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Circulation on the Run


Nov 20, 2017

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 journal features novel results from the NCDR IMPACT Registry that informs us on risk prediction in patients with congenital heart disease undergoing cardiac catheterization. We'll be taking a deep dive into this right after these summaries.

                                                The first original paper provides pre-clinical data showing that delayed repolarization may underlie ventricular arrhythmias in heart failure with preserved ejection fraction or HFpEF. First author Dr. Cho, co-corresponding authors Dr. Marban, and Cingolani from Cedars-Sinai Heart Institute and their colleagues, induced HFpEF in Dahl salt-sensitive rats by feeding them a high-salt diet from seven weeks of age. They showed that susceptibility to ventricular arrhythmias was markedly increased in rats with HFpEF.

                                                Underlying abnormalities included QTc prolongation, delayed repolarization from down-regulation of potassium currents, and multiple re-entry circuits during ventricular arrhythmias. These findings are consistent with the hypothesis that potassium current down-regulation may lead to abnormal repolarization in HFpEF, which in turn predisposes to ventricular arrhythmias and sudden cardiac death.

                                                The next paper shows that genetic testing can help to identify patients with pulmonary veno-occlusive disease who were misclassified as pulmonary arterial hypertension. Now, heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II or BMPR2 are the commonest genetic cause of pulmonary arterial hypertension. Whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene or EIF2AK4 gene are described in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

                                                In the current study, first author Dr. Hadinnapola, corresponding author Dr. Morrell, and colleagues from University of Cambridge performed whole genome sequencing on the DNA from 864 patients with pulmonary arterial hypertension, as well as 16 patients with pulmonary veno-occlusive disease all recruited to the NIHR BioResource – Rare Diseases study. They found that 1% of patients with a clinical diagnosis of pulmonary arterial hypertension actually carry the biallelic EIF2AK4 mutations. Patients who are diagnosed clinically with pulmonary arterial hypertension, but who had a transfer coefficient for carbon monoxide of less than 50% predicted and an age of diagnosis of less than 50 years were much more likely to carry these biallelic EIF2AK4 mutation. In fact, the diagnostic yield for genetic testing in this group was 53%.

                                                Radiological assessment alone was unable to distinguish reliably between these patients and those with idiopathic pulmonary arterial hypertension. Importantly, these patients with biallelic EIF2AK4 mutations had a worst prognosis compared to other patients with pulmonary arterial hypertension. Thus in summary, younger patients diagnosed with idiopathic pulmonary arterial hypertension but with a low transfer coefficient for carbon monoxide, have a high frequency of biallelic EIF2AK4 mutations and should be reclassified as pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. They have a poor prognosis and genetic testing can therefore identify these misclassified patients allowing appropriate management and early referral for lung transplantation.

                                                The next study identifies a novel molecular target for the treatment of pathological cardiac hypertrophy. This target is SIRT2 [inaudible 00:04:33] poorly characterized member of the Sirtuin family of proteins, which is a family of class III NAD-dependent deacetylases that regulate metabolism and age-related diseases including diabetes and cardiovascular diseases. In the current study, first authors Dr. Tang and Chen, corresponding authors Dr. Chen and Liu from the Chinese Academy of Medical Sciences in Peking Union Medical College used wild-type and Sirt2 knockout mice, and showed that SIRT2 protein levels and activity were reduced during pathological cardiac hypertrophy.

                                                SIRT2 deficiency promoted aging and angiotensin II induced pathological cardiac hypertrophy, and blunted metformin-mediated cardioprotective effects. On the other hand, SIRT2 overexpression repressed pathological cardiac hypertrophy. The molecular pathway involved deacetylation of liver kinase B1 at lysine 48 by SIRT2 to activate AMP-activated protein kinase sickling, which prevented hypertrophy of cardiomyocytes. Thus, SIRT2 is a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.

