Circulation January 31, 2017 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 Centre and
Duke-National University of Singapore. Our featured discussion
today relates to 20 year outcomes after mitral valve repair
versus replacement for severe degenerative mitral regurgitation.


                                               
But first, here's your summary of this week's issue. The first
paper suggests that agonistic angiotensin receptor autoantibodies
may be biomarkers of adverse outcomes. In this study from first
author Dr. Abadir, corresponding author Dr. Fedarko, and
colleagues from Johns Hopkins University School of Medicine in
Baltimore, Maryland, authors developed a quantitative immunoassay
for measuring agonistic angiotensin AT1 receptor autoantibodies
in the serum.


                                               
They then assessed its operating characteristics in a discovery
group of 255 community dwelling adults from Baltimore and
validated these findings in a second group of 60 individuals from
Chicago. They found that AT1 receptor autoantibody levels were
significantly associated with higher levels of inflammatory
cytokines, weaker grip strength, slower walking speed, higher
risk for frailty, more falls and increased mortality.


                                               
Furthermore, chronic treatment with angiotensin receptor
blockers, it attenuated the AT1 receptor autoantibody association
with decline in grip strength and increased mortality. These
results therefore suggest that followup studies and intervention
trials in chronic inflammatory diseases should test whether AT1
receptor autoantibody levels can be used to stratify patient risk
and whether they can be used to identify patients who may benefit
from angiotensin receptor blocker treatment.


                                               
The next paper suggests that baseline target mismatch on CT
perfusion imaging may predict the response to tenecteplase in
ischemic stroke. Dr. Bivard and colleagues from John Hunter
Hospital University of Newcastle in Australia pooled two clinical
trials of tenecteplase compared with alteplase for the treatment
of acute ischemic stroke.


                                               
Baseline CT perfusion was analyzed to assess if patients met the
diffused two target mismatch criteria. These criteria are
absolute mismatch volume of more than 15 mL, mismatch ratio of
more than 1.8, baseline ischemic core less than 70 mL and volume
of severely hypoperfused tissue less than 100 mL.


                                               
Among 146 pooled patients, 71 received received alteplase and 75
received tenecteplase. Overall tenecteplase treated patients had
greater early clinical improvement by NIH Stroke Scale change and
less parenchymal hematoma, but did not show a significant
difference in three month patient outcome by the Modified Rankin
Scale.


                                               
74 of the 146 patients met target mismatch criteria. It was only
among these patients with target mismatch that treatment with
tenecteplase result in greater early clinical improvement and
better late independent recovery than those treated with
alteplase. In summary, tenecteplase may offer an improved
efficacy and safety profile versus alteplase, benefits that are
possibly exaggerated in patients with baseline CT perfusion
defined target mismatch.


                                               
The next study is the first to provide a comprehensive analysis
of circulating metabolite levels and relate these to clinical
outcomes in patients with pulmonary arterial hypertension. First
author Dr. Rhodes, corresponding author Dr. Wilkins and
colleagues from Imperial College London conducted a comprehensive
study of plasma metabolites using ultra-performance liquid
chromatography mass-spectrometry in 365 patients with idiopathic
or heritable pulmonary arterial hypertension and 121 healthy
controls.


                                               
They found that increases in circulating modified nucleosides
originating from transfer RNAs, energy metabolism intermediates,
tryptophan and polyamine metabolites and decreased steroids,
sphingomyelins and phosphatidylcholines independently
discriminated pulmonary arterial hypertension from controls and
predicted survival. Furthermore, correction of metabolite levels
overtime was linked to better clinical outcomes and patients who
responded well to calcium channel blocker therapy had metabolic
profiles comparable with healthy controls, thus these findings
suggest that monitoring plasma metabolites overtime could be
useful to assess disease progression and response to therapy in
pulmonary arterial hypertension. Therapeutic strategies targeted
against metabolic disturbances, particularly translational
regulation and energy metabolism, may merit further investigation
in pulmonary arterial hypertension.


