Circulation August 16, 2016 Issue

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Carolyn: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. I am so pleased to be joined this week by Dr. Judd Hollander and Dr. Deborah Diercks to discuss a problem that all of us, as cardiologists and emergency department physicians will recognize. This is a feature paper on the state of the art approach to the patient presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome, but first here are the highlights of this weeks issue.

The first study is from first author's Dr. Wing and Dr. August from Grand Valley State University in Michigan who investigated whether social and physical neighborhood characteristics are related to progression of sub clinical atherosclerosis measured by coronary artery calcium. They studied this in almost six thousand adult participants of Mesa, a multi-ethnic study of atherosclerosis, followed over twelve years. The main result was that increases in density of neighborhood healthy food stores were associated with decreases in coronary artery calcium. This was significant even after adjusting for time varying demographic confiders, time varying behavioral risk factors and depression.

The next study from Dr. Hess and colleagues from the University of Colorado School of Medicine characterized rates of implantable cardioverter defibrillator or ICD counseling and ICD use among more than twenty-one thousand potentially ICD eligible hospitalized heart failure patients in the Get With the Guidelines heart failure program. This study had several notable findings. First, only twenty-two point six percent of patients received ICD counseling. This means that up to four out of five hospitalized heart failure patients, eligible for ICD counseling, did not receive it. Women were counselled less often than men and racial or ethnic minorities were counseled less frequently than white patients.

Among counseled patients, a totally of sixty-two point six percent of patients received an ICD or had a documented plan for ICD placement. Women were just as likely as men to receive an ICD, however, ICD used differences by race and ethnicity persisted. The clinical implications of this study are that future quality improvement initiatives should incorporate culturally competent ICD counseling and elevating ICD counseling to a full performance measure and publicly reporting it by sex or race or ethnicity may need to be considered.

The next paper is from first author Dr. Resconey and corresponding author, Dr. Catalucci and colleagues from the Institute of Genetic and BioMedical Research in Milan, Italy. These authors looked at the voltage dependent [inaudible 00:03:31] calcium channel which is a key mediator of interest [inaudible 00:03:34] calcium entry associated with various cardiovascular conditions such as hypertrophy, atrial fibrillation, hypertension and diabetic cardio myopathy. The author's aim to address the problem that [inaudible 00:03:47] approaches aimed at enhancing calcium current and inotropism in heart failure have also frequently been found to favor arrhythmogenesis and diastolic dysfunction. Thus, limiting their clinical use.

The novel hypothesis addressed in this study is that a peptidome emetic therapeutic approach may overcome the arrhythmogenic limitations of current channel activator inotropes. To test this hypothesis, the author's used a whole host of methods to dissect new regulatory pathways modulating the [inaudible 00:04:24] tight calcium channel life cycle. This included yeast, two hybrid screenings, biochemical and molecular evaluations, protein interaction essays, fluorescence, microscopy, and structural molecular modeling and functional studies. Having uncovered a novel mechanism involving the [inaudible 00:04:44] tight calcium channel, calcium beta two chaperon, the author's then generated a mimetic peptide that specifically targets this calcium beta two chaperon. Thereby controlling the channel assembly and density of the plasma membrane while preserving its physiological channel function.

Finally, they showed that delivery of this mimetic peptide into a mouse model of diabetic cardiomyopathy restored calcium balance and recovered cardiac function. This study is so significant because it provides the proof of concept for the exploitation of novel therapy based on mimetic peptide technology. Really opens the field to mimetic peptides being used as innovative therapeutic tools for the treatment of cardiac disease.

The last study is from Dr. Cammel from the Feil Family Brain and Mind Research Institute in New York and colleagues who studied the association between pregnancy and aortic complications such as dissection or rupture. They used data on all emergency department visits and acute care hospitalizations at nonfederal health care facilities in California and New York between the period of 2005 to 2013. This was a cohort crossover study where they authors defined the period of risk as six months before delivery until three months after delivery. Compared each patient's likelihood of aortic complications during this high risk period to an equivalent control period of two hundred and seventy days exactly one year later.