                                                The next study is the largest comparison of the prognostic value of coronary artery calcium with functional stress testing in patients with stable chest pain. In this study from first and corresponding author Dr. Budoff from Los Angeles Biomedical Research Institute and colleagues, authors looked at the PROMISE trial where patients with stable chest pain or dyspnea, and intermediate pre-test probability for obstructive coronary artery disease were randomized to functional testing or anatomic testing.

                                                Their main finding was that these chest pain populations referred for testing had a low event rate and both tests had different strengths. Coronary artery calcium had a high sensitivity for future cardiovascular events whereas functional testing had a high specificity. The clinical implications are that a normal coronary artery calcium score has a very low event rate and perhaps maybe used to avoid further cardiac testing in a stable chest pain population. On the other hand, an abnormal functional test result including information on exercise and symptoms has a moderate prognostic value.

                                                Of note, coronary CT angiography provided better prognostic and discriminatory power than either coronary artery calcium or functional testing. The implications of these important results are discussed in an accompanying editorial by Dr. David Newby from Edinburgh entitled, Can I Have My Cake and Eat It? On that intriguing note, we've come to the end of today's summaries, now for our feature discussion.

                                                For today's feature discussion, we are talking about an increasingly important population that is pediatric and adult patients with congenital heart disease undergoing cardiac catheterization. A little bit out of my usual comfort zone, but then you see, I'm with two spectacular experts today, Dr. Gerard Martin from Children's National Health System in Washington DC, one of the authors of today's feature paper; and Dr. Gerald Greil, Associate Editor from UT Southwestern. Welcome gentlemen.

Dr. Gerard Martin:           Thank you Carolyn.

Dr. Gerald Greil:                Thank you Carol.

Dr. Carolyn Lam:               Gerard, no that would be Dr. Martin. Enlighten people like me who don't think about this every day, why the importance of looking at cardiac catheterization, and adverse outcomes in this particular population?

Dr. Gerard Martin:           Carolyn, that's because of the tremendous advances in medicine, and particularly medicine that's dealing with children with congenital heart defects. Cardiac catheterization was once purely a diagnostic study. Now, it's a less invasive definitive treatment option for many of our pediatric and adult patients with congenital heart defects. As you may or may not know, congenital heart defects are the most common birth defects that impact nearly one out of every hundred live births.

                                                As I mentioned, we have these tremendous advances. As a result of that, there are now over a million children living with congenital heart defects. In the USA alone, improvements in care over the past 50 years, there are now more adults than children living with congenital heart defects.

Dr. Carolyn Lam:               Wow. Now, I understand. I mean, cardiac catheterization not just meeting diagnostic but therapeutic, and such an important patient population. Tell us about your study?

Dr. Gerard Martin:           As we said, cardiac catheterization is now replacing surgery for some of our defects. For some of the more complex defects, catheterization is providing treatments that make the surgery easier. Now in surgery, we've had registries for many years. These registries provided measurement of survival that allow comparison of programs, and we didn't have that ability with cardiac catheterization. The American College of Cardiology developed the IMPACT Registry. That was to solely provide measurements of the outcomes of catheterization procedures in the children and adults with congenital heart disease.

                                                Now, one aspect of the quality of the program is your rate of adverse outcomes; but simply measuring the number of adverse outcomes does not provide enough discrimination to compare programs. I think you can probably imagine that adverse outcomes will increase based upon the complexity of the type of patients you see, or the types of procedures that you might be performing. What we wanted to do was to create a risk standardization tool for our population where we can measure variation and performance between programs. If we can do that, then we can learn from the best performers to improve all the others.

Dr. Carolyn Lam:               That's beautifully put. Could you tell us what you found?

Dr. Gerard Martin:           Sure. The IMPACT Registry began on about 2011 and has grown from 50 sites to 111 sites in 2017. That's the majority of the sites in the United States that perform cardiac catheterization on children. We have now over 115,000 procedures. What we wanted to do with this is to look at some of the early procedures that were included and to see how adverse events were occurring. When we created the registry though, we used data variables from a previous research study in Boston called the CHARM.

