Circulation June 19, 2018 Issue 24

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. This week's issue is so
special. It is an autopsy issue. I think it's actually the first
of its kind in the history of Circulation. I am so pleased to
have with me today Dr Jeffrey Saffitz from Beth Israel Deaconess
Medical Center, who's the content editor for Pathology for
Circulation and the guest editor for this entire autopsy issue.
Welcome, Jeff.


Dr Jeffrey
Saffitz:            
Thank you.


Dr Carolyn
Lam:               
We also have Dr Lee Goldman from Columbia University Medical
Center who wrote a beautiful perspective piece on autopsy. Thank
you and welcome, Lee.


Dr Lee
Goldman:             
Morning.


Dr Carolyn
Lam:               
Jeff, could you start us off? I mean, an autopsy issue. How in
the world did this come about?


Dr Jeffrey
Saffitz:            
I think it really began by coincidence. The journal received
submissions from several authors, each involving studies of
autopsies, and the editors approached me and asked if we might
consider grouping them together in a special issue focused on the
role of the autopsy and cardiovascular medicine. I thought that
would be a very interesting idea and this evolved into actually
something much greater. Two additional papers came in focusing on
the autopsy and I think looking at these papers in the aggregate,
they represent what we can now consider to be the contemporary
utility of the autopsy in understanding the way cardiovascular
disease works. So I was particularly pleased that the editors
agreed to group these papers into a single issue focused on the
autopsy. We were really delighted that Lee Goldman agreed to
write a perspective. He has had a longstanding history of
studying the role of the autopsy and I hope the readers will find
this to be a really interesting and useful issue which will, I
hope, chart the course for future discovery.


Dr Carolyn
Lam:               
Just listening to you, I love the way you say it's a contemporary
look at autopsy. I mean, we covered things like molecular
genetic, proteomic, autopsies, even like electronic autopsies
using device. That's really cool. Lee, thank you again for
sharing your time and incredible perspectives with us. The long
history of autopsy. Do you think it's still necessary now?


Dr Lee
Goldman:             
Maybe give some perspective. I first got involved in this a
number of decades ago, when as a junior faculty member, I was
assigned to be on the medical audit committee of the hospital
where I saw patients as a cardiologist. And two of the senior
people in the committee got into a debate about whether autopsies
were still important given the advent of CT scans and other
modern diagnostic technology. And to listen to them debate for 15
or 20 minutes, I finally had the temerity to pipe in and say we
can actually study this, and so we did. We looked at autopsies in
three different decades: 1960, 1970, 1980, and much to everyone's
surprise, I think found, A. that the rate of which autopsies
found diagnoses that doctors had missed and for which treatment
would almost certainly have prolonged life was about 10 percent,
and it was 10 percent, 1960, 10 percent, 1970, 10 percent, 1980.


                                               
But the difference was that doctors were missing different
diagnoses. The things that got missed in 1960, and where
autopsies showed there were being missed led to better diagnostic
approaches and those things were rarely missed in 1980. But since
people stayed alive longer, they got new things that we didn't
really know much about in 1960. A big difference, fewer people
missed heart attacks, pulmonary emboli, and things of that sort,
but far more people had missed infections, especially fungal
infections that were complication of multiple antibiotics or
immunosuppressive therapies.


                                               
And so, as I followed this in 1980, if you will, to now, 2018, we
find this gets recapitulated over and over again. Medicine moves
forward, things we used to miss, we no longer miss, but people
still die, and they still die from things that we don't always
diagnose. We've done statistical analyses to show that probably
the rate of misdiagnosis is going down a little bit, but it's
still substantial and we still estimate that thousands of people
each year die in the U.S. from things that are not what the
doctors thought they had, and if that diagnosis had been made,
the patient would have lived longer.


Dr Carolyn
Lam:               
Lee, I just love that perspective. I have to say, it's really
humbling. I mean, 1960s and so on would predate me as well, so
I'm really humbled, and I love that reminder. Jeff, in fact,
quite a number of our papers illustrate exactly what Lee said. We
have four papers just dealing with sudden cardiac death, and that
is still what diagnosis was struggled with. Could you tell us a
little bit more about those?


