Dec 19, 2022
This week, please join author Mads Liisberg and Guest Host Mercedes Carnethon as they discuss the article "Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study from 1996 to 2016."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke, National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, today's feature paper is about aortic dissections and it's the first nationwide population based study investigating the clinical characteristic, incidents, and mortality based on validated diagnosis of aortic dissection in a national patient registry. You want to hear more? Well, you have to just keep listening. Let's go on though first to discuss the other really important papers in today's issue, shall we?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
You know what, Greg? I'm going to start while you grab a coffee. I want to talk about high sensitivity cardiac troponins and how they have allowed the use of strategies in the emergency department, for example, to rapidly rule out acute MI within one to three hours and potentially facilitate early discharge of low-risk patients. Now, the ability to rapidly rule out MI of course depends on the turnaround time of these high sensitivity cardiac troponin results from the central laboratory, which is often delayed due to specimen transport and handling and all these things.
So, point-of-care assays can reduce this turnaround time by even 40 minutes, and early studies have actually used frozen plasma bio banks to assess these point-of-care assays... But no study has evaluated these point-of-care assays with fresh whole blood to safely rule out MI in the emergency department. That is until today's paper. So in today's study led by corresponding other Doctor Fred Apple from Hennepin Medical Center in Minneapolis, Minnesota and his team, they aimed to derive and validate an optimal high sensitivity cardiac troponin threshold concentration using whole blood point-of-care troponin eye assay on a single sample at presentation in the emergency department to identify patients at low risk of index MI for potential early discharge.
Dr. Greg Hundley:
Fascinating study Carolyn. So point-of-care testing, high sensitivity troponin from whole blood in the ED. So what did they find?
Dr. Carolyn Lam:
Among consecutive emergency department patients from two prospective observational studies with suspected acute coronary syndrome, a point-of-care, whole blood, high sensitivity cardiac troponin eye assay, the Atellica VTli provided a sensitivity of 98.9% and a negative predictive value of 99.5% for ruling out MI. A single measurement using a cutoff of less than four nanograms per liter for whole blood was successful in rapidly identifying patients at low risk of MI cardiac and all cause death and unplanned revascularization at 30 days.
Dr. Greg Hundley:
Very nice Carolyn, and could be quite practical. So Carolyn, my next paper comes to us from the world of preclinical science and it pertains to cardiac regeneration. So cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes. However, certain animals readily regenerate lost myocardium via process involving dedifferentiation, which unlocks their proliferative capacities. So inspired by this concept, these investigators led by Professor Patrick Hsieh from Academic Sinica, generated mice with inducible cardiomyocyte specific expression of the Yamanaka factors enabling adult cardiomyocyte reprogramming and dedifferentiation in vivo.
Dr. Carolyn Lam:
Wow. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So two days following induction, adult cardiomyocytes presented with a dedifferentiated phenotype, an increase proliferation in vivo. Microarray analysis revealed that the up-regulation of ketogenesis was central to this process. Now adenovirus driven HMGCS2 over-expression induced ketogenesis in adult cardiomyocytes and recapitulated cardiomyocyte dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue. And HMGCS2 knockout mice showed impaired cardiac function and response to injury, and so in summary, Carolyn, these data demonstrated the importance of HMGCS2 induced ketogenesis as a means to regulate metabolic response to cardiomyocyte injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.
Dr. Carolyn Lam:
Wow, that's so cool. From cell regeneration to autoimmunity in this next paper. Now autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. However, the functional features of cardiac autoimmunity in humans remain undefined due to the challenge of studying immune responses in situ. Now, these authors previously described a subset of c-Met expressing memory T lymphocytes, which preferentially migrate to cardiac tissue in mice and humans. In today's study, these authors led by co-corresponding authors, Dr. Federica Marielli-Berg and Saidi Mohidden from William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, and Queen Mary University of London, and their colleagues performed in-depth phenotyping of peripheral blood T cells in groups of patients with inflammatory and non-inflammatory cardiomyopathies, patients with non-cardiac autoimmunity and healthy controls... And they found that c-Met positive T cells were selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies.