Among more than six and a half million pregnancies in almost five million women, they identify thirty-six cases of aortic dissectional rupture during the high risk pregnancy period and nine cases during the control period. This gives the rate of aortic complications a five point five per million patients during pregnancy compared to one point four per million during the equivalent period one year later. Thus, pregnancy was associated with a significantly increased risk of aortic dissectional rupture with an incidence rate ratio of four compared to the control period one year later.

Furthermore, absolute risks were particularly elevated in those with a documented diagnosis of hypertension or a connective tissue disease. These findings have clinical implications for the counseling of patients at high base line risk of aortic complications and they also further suggest that clinicians may need to have a lower threshold for initiating diagnostic testing for symptoms of a possible aortic dissection or rupture in pregnant or postpartum patients and especially in those with connective tissue disorders or hypertension.

Our feature paper this week discusses a problem that impacts twenty million patients in North America and Europe every year. What am I talking about? These are patients presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome. Who am I talking with? Well, today we have first author Dr. Judd Hollander from Thomas Jefferson University and Dr. Deborah Diercks associate editor from UT Southwestern. Welcome Judd and Deborah.

Dr. Deborah: Thank you.

Dr. Judd: Thank you.

Carolyn: Let's start with a behind the scenes look at this paper. It's an in depth review that was invited by the editorial team. Deborah, can you tell us how this idea came about?

Dr. Deborah: I think one of the goals of the editorial board of circulation is really to provide great clinical reviews that really could benefit the members. I have a unique aspect in that I'm an emergency physician. This idea was really brought about by discussion of really what can we merge cardiology and emergency medicine with. What would be the most clinically issue we're challenged with right now? You can't get two emergency physicians in a cardiologist's room together without some discussion and challenge around the [inaudible 00:09:11].

There's been so many changes in the last decade and so much more information about how we can use these in a clinically relevant way. It really fit nicely into a really great review article and I am really happy that we are able to invite Judd who's well known to the US and one of the leaders in the United States in this area and also an international group inviting a cardiologist from Europe and also an emergency physician from New Zealand to participate in it.

Carolyn: Judd, what is the take home message of this in depth review from your point of view?

Dr. Judd: I think the biggest take home message is we have known for decades and decades that if we rely on our clinical judgement we miss too many patients. We send home people that will be having acute coronary syndromes and acute myocardial infraction and the challenge over the last decades of trying to find ways where we're not going to spend a ton of money over admitting people to the hospital because of a fear of missing an event that may happen five percent of the time.

The beauty of the advances in troponins is we now have troponins that now have increasing sensitivity whether they be the non high sensitivity troponins used in the US or the high sensitivity troponins that are actually used in Europe and the rest of the world. We can use those better [inaudible 00:10:29] and combine them with clinical decision rules to create accelerated diagnostic pathways which is a big term. For now, if we put a blood test together with a structured clinical decision rule, we can, with more than ninety-nine percent negative predictor value, find patients who are safe to send home.

Carolyn: Judd, I really have to congratulate you on such a beautiful paper. You really did cover all of that but what I love most is the way that you've managed to summarize very clearly a whole wealth of information because when you talk about biomarkers, there's so many out there and there's zero hour, one hour, two hours, this score and that score. I'm actually looking at table one now where you show a summary of the biomarkers strategies and then, in table two, you show a summary of the risk scores and then the performance measures of each of these scores. That must have taken quite a lot to put together.

Dr. Judd: I think that's why Deb was very smart and invited authors from around the world. We have Christian Muller from Switzerland and Martin Tann from New Zealand which, literally, means we're all on different time zones and we were able to work around the clock to do that. There as always somebody awake. Getting more series, the nice thing is that my colleagues on this paper are some of the leaders in doing this kind of research. In fact, they are the leaders in doing this kind of research.

What I think is very challenging for the average cardiologist or the average emergency physician is there have been so many different approaches and many of them actually work. The challenge for us was to try and make it relatively simple so you can choose the approach at your institution and put it into a structured pathway and pick the one that works best for you. You can get a ninety-nine percent negative predicted value using the right essays with samples that the time of presentation and one hour later, you can get a ninety-nine percent negative predictor value at zero and two hours. You can combine it with an accelerated diagnostic pathway and do that at zero and two hours and zero and three hours.