Dr Jeffrey
Saffitz:            
Yes, of course. I think we all recognize that sudden death
remains a huge public health issue. We also realize that most
people who die suddenly and unexpectedly don't do so in the
hospital when they're being followed and monitored; rather, they
die out in the community, and in many cases, these are
individuals in whom major risk for coronary disease or other
potentially lethal cardiovascular conditions was really not
known. So I think it remains a major public health issue, and we
still have a great deal to learn. So perhaps it's not surprising
that four of the five papers involved autopsy studies of sudden
death victims of individuals who died out in the community. A
couple of them focused on sudden death in young people.


                                               
We know that these individuals often will have familial diseases,
and the autopsy has been one mechanism for studying these
individuals, so one of the papers from Michael Ackerman at Mayo
Clinic, advanced the concept that they started many years ago,
the so-called molecular autopsy in which they apply a whole exome
sequencing in cases of sudden unexpected death in young people
defined here as age under 40, and they identified some rare
variants which were likely to be of potential pathogenic
significance in sudden death. A related paper from Junttila et al
in Finland looks at the finding of myocardial fibrosis in young
victims of sudden death. They identified several cases in which
that was the only structural change in the myocardium, and when
they applied next gen sequencing, the identified variance that we
typically associate with the familial non-ischemic
cardiomyopathies, arrhythmogenic, dilated, and hypertrophic
cardiomyopathy. But the key insight here is that we traditionally
think of these diseases as having rather characteristic
structural changes which we can recognize at autopsy. What they
showed is that those structural changes might be limited to
nothing more than some fibrosis. And so the key here is that this
expands our potential opportunity to recognize these familial
cardiomyopathies, and the overarching idea is we use the autopsy
to serve the living. This is a way to gain information at autopsy
that we can then use to help family members and other individuals
by virtue of the insights gained at autopsy.


Dr Lee
Goldman:             
When we did the estimates in my editorial, and I estimated that
roughly 28,000 people die each year in America with diagnoses
that doctors missed and for which treatment would have been
different if they hadn't missed it, that's really based on, I'll
call traditional autopsy methods, which are anatomical, include
microscopic evaluation, include culture, but it's not
historically included genetic testing. I believe, as these
articles show, that the advent of genetic testing, which you
could argue could have been done while the patient was alive, but
we're not quite there yet in terms of testing everyone's genome,
now help you autopsies find even more things that might've been
missed. And as you just heard, also can have important
information for the family. So, one of the issues you often get
into in autopsies is what's in it for the family, and one of the
problems here is that the pathologists don't get paid. For the
family members, it's mostly an aggravation. The doctors are
worried they're going to get sued if something that gets found.
And so, to make this work you need to bring in some incentives.
Doctors not getting sued if they find things because they should
get credit for trying to learn more, some way to reimburse
reasonably pathologists and hospitals who do the autopsies, and
the understanding of family members that they not only will
perhaps be more reassured about what happens to the loved one,
but also may learn things that will affect their future, because
certainly, these cardiomyopathies, instead of them being
diagnosed, are familial and oftentimes will lead to testing and
hopefully interventions in family members that'll be to their
benefit.


Dr Carolyn
Lam:               
Lee, what great comments about bringing this into the clinical
perspective and I just love what you said, Jeff, about autopsy
for the living. That is just a quotable quote. That's so cool. I
noticed that you did ask Dr Judge to write an editorial
specifically about bringing autopsies into the molecular genetic
era. So I just want to encourage all our listeners to make sure
you read that as well. But Jeff, back to you about the other two
papers.


Dr Jeffrey
Saffitz:            
Well, I think one that I found particularly significant is this
idea that nowadays, patients come to autopsy with implantable
cardiac electronic devices, and the point of this paper is that
interrogation of these devices postmortem can provide really
important information about the cause and timing of those deaths.
I think the reality is that most pathologists who do these
autopsies are entirely unprepared or ill equipped to do such
interrogations, and so I think the point of this paper is simply
to encourage pathologists who do these autopsies to develop
partnerships and relationships with cardiologists who are able to
get this type of information from these devices. And again, it
not only provides information about what happened to that one
individual and what the death was all about, but it provides
important information to the family and potentially information
that allows the family to recognize particular risks that might
impact the living members. So I thought this was just another
really interesting example of how information that is potentially
available at autopsy may not be fully utilized, and I hope that
this paper will have an impact in that regard.


Dr Carolyn
Lam:               
That's great. Lee, did you have any perspectives on devices and
its role in autopsy now?