                                                They created a tool to risk standardized outcomes during procedures. They did it by coming up with four categories of procedures, and some four markers of hemodynamic vulnerability. We tested their methodology with IMPACT, and it didn't really performed particularly well. In this study, what we did was to increase the number of risk categories. We took the nearly 200 types of procedures we do in the cath lab and divided them into six categories. We also increased the indicators of hemodynamic vulnerability from four to six.

                                                Now, what I mean by hemodynamic vulnerability? What is the patient's oxygen level when they go into the procedure? What is their blood pressure when they're in the procedure? Do they have one ventricle, or do they have two ventricles? What is the resistance in the lung vessels? All these are critically important. Lastly, we looked at some baseline patient characteristics. In other words, was age important? Sex, genetic conditions, or other comorbid conditions like the level of mechanical support that the patients were on. Then we put all that into our model to see if we could come up with a risk score.

Dr. Carolyn Lam:               Right. The final adjustment model? Which factors that they include in the end?

Dr. Gerard Martin:           We did find that there are lot of adverse events that do occur. We found major adverse events occurring in about same 7% of our patients. Most common adverse events were bleeding, or rhythm disturbances that require some medicine, or cardioversion during the procedure, or death during the hospitalizations. We did find that these major events were more common in the youngest patients or neonates, children under a month of age, or in patients with genetic disorders, or single ventricle physiology, and also patients that went to the cath lab with their kidneys not working very well.

                                                In the end, we did create a risk adjustment model that included the type of procedure that was done, the number of hemodynamic vulnerability indicators, and whether or not the patient had renal insufficiency, or single ventricle physiology, or coagulation, and we found really good discrimination. Our discrimination had a C-stat of 0.76 in the derivation cohort, and 0.75 in the validation cohort. The slope of the curve was excellent, so we really think we have something now that we can use as a tool.

Dr. Carolyn Lam:               Gerald, you're a pediatric cardiologist. Could you give us your perspective on how important these results are?

Dr. Gerald Greil:                I think it's the largest and the first study, which kinds of give us a calibration in our field how successful interventions are. How we can make centers better without finger pointing on specific centers, and how to advance the field as a whole? From that perspective, I'm quite excited that the group offered us to publish this paper in circulation. I was kind of asking a question to Dr. Martin because obviously, all essentials are closely monitored. There's obviously data publicly available. Do you think there's a risk that this way to monitor centers within the United States or probably worldwide, that it's potentially preventing innovation or risky procedures?

Dr. Gerard Martin:           I think that, that's a good question. I think it's one thing that whenever we talk about transparency or public reporting, it's an argument against it. I think that having a model like this, actually levels the playing field. In other words, centers that are risk averse who aren't particularly innovative, you'll be able to look at those centers, see what type of patients they're doing and look at their adverse events for a low-risk population. Then, you can also look and see some other centers that are doing more complicated procedures, higher risk, and you can see what their adverse event rate is.

                                                Certainly, this is only talking about the adverse events. This has to be put together with the outcome of the procedure. In other words, if you're trying to relieve an obstruction, did you relieve it? Did you meet the intended goal of the procedure? This is only half of the story. The other part of it is, did you get the intended goal of the procedure? When you put the two of them together, perhaps some of those centers that are risk averse have lower complications, but maybe their success rate is lower. This will be able to tell the public everything they know, and they'll be able to tell their providers what they need to know to get better.

Dr. Carolyn Lam:               I have to agree. Your paper does highlight, I think. Gerard, just one other question. What do you think our next steps?

Dr. Gerard Martin:           The next step is to test the data. We have a new version of IMPACT that has rolled out, version 2 that has new procedures in it. Now, we have to test the data and we actually have to look for variability. Can we see a variation between the programs? Then, once we see if there's variation, if we see there is best performers and those performers that could improve, a question then is how do we take from what the best performers are doing to try and lift those that need to improve up. That's going to be the true hard work for this registry.

Dr. Carolyn Lam:               Thank you so much for publishing it with us. Thank you so much audience for listening with us today. Don't forget to tune in again next week.