The phenotype and function of c-Met positive T-cells were distinct from c-Met negative T cells, including preferential proliferation to cardiac myosin and co-production of multiple cytokines. Further, circulating c-Met positive T cell subpopulations in different heart muscle diseases identified distinct and overlapping mechanisms of heart inflammation. Furthermore, validation studies in experimental autoimmune myocarditis showed that elevations of auto-antigens specific c-Met positive T cells in peripheral blood, marked the loss of immune tolerance to the heart. Importantly, disease development could be halted by pharmacologic c-Met inhibition indicating a positive role for these c-Met positive T cells.
Dr. Greg Hundley:
All right, Carolyn, as you always ask me. So what's the take home message here?
Dr. Carolyn Lam:
This study demonstrates that the detection of circulating c-Met positive T cells may have utility in the diagnosis and monitoring of adaptive cardiac inflammation and additionally defined new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury... And this is discussed in an editorial by doctors at Abplanalp, Merten, and Dimmeler.
Dr. Greg Hundley:
Very nice, Carolyn. Wow. More fantastic preclinical science. Well, in the mail of the bag today, there is a Research Letter by Professor Burr entitled “Cannabis Inhalation Acutely Reduces Muscle Sympathetic Nerve Activity in Humans.”
Dr. Carolyn Lam:
There's an ECG Challenge by Dr. Reddy entitled “Shortness of Breath and Near Syncope During Exertion In a Child, When Patient Worry Syndrome.” There's also a Perspective by Dr. Weitz on what is the future of Factor 11 inhibitors.
Dr. Greg Hundley:
Well Carolyn, I'm looking forward to learning more about aortic dissections and that large Danish population-based study. Wow.
Dr. Carolyn Lam:
That's great. Let's go Greg.
Dr. Mercedes Carnethon:
Well, welcome to this episode of Circulation on the Run. My name is Mercedes Carnethon, an Associate Editor of Circulation, and Professor and Vice Chair of Preventive Medicine at Northwestern University. I'm really excited today to be here with the senior author of a really exciting paper that we're featuring on clinical characteristics, incidences and mortality rates for aortic dissections type A and B, a nationwide Danish population-based cohort study, and we have with us today Mads Liisberg. So welcome today.
Dr. Mads Liisberg:
Thank you.
Dr. Mercedes Carnethon:
So thank you so much for joining us and really thank you for sharing your important research with Circulation. This topic is so critically important, particularly given the high mortality rates associated with aortic dissections. Can you tell us a little bit about the work that you and your co-authors did in this important space?
Dr. Mads Liisberg:
Yes. Well actually the work originated when I started my PhD thesis and we got a registry data dump from the Danish medical registries and we found that almost none of our patients in the registry were registered with a specific aortic dissection code.
So we did a validation study on the same time period from 1999 to 2006 where we went through all these medical records to ensure that we had the right aortic dissection TC 10 codes on population. Then we went a bit further and looked at the clinical characteristics of this patient, 'cause that's one of the really major things about Danish medical registries in our country, is that we have access to not only every patient's specific in hospital contacts, but also their medicine abuse, their drug use based on a TC code. So we can go really deep into each and everyone's drug history. When we did this study, we wanted to find out if the incidence rates during this timeframe had changed, which we find that it did, but also looking at mortality rates because, as you said, it's really high risk disease to be diagnosed with. So that's more the rationale for this study.
Dr. Mercedes Carnethon:
Thank you so much for sharing that. Certainly we know that the mortality rates from this are very high. I note that you report some changes over time between 1996 and 2016 in the incidents of these types of aortic dissections. So what did you find about the patterns of change in type A aortic dissections?
Dr. Mads Liisberg:
We found that it almost doubled from the beginning of our time period to the last, and the question is why is this? 'Cause that's one of the thing that the data doesn't reveal. We are only able to see that the incidence actually rises, but is it because that they are underdiagnosed in the beginning? Or is it because that we are better diagnosing in the end of the study that really are progressed?
Dr. Mercedes Carnethon:
That's a good question. I noted that when you studied the correlates of aortic dissection, you identified a number of characteristics and what stood out to me was the finding about the strong association of hypertension. I'm less aware of patterns of hypertension in the Danish population. Do you think that the changes in the prevalence of hypertension in the population contributed at all to these findings?
