30 years later, we found those same five guys and
brought them back to Dallas to study them again.


                                               
Now, these are the most intensively studied humans probably in
the history of the world. 78 pages of circulation in 1968. What
we found was quite amazing. We found that not a single one of
those five guys was in worse shape 30 years later, than they were
after three weeks of bed rest when they were in their 20s.


                                               
So, three weeks of bed rest was worse for the body's ability to
physically work than 30 years of aging. And so, we sort of
launched off that in a series of experiments, trying to figure
out when in the aging process does the shrinking and stiffening
of the heart develop, that is the sine qua non. if you will, of
the cardiac aging. So, when does it start? How much exercise do
you have to do to prevent that?


                                               
We did one interesting study where we compared a group of very
highly selected seniors, all aged around 70, who were healthy,
but did no exercise, compared to a group of elite Masters
Athletes. Amazingly, the healthy seniors, their hearts got
smaller and it shrunk and they got stiffer and the athletes had
hearts that were indistinguishable from healthy 30 year olds.


                                               
So, a lifelong training at the level of being an elite athlete
completely prevented that aging response, which is really
interesting scientifically, but not a very good public health
measure.


                                               
So, we then asked how much exercise do you need to do over a
lifetime to preserve the compliance, the youthfulness, if you
will, of the circulation, and at times, they act like you need to
do about 4 or 5 days a week over a lifetime. 2 to 3 days a week
didn't do anything. 4 to 5 days a week did almost as much as
being an elite competitive athlete. So, now we've got the dose. 4
to 5 days a week.


                                               
We said, "okay, if we do that, can we reverse cardiac aging once
it's occurred?" So, we took our healthy sedentary people and we
also looked at a group of HFpEF patients and we trained them for
a year, at the right dose, using high intensity exercises. We
made them fitter, but we couldn't touch their cardiac or vascular
stiffness. Quite disappointing actually.


                                               
Last thing then, we said "okay, this leads up in to our current
study maybe, just maybe, if we pick the right sweet spot in time,
when the heart is just beginning to stiffen in that late middle
age period and deal the right dose at the right time for a long
enough period, we could reverse the effects. And, that's what we
did. We took 60 people, healthy, middle aged, 45-64, mean age
around 50. We randomly assigned them to two years of exercise
training or two years of yoga, balance, flexibility, and we did 2
light heart caths. We measured their cardiac compliance directly
invasively and we showed that our 2 year training program, which
included high intensity intervals, reversed the effects of
decades of sedentary aging.


Dr. Carolyn
Lam:              
Wow, Ben, you know, no one tells the story like you and I have to
tell you, I've been a fan of your work, citing it since I was 10.
Thank you so much for this amazing contribution to the Journal
this week. I just know everybody's asking questions like "So,
you've given us when to start, you given us the dose, but we want
to understand a bit better, what do you mean high intensity, how
many minutes and what exactly." Could you give us an idea?


Dr. Ben
Levine:                
Sure. There are multiple different ways to go about doing HIIT or
High Intensity Interval Training. And there's no magic to
intervals. Intervals just allow you to do something for a shorter
period of time and harder than you could do for a longer period
of time. That is the strategy that athletes use to go faster and
stronger and higher, because the body adapts to the load that's
placed on it.


                                               
Interval training, what I like, is based on an old Norwegian ski
team workout. It's called the "4x4". What that means is 4 minutes
at 95% of your maximum followed by 3 minutes of recovery, active
recovery, repeated 4 times. So, basically, you go as hard as you
can go for 4 minutes and at the end of those 4 minutes, you
should be ready to stop. Typically, your heart rate will drift up
towards 95% of maximum or so. Then, at the end of the 3 minutes
of recovery, you should be ready to do the next interval.


                                               
As it turns out, that's extremely effective training stimulus.
Not just for healthy people or athletes, for the patients with
hypertension and with heart failure.


Dr. Carolyn
Lam:              
I noticed that you have to screen over 260 individuals to finally
get your 60, so how doable is this and what was the compliance?