Dr Lee
Goldman:             
I guess that the point that I would just reinforce would be that
diagnostic technologies, including the ability to monitor
someone's heart rate, have helped us diagnose things that were
missed in previous eras, but medicine is always pushing the
frontier forward, and as long as we develop new therapies,
develop new devices, there'll be new things to learn. I want to
make one other point about what I'll call overconfidence in
diagnoses. The published statistics for the accuracy of most
diagnostic tests are based on what doctors think the diagnosis
ends up being, not the autopsy, which is the ultimate gold
standard. So, if you actually go through some not-so-complicated
arithmetic, you'll find that many of the tests that we think are
almost perfect at finding things really aren't because the people
who die with those things found that autopsies that the test
missed. There's something called a virtuous circle, there's also
a vicious cycle. There's a bit of a vicious cycle here that if
you don't do autopsies to be sure you aren't missing things, you
become overconfident in the tests that you think are finding
them, and therefore think you already know everything and don't
need to do an autopsy. To me, in some ways, that's the most
perverse result of the plummeting autopsy rate, which, by the
way, can be linked directly to changes in how hospitals get
accredited, that in prior years there was a minimal autopsy rate
required for accreditation. When that was removed, not
surprisingly, autopsy rates plummeted, and now, most autopsies
done in the US are not done in hospitals because doctors aren't
sure what's going on. They've done by medical examiners as part
of the laws for autopsies least being considered and people who
die without having had a medical attention to some degree.


Dr Jeffrey
Saffitz:            
You are exactly right on all of these points. I'll just say this
is the point of one of the other papers from Tseng et al. This
was a prospective autopsy study of sudden death in the city and
county of San Francisco, and what they showed here is that only
about half of the deaths that were considered to be sudden
cardiac deaths as defined by the conventional criteria actually
turned out to be deaths due to a rhythmic disorder. So Lee's
point is exactly right. Doctors think they know a lot of things,
but they're not always right about that, and the autopsy is
probably one of the best ways to bring some quality control to
this, and to really provide, I think, objective data that often
is the case flies in the face of what the previous thinking was,
and I think this paper in this issue of Circulation really brings
that point home very clearly.


Dr Carolyn
Lam:               
Yikes. OK, so here I am, I practice in Asia, and I think the
autopsy rates are even lower, so this is a great wake up call for
me just listening. Let's switch gears a little bit. How about the
paper by Dr Herrington? Now this goes to a proteomic bisection
almost of maybe preclinical disease and atherosclerosis. Would
you like to comment on that on, Jeff?


Dr Jeffrey
Saffitz:            
In the perspective that I wrote with Gaetano Thiene, in addition
to looking at the history of the autopsy, we looked to the future
and just considered briefly what role will the autopsy play going
forward, and I think the paper by Herrington is a great example
of how we can use the autopsy to learn so much more about the way
human disease works. The basic idea here is that something like
coronary artery disease or atherosclerosis, we think of as being
a disease that only involves the blood vessels, and we tend not
to recognize it until it is rather advanced and clinically
manifest, but we recognize that these diseases begin decades
before they become clinically manifest. We really don't know how
to identify the earliest antecedents, and without knowing that we
really, I think, very much limit our ability to identify the
disease way early before it becomes clinically manifest, and then
be able to practice preventive measures and intervene to prevent
the disease from occurring.


                                               
So, what this paper showed is that it's an application of
high-throughput proteomics looking at coronary artery and aortic
samples obtained at autopsy, and these authors identified
particular changes in proteins that they then were able to show
in a prospective independent clinical cohort were able to predict
the development of coronary artery disease. So I think going
forward, we are going to redefine our understanding of human
disease by learning about its earliest expressions and its full
systemic distribution, and in doing so, we'll be much better
prepared to diagnose earlier and intervene and prevent disease.
So I think this was a great example of how the autopsy can help
in that effort.


Dr Carolyn
Lam:               
I feel like we are going full circle in history and going back to
learn about how to go forward. I don't know if I expressed that
well, but I am just in awe of what I've learned from both of you.
Thank you so much, Jeff, for putting together this amazing issue,
and thank you so much, Lee, for sharing your perspectives. Thank
you, audience, for joining us this week. You've been listening to
Circulation On The Run. Don't forget to tune in again next week.