                                               
The final study takes a contemporary look at age associated
changes in left ventricular diastolic function. Dr. Shah and
colleagues from Brigham and Women's Hospital in Boston,
Massachusetts related diastolic measures including tissue Doppler
E prime, E to e prime and left atrial size, to the risk of heart
failure hospitalization or death in 5801 elderly participants in
the ARIC study. They further defined sex-specific 10th percentile
limits in 401 participants free of cardiovascular disease or risk
factors. They found that each diastolic measure was robustly
associated with incident heart failure hospitalization or death.
Reference limits for E to e prime and LA size were generally in
agreement with existing guidelines, whereas limits for tissue
Doppler E prime were substantially lower at 4.6 for septal E
prime and 5.2 for lateral E prime in the ARIC study compared to 7
and 10 respectively in international guidelines. Compared to the
guideline cut points, the ARIC base limits improved risk
discrimination and reclassified over one-third of the study
population as having normal diastolic function. These findings
were further replicated in the Copenhagen City Heart Study.


                                               
In summary, this study suggests that a decline in left
ventricular longitudinal relaxation velocity occurs maybe as part
of healthy aging and is largely prognostically benign. This
supports the use of age-based normative values when considering
an elderly population.


                                               
Well, that wraps it up for the summaries, now for our featured
discussion.


                                               
Today we are discussing the very important result of the mitral
regurgitation international database and we have with us today no
other than the corresponding author Dr. Jean-Louis
Vanoverschelde, and he is from University of Louvain in Brussels.
Welcome Jean-Louis, I made it.


Dr Jean-Louis Vanoverschelde:  Hey, how are you?


Dr Carolyn
Lam:               
Thank you so much for joining us. Also joining us today is Dr.
Victoria Delgado, associate editor from Leiden University Medical
Center in the Netherlands. Welcome Victoria.


Dr Victoria Delgado:       
Hello. Thank you very much for having me in this podcast.


Dr Carolyn
Lam:               
So, severe degenerative mitral regurgitation with flail leaflets,
a very important condition and your study, Jean-Louis, really
provides important clinically applicable information. Could you
please address our clinicians out there with a take home message
from your paper.


Dr Jean-Louis Vanoverschelde:  Well, the take home message
is very easy, once this condition needs to be operated on, there
are really two options, one which is to repair the valve and keep
the native tissue and the other is to replace the valve and trash
the native tissue if I can say so. The results of the study are
really clear. There is a major survival advantage by repairing
the valve as opposed to replacing it. So for everyone of those
who have degenerative mitral regurgitation with flail leaflets,
the best treatment option is mitral repair.


Dr Carolyn
Lam:               
Now these results came from a multi-center registry of thousands
of patients. I was really struck with the duration of the study.
I think that's something that's really novel. You had a 20 year
follow up but also patients were recruited from 1980 all the way
to 2005, am I right? So could you expand a little bit about the
possibility of techniques changing during that period?


Dr Jean-Louis Vanoverschelde:  Although there has been
subtle changes in the practice, the basic principle have remained
the same. So we have not really accounted for these changes in
the practice over time, with regard to what happened to mitral
valve replacement, clearly the prostheses that were there 30
years ago are not the same as the ones that are currently
implanted to the patients, but none the less when we performed an
analysis, a sensitivity analysis to look at whether the results
were different from 20 years ago compared to those that were more
recent, we found exactly the same result.


Dr Carolyn
Lam:               
Yes, I thought that was a very important sensitivity analysis.
Tell us a bit more about the propensity score matching as well
because another thing people will be thinking is, you know, this
is a registry, huge numbers very important but obviously there
would be differences in indication for repair versus surgery.


Dr Jean-Louis Vanoverschelde:  For sure, the fact is that
there are statistical means that allow you to mimic not to be the
exactly the same as, but to mimic randomization and it is the
propensity score matching. That means that you perform a prior
analysis that will identify similar patients in the two cohorts
and match them so that you are basically having the same kind of
patients that are treated with two different ways. So it's not
randomization but it’s getting close to randomization when you
use cohorts like the one from the MIDA registry.