Dr. Ben
Levine:                
Right. You have to remember that out of those 260 individuals
that we screened, the majority of them were excluded up front
because they had hypertension or if they were obese or they
already had heart disease. So, the first round of screening was
making sure we're getting people of the right age and were
healthy. And, then another fraction, say 40 of them or so, didn't
wanna undergo two light heart catheterizations. And, I get that.
We were pretty pleased that somebody volunteered to do it, but
you know, it's an intense commitment. People have to be willing
to be randomized. So, they couldn't say "Well, I wanna do your
study, but only if I get randomized to exercise", that was not
acceptable.


                                               
So, everybody had to be prepared to be randomized to either yoga
or the fitness training and the yoga, it makes people feel
better, it's relaxing. I think it provided that clinical
equipoise and it ensured that even the controlled patients had
close contact with our research team.


                                               
Then, what we had was, on average 88% of the prescribed sessions
were followed by our exercisers and a fraction of them, 15 or
20%, actually did 100% of their prescribed sessions over two
years, didn't miss a single one.


Dr. Carolyn
Lam:              
So, Jarett, have you started doing that yourself now?


Dr. J
Berry:                         
I tell you, I pried my kids out of bed last summer, to go do 4x4s
and get them ready for cross country. I talked all about Ben
Levine and told my kids that we were doing what Dr. Levine
recommended. That didn't help too much, they found it rather
challenging. It was interesting that the VO2 plateaus a little
bit at that 10 month mark, when you guys backed off on that
additional interval training. Do you think that the plateau is
just a limitation of the training effect or do you think that
something that has to do with the lower level of interval
training at that time?


Dr. Ben
Levine:                
You know Jarett, I think that's a fascinating question and it's
one of the things that really surprised me. So, Jarett pointing
to the fact that at that 10 month mark, we measured VO2 max, we
didn't cath them, but we did an Echo, and it showed that from 10
months to 2 years VO2 max didn't increase very much.


                                               
There was a dramatic increase from baseline to 10 months. It took
3 months at that peak dose. But then, when we dropped one
interval and did the same thing every week for 2 years, there
wasn't an influence of time. The heart didn't continue to get
bigger, the stroke volume didn't continue to enlarge.


                                               
I think it highlights a critical part, an essential element, to
that exercise training and that is, doing the same thing, over
and over again doesn't get you fitter. If you wanna get fitter
than you are, you have to change things around, you have to
increase the load. So, I think that if we had wanted to make them
even fitter than they were at 10 months, we'd have had to either
kept that second interval or added another one or increase the
duration of some of the base training sessions.


                                               
It's really interesting to me, that they didn't continue to
improve simply on the basis of time. That surprised me.


Dr. Jarett
Berry:               
Yeah, cause you wonder. You think about, the guidelines suggest
moderate intensity exercise, which is obviously much lower
intensity than what you're talking about with this interval
training, but very little guidance with regard to interval
training.


                                               
Your data here obviously suggests that it's not just getting off
the couch and doing something, and not just doing a decent
amount, it seems to suggest that the interval training component
may be a secret ingredient that might be most helpful, at least
for those patients who can tolerate that level of training.


Dr. Ben
Levine:                
Yeah, I think that maybe it's the secret sauce, Jarett, but I
think, you do have to ask yourself, what is the goal of training
and what is your objective outcome? What you want is to reduce
cardiovascular mortality. I think we would all agree that you get
the biggest bang for your buck by going from sedentary to active.
And, the mechanism of that is uncertain, but could relate to
autonomic function or clotting or improving stabilization of
endothelium or other risk factors, inflammation, who knows,
there's a lot of different candidates. So, I think that
particularly for people who are at the highest risk for heart
failure, either from their family history or other risk factors,
like hypertension and diabetes, those are the ones who were
likely to get in a special benefit on altering cardiac structure.


                                               
That's why I think our data is still an important poll. We didn't
really know why do you get the biggest bank for your buck with a
little training, but if you really wanna prevent heart failure,
you gotta do more.


                                               
In our data that we did partnered with the Cooper Clinic and
looked at people who had done the same number of exercise
sessions over 25 years. None, 2-3, 4-5 or 6-7, over 25 years, we
saw virtually no effect of 2-3 days a week of what we call casual
training on anything we could measure, related to cardiac
structure. Their vascular stiffness was the same as people who
were sedentary, their cardiac stiffness was the same as people
who were sedentary. They were a little fitter and perhaps there
were other important differences that are related to just
improving immortality, but you have to get past that low to
moderate dose to have the structural effects on the circulation.