I think the important thing is you need to figure out what will your clinicians use? Certain clinicians may be very comfortable with one risk score and not another and then they need to combine the timing of testing with the risk score their comfortable with in order for us to achieve the great possibilities we have with these new tasks. I think when you try and do a one size fits all, there are going to be people who push back because they don't like one component of the risk score. Really what we're trying to do and we didn't say everybody should do A, B or C but we present the data on five or six different options and let people choose what is most feasible for them.

Carolyn: How wonderful. Deborah, what were you thinking when you were reviewing this paper and trying to structure it for the clinician out there who wants to use this information?

Dr. Deborah: I think that, overall, we were really impressed by the clarity and the ease that a reader can take this information home. There is so much information out there and there are so many different ways to apply it that we're really impressed how the authors put it in a really pretty clear manner so you can actually see the risk stratification tools that are out there, what they're used with and what type of troponins. Think about your own clinical practice and what you can adapt really based on the evidence that is out there.

Carolyn: I couldn't agree more. Judd, how about this issue of the coronary CT angiogram and where that falls?

Dr. Judd: That's really an interesting question because there's been a lot of publicity and a lot of editorializing in recent years that maybe you can make a decision with your two troponins and your biomarkers and decrease the number of people that need downstream testing. One of the dilemma with this, like I said before, is we know we're not really good at predicting who has acute coronary syndrome based on clinical things and for that reason the European Society guidelines as well as the American AHAACC guidelines have always said you need to do two things. You need to rule out acute myocardial infraction and you need to risk stratify patients for underlying coronary disease. When a patient comes into the emergency department, if I'm going to be guideline compliant with the recommendations in the world, I need to do both things.

The paper, we summarize really clearly ways you can get out of the woods with biomarket testing and clinical pathways but then you still want to risk strategy for coronary disease. There are sometimes where you might not need that downstream testing but what coronary CTA really lets us do is it makes us more efficient than a stress test. A stress test I like to say is a next day test; although there is data that you can do it when the patient's in the emergency department rapidly. It certainly is not the standard practice.

There are people afraid of putting people on the treadmill too soon in case they have unstable angina but a coronary CTA lets me look at the coronary arteries, immediately, when they're in the emergency department. There's very few areas in emergency medicine where there are three large randomized control trials that all give the same results. It doesn't say coronary CTA is better than a next day stress test but it does say you can avoid admission and, hence, save some dollars. It says you can send patients home sooner and, hence, save some angst that the patients may feel while they're in that diagnostic indecision area.

Carolyn: That's such a practical summary and, in fact, it really reflects the entire paper which is really so clearly presenting the information. Judd, one last thing, could I check is this correct, in my understanding, that the main difference between this and say the guidelines that you just measured is that what you do here is really give the readers all the information? As you say, allow the readers to choose what suits them best. This is not making recommendations, it's summarizing all the information. Is that right?

Dr. Judd: Yeah, that's exactly right. If you look, I think it's table number four, where we go through each one of the decision aids and how many or what percent of patients actually fit into that decision aid and what the negative predictive value is for that decision aid combined with troponin. Then what type of troponin was used to achieve those results, you'll see that about half the studies are done with, what we call, the contemporary troponin or just the regular sensitivity troponin that we use in the United States. The other half of the data we show is with high sensitivity troponins. It would not be a good idea for somebody creating their quality program in their emergency department to take something that was tested with a high sensitivity troponin and validate it there and then apply it in an emergency department in the United States where we don't have those [inaudible 00:17:18].

We thought it was critically important to lay out the data and as the high sensitivity troponins come on the market, hopefully in the next year in the US, people can begin with something now and switch to something else later if they want. If we made a recommendation that was firm, the world changes too fast. I don't think we would be doing the best for our patients.

Carolyn: That is such a great statement to end this on. Thank you so much Judd and Deborah. This was an excellent discussion.

Dr. Judd: Thank you.

Dr. Deborah: Thank you.

Carolyn: You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week for more exciting cardiology needs from all over the world.

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