Dr Carolyn
Lam:               
Perfect. Victoria, did you take the same take home messages and
are you applying this clinically? I noticed that you invited an
editorial, a lovely editorial on this paper as well, so please
share your thoughts.


Dr Victoria Delgado:       
Yeah, I share the same take home message that Dr. Vanoverschelde
has outlined. I think that this is very important article, it's a
landmark article highlighting one of the most important things
that mitral valve repair should be probably the standard of care
for patients with severe mitral regurgitation without
degenerative cause with a flail and the article basically what it
does is also endorsing the recommendations of current guidelines
highlighting the value of mitral valve repair. Of course that
mitral valve repair should be performed in centers with
experience and with good durability of these repairs, so the
centers need to have a good heart team where they can analyze
their results in such a way like the MIDA registry has done
demonstrating a good durability of the repair.


Dr Carolyn
Lam:               
And do you have anything to add to that Jean-Louis?


Dr Jean-Louis Vanoverschelde:  No, I think basically
Victoria very well summarized the basic features not only of the
paper itself but also of the condition and what currently is in
the guidelines. In fact, the guidelines have already said that we
should be preferring mitral valve repair over replacement, but
the data on which this was based were probably not as conclusive
as the one that are provided by this analysis of our registry, so
I think it's really reinforcing the idea that we should go ahead
and try to perform repair as much as possible, now with a caveat
of course that the surgeons need to be skilled enough to perform
that. But with the type of differences that we see in survival
between the two cohorts I think that if a surgeon does not feel
comfortable with repairing the valve and would rather replace it,
he might refer the patient to another surgeon that is capable of
repairing the valve. The impact and outcome is such that I think
this really supports the idea that the patient should be referred
to high volume and skilled centers.


Dr Carolyn
Lam:               
Could you give us an idea of what kind of impact you're talking
about, what kind of numbers that you see?


Dr Jean-Louis Vanoverschelde:  It's the same in all the
analysis, whether it's in the overall population or in the
matched cohorts by 20 years, we have something like 20 to 25%
survival difference, absolute survival difference between the two
groups. So it's a reduction of mortality approximately by half if
you perform repair compared to replacement, and it is increasing
with time, so it's not something that is only present in the
first years but is increasing with time, so it's about 20 to 25%
absolute difference between the two cohorts.


Dr Carolyn
Lam:               
That truly is remarkable. Congratulations again on such a
landmark paper like Victoria said. Now to either of you, question
that's a bit left field maybe, but what do you think the role is
now for percutaneous techniques of mitral valve repair or
replacement then?


Dr Jean-Louis Vanoverschelde:  That's an interesting
question. I think that if you really look far away into the
future probably everything at some point in time will be
percutaneous. At this stage I’m not sure that the percutaneous
technique able to mimic what we can do with surgery in terms of
mitral valve repair. So, it's an alternative to surgery in
patients who are inoperable. In those who can undergo a surgical
mitral repair, my first choice will certainly be to go surgically
rather than percutaneously, at least right now.


Dr Carolyn
Lam:               
Victoria?


Dr Victoria Delgado:        I
also agree with those comments. I think that now we have a lot of
possibilities to treat these patients but the most important
thing is to have the entire clinical picture of the patient, to
see the pros and cons of preparing the patient for surgery or for
percutaneous valve. There should be also an integration of
imaging to know which is the cause of the valve dysfunction and
to see whether the anatomy could be easily repaired by surgery or
instead if the patient has contraindication for surgery, if it
could be repairable as well with transcatheter therapy. But then
for that I think that is really important and this is what the
editorial also highlights, the role of the heart team, where
there are different specialist surgeons, clinical cardiologists,
heart failure specialists, imaging specialists that can integrate
the entire information of the patient in order to select the most
appropriate therapy. But still for patients who do not have
contraindications for surgery who have repairable valve and as
you can see from this registry, the percentage of repairability
is quite high, I would still refer the patient as well for
surgical valve repair.


Dr Carolyn
Lam:               
You heard it right here. Thank you so much for joining us today
and please don't forget to tune in next week.