Circulation October 2, 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'm Dr Carolyn
Lam, associate editor from the National Heart Center and Duke
National University of Singapore.


                                               
FDG-PET CT was recently introduced as a new tool for the
diagnosis of prosthetic valve endocarditis. However, can we
improve on its diagnostic performance? Well, to learn more you
have to listen to the upcoming featured discussion, right after
these summaries.


                                               
Our first original paper this week describes a potential novel
therapy for hypertension. In this study from first author Dr Hu,
corresponding author Dr Soong, from Yong Loo Lin School of
Medicine National University of Singapore, authors showed that
galectin-1 is a key regulator for proteasomal degradation of CaV
1.2 channels. L-type CaV 1.2 channels are known to play crucial
roles in the regulation of blood pressure. In a series of elegant
in vitro and in vivo experiments, the authors showed that
galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and
thereby, exposing specific glycines for polyubiquitination. This
mechanistic understanding provided the basis for targeting CaV
1.2 galectin-1 interaction and demonstrated the modulatory role
that galectin plays in regulating blood pressure. The study,
therefore, offers a potential novel approach for the therapeutic
management of hypertension.


                                               
Direct oral anticoagulants or DOACs, are surpassing warfarin as
the anticoagulant of choice for stroke prevention in non-valvular
atrial fibrillation. However, DOACs outcomes in elective
peri-procedural settings have not been well elucidated and remain
a source of concern for clinicians.


                                               
The next paper in today's issue was a meta-analysis designed to
evaluate the peri-procedural safety and ethicacy of DOACs versus
warfarin. For author Dr Nazha, corresponding author Dr
Spyropoulos, from the Feinstein Institute for Medical Research in
Northwell Health at Lenox Hill Hospital in New York, reviewed the
literature for data from phase three randomized controlled trials
comparing DOACs with warfarin in the peri-procedural period among
patients with non-valvular atrial fibrillation. Sub study from
four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and
ENGAGE-AF. The short-term safety and ethicacy of DOACs and
warfarin were not different in patients with non-valvular atrial
fibrillation peri-procedurally. Under an uninterrupted
anticoagulation strategy, DOACs were associated with a 38% lower
risk of major bleeds compared to warfarin.


                                               
The next paper presents results from the Sarcomeric Human
Cardiomyopathy Registry or SHARE, which combined longitudinal
data sets curated by eight international hypertrophic
cardiomyopathy specialty centers to provide a better
understanding of the factors that contribute to heterogeneous
outcomes in lifetime disease burden in patients with hypertrophic
cardiomyopathy. First and corresponding author Dr Ho from Brigham
and Women's Hospital and colleagues analyzed longitudinal
clinical information on 4,591 patients with hypertrophic
cardiomyopathy. By examining the data set spanning more than
24,000 patient-years, the mortality of patients with hypertrophic
cardiomyopathy was shown to be 3-fold higher than the general
population at similar ages. The lifetime cumulative morbidity of
hypertrophic cardiomyopathy was considerable, particularly for
patients diagnosed before age 40 years and patients with
sarcomere mutations. Atrial fibrillation and heart failure were
the dominant components of disease burden. Thus, young age of
diagnosis and the presence of sarcomere mutations are powerful
predictors of adverse outcomes in hypertrophic cardiomyopathy.
These findings highlight the need for close surveillance
throughout life and the need to develop disease-modifying
therapies.


                                               
The final original paper this week provides molecular insights
into atherosclerosis and it shows that defective base excision
repair of oxidative DNA damage in vascular smooth muscle cells
promotes atherosclerosis. Now, we know that atherosclerotic
blocks demonstrate extensive accumulation of oxidative DNA
damage, predominantly as 8-oxoguanine lesions. In today's paper,
first author Dr Shah, corresponding author Dr Bennett from
University of Cambridge and colleagues studied levels of
8-oxoguanine and its regulatory enzymes in human atherosclerosis.
They found that human plaque vascular smooth muscle cells showed
defective nuclear 8-oxoguanine repair, associated with reduced
acetylation of the base excision repair enzyme
8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base
excision repair defect in vascular smooth muscle cells alone
markedly reduced plaque formation, thus indicating that
endogenous levels of oxidative DNA damage in vascular smooth
muscle cells promoted plaque development.


                                               
And that brings us to the end of this week's summaries. Now for
our feature discussion.