Dr. Mads Liisberg:
Well, most certainly, 'cause when you look at the prevalence of hypertension throughout any person's lifespan, the older they get the more likely they are to suffer from hypertension, and the Danish population has aged quite a lot in recent years. So I think that's one of the main reasons we find this, and also that most of our arctic dissection patients are actually quite old, which would correlate with hypertension as well.
Dr. Mercedes Carnethon:
One thing I really like, and you pointed this out, is really the richness of the data that you have in your health system, and I wonder, just going even a little deeper on the hypertension question, given that it is the most common medical diagnosis worldwide, were you able to study characteristics of hypertension that would be more strongly associated with aortic dissection? So for example, duration of hypertension, severity, prevalence of hypertension control?
Dr. Mads Liisberg:
That's actually a funny question 'cause the last study of my thesis, which hasn't been published yet or even submitted for that fact, examines the correlation between use and the risk of arctic dissection. On a very specific level, the way that hypertension is treated mostly in Denmark is with your general practitioner. So the way that we examine in studies like these, is that we look at prescription drug use. So if we find that an individual has a TC codes corresponding with anti-hypertensive drugs, then we are able to code them as hypertensive patients.
Dr. Mercedes Carnethon:
Okay, thank you for that. I always... I'm an epidemiologist myself, so I really love to see great population science studies and this registry is large, you have long-term follow up and you've got a great deal of data, but those people who feel as though it's obviously not appropriate to make causal conclusions around epidemiology and that perhaps epidemiologic findings shouldn't be driving clinical decision-making. In response to that, I think I would pose the question to you, which is how do you see clinicians and providers using this information from your observational study?
Dr. Mads Liisberg:
I think that's rather difficult. One of the findings that we present is to pose it over mortality for type B dissections when we exclude the 30-day mortality, but then we show that type A dissections have almost a corresponding mortality rate compared to a hypertensive cohort... And this finding is difficult to draw any clinical conclusions from, but there's actually a Danish randomized controlled trial just starting up in the next year. I think it's called the Sunday trial, where they will include all uncomplicated type B dissections and randomize them for treatment or no treatment, and the issue here is that you'll probably be over-treating some patients and under-treating others, but this discussion with the uncomplicated type B dissection has been ongoing for so many years. So it's difficult for me to just give one golden answer.
Dr. Mercedes Carnethon:
Certainly, and I appreciate the caution as we certainly don't want to overstep our findings. You did make a recommendation in the conclusion that it might be beneficial to treat type B aortic dissections more aggressively. Is this what you're alluding to, based on the other study that you're referencing?
Dr. Mads Liisberg:
Yes, yes, definitely. We see some clinicians being more cautious treating type B dissections with a TIVA or a surgery. So it's a difficult thing when they're uncomplicated, why treat them? But they can't be or become complicated quite easily and fast and then it's a difficult thing, because should you have treated them earlier? Or do you need to treat them now in their acute phase? Or wait for a chronic phase? It's a really good question.
Dr. Mercedes Carnethon:
No, I appreciate that and what I really love are the types of research studies that leave you with many more questions and next steps, and so I would like to really sort of bring us to a close with the big picture question, which is what do you see as the next steps in this line of research, given really what we all agree on is a very significant clinical problem.
Dr. Mads Liisberg:
We would really like to expand our database with even more clinical data as of now and include any image diagnostics for our cohort. So we're might be able to see any trends in our modulation before the dissection occurs. If any of our patients have any diagnostics done prior to being diagnosed.
Dr. Mercedes Carnethon:
I really want to thank you today for spending time talking with us. I know that our readers rarely have an opportunity to hear from everybody behind the scenes views on what the rationale was for carrying out a paper and really how the authors themselves hope that the paper will be used. So I really thank you for sharing that with us today, Matts, on behalf of your co-authors, this has been really a wonderful conversation, and thank you again for sharing your research with the journal, Circulation.
Dr. Mads Liisberg:
Oh, thank you for having me in for accepting our paper.
Dr. Mercedes Carnethon:
So thank you so much to our listeners for listening to us on this episode of Circulation on the Run. Please tune in next week as we will have more exciting insights.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.