Dr. Jarett
Berry:               
These are really great points here, Ben. I want for our listeners
to hear you comment a little bit more on the primary outcome and
how you guys measured stiffness, because I think in addition to
the level of training, it's also the approach and the phenotype
that you collected to measure this and I think it would be
helpful for you to walk us through that a little bit and how you
guys measured stiffness.


Dr. Ben
Levine:                
We used an old physiological technique called "Lower Body
Negative Pressure". We first let the subject settle down, we
measure a variety of cardiovascular variables, cardiac output,
and we do an advanced ECHO imaging and some arterial stiffness
measures and after about 40-45 minutes or so, we'll measure the
pulmonary capillary wedge pressure, that's what we use as an
index, and plus ventricular and diastolic pressure. We'll do 3D
ECHO volumes and then we unload the heart by doing Lower Body
Negative Pressure. We basically seal the subject in a box at the
iliac crest and turn on a vacuum cleaner and suck blood into
their venous capacitance. It's a very simple way to unload the
heart.


                                               
In contrast to people who do put in conductants or reflectant
catheters and occlude the IVC and do pressure volume rudes, we
have taken a little bit of a different approach. I do steady
state and diastolic pressure volume curves. So that means, we
look at the pressure and volume in the heart at baseline at two
different unloading levels. So, let's say the baseline ledge is
10. The first level of LBNT of minus 15 will get it down to 6 or
7. The next level of minus 30 gets it down to 2 or 3. And, so we
get a nice unloading of the heart and we're able to establish a
steady state, which is probably more afunctional than a release
of an IVC occlusion.


                                               
Then, we let go of the suction, everything returns to normal. We
repeat our baseline measures and then we give the rapid saline
infusion. When I say rapid saline, I mean 15 and 30 mls per
kilogram, that's at 200 mls a minute. That's a big volume
infusion, but we'll give those doses and we'll raise the ceiling
pressure from 10 at baseline to 15 and then 19, 18, 19. So, we
get a large physiologic range of the diastolic pressure volume
curve, and then we'll fit that to an extremely widely accepted
exponential equation, which allows us to calculate the overall
stiffness of the heart, the diastolic component, and then we'll
do a few other things, we'll measure distensibility , which is
the volume at any given pressure and DPDV, the change in pressure
for a given volume, which is the hansen float to the exponential
curve fitting.


Dr. Jarett
Berry:               
Can you comment a little bit about what this means for how this
is distinguished perhaps from maybe more conventional non
invasive measurements of cardiac stiffness?


Dr. Ben
Levine:                
I think the most important thing to realize is that, cardiac
compliance is dynamic. It depends on the volume at which you're
making that measurement. So, as you unload the heart, any heart,
even the stiff heart, it gets more compliant, and as you load the
heart, even a compliant heart, it gets stiffer. Part of that is a
function of pericardial constraint, as well as myocardial
stiffness.


                                               
The whole idea that there is a measure of diastolic function that
you can measure by ECHO that is load independent is frankly an
oxymoron, because, diastole is load dependent. I think the ECHO
measurements are interesting and useful, depending on what you're
trying to find out, because there are many different aspects of
feeling and diastolic suction and diastolic stiffness. All of
which influence how well the heart feels at rest and during
exercise.


Dr. Carolyn
Lam:              
I have to ask you one last question. I am so pleased that you
included at least 52% women. Were there any differences by sex?


Dr. Ben
Levine:                
Of course, Carolyn, it's critical to include women, since they're
50% of the population. We've been very interested in their
training responses in men and women at different age groups in
many of our other studies. What's interesting is that in
premenopausal women, there's a quite clear distinction in how
women respond to training. They don't hypertrophy as much, even
for the same stimulus, heart beats a heart beat, over a year,
there's a much less hypertrophic response to premenopausal women
than young men.


                                               
We didn't see anywhere near that difference in our mostly
postmenopausal middle aged men and women. We didn't have enough
power to clearly be confident that there was no difference, but
when we tried to test that hypothesis, whether there was a
different response in men or women, we could not detect a
difference.


Dr. Carolyn
Lam:              
That is a good thing. So, women out there, you heard it from Dr.
Levine. We got to exercise too. High intensity. All the time.


                                               
Thank you audience, for listening today. Don't forget to tune in
again next week.