                                               
Prosthetic valve endocarditis is a life-threatening complication.
However, making a timely diagnosis of prosthetic valve
endocarditis before the occurrence of severe complications is
really difficult. Now, FDG-PET CT has recently been introduced as
a new tool for the diagnosis of prosthetic valve endocarditis.
However, previous studies reported only modest diagnostic
accuracy and may have been hampered by confounders. But today's
study, our feature study in Circulation, addresses this issue. We
have none other than the corresponding author, Dr Ricardo Budde
from Erasmus Medical Center in Rotterdam, the Netherlands, and
our dear associate editor, Dr Victoria Delgado, who is in Leiden
University Medical Center, also in the Netherlands.


                                               
So please tell us, how does your study help us address this issue
of the accuracy of FDG-PET CT


Dr Ricardo
Budde:          
What we actually did is that of course endocarditis is a
relatively rare disease, so we had six hospitals in the
Netherlands that collaborated on this study and in each of the
hospitals we searched for PET CT scans that were performed in
patients with a prosthetic heart valve, either because they were
suspected of having endocarditis, or if they were meant for other
purposes, for example oncological follow-up. Then we grouped all
those CT scans together, interpreted the PET CTs anew by
dedicated interpreters, and then compared the findings with the
actual diagnosis in the patient, which of course is always
difficult in endocarditis because to make the diagnosis is
difficult. So, also, one year follow-up period was included in
that to be absolutely certain whether the patient had
endocarditis or not. By taking this whole cohort of patients, we
were able to determine the diagnostic accuracy of PET CT, as well
as by using a logistics model, identify confounders which
influence the diagnostic accuracy of PET CT.


                                               
I think the study that we did addresses several important aspects
and the way it helps physicians in actually interpreting and
implementing PET CT to diagnose endocarditis is two-fold. First
of all, we identified confounders that have to be taken into
account when interpreting and using the PET CT. For instance, low
inflammatory activity at the time of imaging and the use of
surgical adhesive during a prosthetic heart valve implantation
are confounders which should be taken into account when
interpreting the PET CT. Furthermore, the guidelines have always
insisted on not to use or use it very cautiously PET CT within
the first three months after prosthetic heart valve implantation.
However, we showed that actually this period after implantation
does not necessarily have to be taken into account as also a good
diagnostic accuracy can be obtained within the first three months
after implantation.


Dr Carolyn
Lam:               
Ricardo, that's wonderfully put. I don't do a CT, PET CT,
routinely. In fact, I am echocardiologist and it used to be that
infective endocarditis was diagnosed with echo. So Victoria, tell
us, how does echo stand now with this information?


Dr Victoria Delgado:       
That's a very good question but I think the guidelines set a very
clear figure of how the diagnostic workup of patients with
prosthetic valve endocarditis should be performed. An
echocardiography is the first imaging technique. The point is
that transthoracic echocardiography in patients with suspicion of
prosthetic valve endocarditis is very challenging. In terms of
ideal, echocardiography is probably the best imaging technique to
do first to evaluate whether it is endocarditis or not. It's
difficult, we have to take into account that for a specific
prosthetic valve, particularly mechanical, the shadowing can make
that we don't see the [inaudible 00:10:22] and sometimes it's
difficult, particularly in the early phase immediately after
implantation, all the inflammation can be confounder for presence
of endocarditis. In those cases, I think that this study provides
additional and important data highlighting which are the
confounders when you use PET CT to evaluate depressions of
endocarditis. I think that, when you take into account those
confounders, the accuracy of this technique is very good in order
to make or help in the diagnosis of these patients. So,
echocardiography, I think that will remain as our first imaging
technique to rule out [inaudible 00:11:10] we can see but in
those cases where the diagnosis is not confirm or rule out with
transthoracic and transesophageal echocardiography this study
provides additional data and important data showing that PET CT
is a valuable complementary imaging diagnostic test for these
patients.


Dr Carolyn
Lam:               
Ricardo, would you agree with that because I think your study
also emphasized that perhaps FDG-PET CT should be implemented
early in the diagnostic workup to prevent the negative
confounding effect of the low inflammatory activity? So how do we
put this all together?


Dr Ricardo
Budde:          
Well actually, I agree with Dr Delgado that echocardiography is
and should be the first-line test that you do if you have a
patient that has a suspicion of endocarditis. I mean, the
advantages of echocardiography are many and it's non-invasive,
it's bedside-available if needed, it's patient-friendly, and it
provides a huge amount of information so you should always start
with echocardiography. However, sometimes it can be difficult by
echocardiography, for the reasons just explained by Dr Delgado,
and I think then PET CT should be considered. And when you want
to do a PET CT, then you should do it early within the diagnostic
workup.


                                               
Actually, in the article, one of the figures is a flow chart
which we provide, and it provides information on how we think PET
CT can best be implemented in the workup of endocarditis. In this
flow chart we also start with doing an echocardiography and also,
importantly, consult the endocarditis time to make initial
classification of whether it's a rejected, possible, or definite
prosthetic heart valve endocarditis. After that, you can follow
the flow chart and see when you can best implement PET CT, in our
opinion.


Dr Carolyn
Lam:               
Indeed Ricardo, I am so glad you brought up this figure and
listeners, you have to take a look at it. I can imagine that
everybody will be using this and discussing it and how to
incorporate this in the workflow. And indeed you do start with
either transthoracic or transesophageal echo and blood cultures,
so thank you for clarifying that.


                                               
Now, for our clinicians out there, are there any situations you
may be telling us to be a little more careful? Could you put it
simply for us when it comes to the FDG-PET?


Dr Ricardo
Budde:          
You mean when not to perform a PET CT?


Dr Carolyn
Lam:               
Yeah, or when we have to be really careful about inaccuracies.


Dr Ricardo
Budde:          
I think, of course, the confounders that we indicate in the
article, especially if bioglue has been used by the surgeon
during the initial surgery. We know that bioglue can be seen on a
PET CT as a false positive uptake of FDG and it's also important
to note that this is a phenomenon that can persist for a very
long time after a valve implantation. It could be for years, so
especially that I think is a very important confounder to take
into account and be careful when you interpret PET CT or use the
PET CT and always read the original surgical report if it is
available to obtain this information.


Dr Carolyn
Lam:               
That's wonderful advice. Victoria, do you have anything to add?


Dr Victoria Delgado:       
No, I think that Dr Budde explained perfectly this figure that is
key in the article and also how to evaluate patients with
suspected endocarditis of prosthetic valve. One thing that
sometimes we forget is starting from the first step that is a
good clinical history which includes also a good evaluation of
previous history and, if possible, what has been done in the
patient. I think that this key information to understand the
findings on the echocardiography, transthoracic or
transesophageal, and the subsequent investigations that you are
going to perform. Either CT which is considered, for example,
when you have a definitive prosthetic valve endocarditis and you
want to rule out potential complications such as abscess, for
example, and if you perform a PET CT or other imaging modalities
that then also indicate the presence of infection like, for
example, [inaudible 00:15:26] leukocytes with PET, for example.


Dr Carolyn
Lam:               
And I just want to end up with one little point. Ricardo, how
about the fact that part of your results don't corroborate the
ESC guideline recommendations that they say you have to avoid
FDG-PET in the recently implanted prosthetic valve. How do you
feel it's going to play out for clinicians?


Dr Ricardo
Budde:          
Well, I think the 2015 ESC guidelines on endocarditis are a very
important document. One must take into account that the inclusion
of PET CT in the ESC guidelines was a major step, and some might
say that it was a little premature to include the use of PET CT
because the number of data that was out there were still
relatively limited. I think it's something that we are learning
along the way. Now that we are using PET CT more often we are
more aware of what we do to findings that we get and also the
findings that we have within specific timeframes after the
implantation of a prosthetic heart valve. One of the things that
I think is desperately needed also at the moment is to have a
prospective study where we would do PET CT in patients after
implantation of a prosthetic heart valve that do not show any
signs of endocarditis where we do PET CT just to determine these
normal uptake values. I think that would be a major contribution
to the whole learning experience that we're currently having with
implementing PET CT within prosthetic heart valve endocarditis.


Dr Carolyn
Lam:               
Indeed, and Ricardo your paper has added significantly to our
understanding. Readers, remember, it's Figure 6 of our feature
paper this week. It is a beautiful figure. Pick it up, take a
look. In the meantime just thank you so much Ricardo and Victoria
for joining me today.


                                               
Listeners, don't forget to tune in again next week.