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Circulation on the Run

Jul 15, 2019

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-hosts, 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: Hundley, Associate Editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Well Carolyn, our featured article this week addresses the age at which to initiate clinical screening of relatives for hypertrophic cardiomyopathy. Our guidelines suggest screening of relatives from age ten and onwards but data are lacking to substantiate this suggestion. I look forward to the authors' discussion of their findings regarding initiation of screening in children. For now though, do you have an article that you'd like to share?

Dr Carolyn Lam:                You bet, Greg. So, the first paper I chose really demonstrates that patients inducible pluripotent stem cells or IPSC cardio derived myocytes can be used as a disease modeling platform to delineate the functional mechanisms that underlie cardiac hypertrophy and in this particular case they looked at Noonan Syndrome and showed that how these techniques can be subsequently used to identify novel molecular and genetic therapeutic targets. So, Greg, here's your quiz. The genetics of Noonan Syndrome.

Dr Greg Hundley:             I remember it was on our board exam.

Dr Carolyn Lam:                Let me tell you about it. So more than 90% of patients with Noonan Syndrome have a mutation in the hinge region CR2 domain of Raf-1 and they exhibit severe hypertrophic cardiomyopathy for which there is no treatment. Authors, Dr Jaffrey from Cornell University and Dr Kontaridis from Masonic Medical Research Institute in Utica in New York and their colleagues used Noonan Syndrome Raf-1 patient and CRISPR corrected IPSC cardiomyocytes to recapitulate the Noonan Syndrome cardiac phenotype.

                                                These Noonan Syndrome IPSC derived cardiomyocytes exhibited the same hypertrophy and myofibrillar disarray that's really observed in Noonan Syndrome patient hearts, so mechanistically the authors showed that activation of mitogen-activated protein kinase or mech-1 or -2, but not the extracellular regulated kinase, which is ERK1 or 2 triggered abnormal cardiomyocytes structure and conversely ERK5 mediated increased cell size in these Noonan Syndrome mutant IPSC derived cardiomyocytes.

                                                RNA sequencing further identified genes dysregulated in the Noonan Syndrome cardiomyocytes that may underlie hypertrophic cardiomyopathy downstream if the mech-1 or -2 and ERK5 genes.

Dr Greg Hundley:             So, Carolyn, that's a lot of genetic information, so what can I take home as I think about this further and what may come down the line as we manage patients with Noonan Syndrome?

Dr Carolyn Lam:                Thanks, Greg. The real take home message is that these pathways could serve as novel therapeutic targets to treat hypertrophic cardiomyopathy in patients with Noonan Syndrome and Raf-1 mutations. Overall, the elucidation of rare disease mechanism of hypertrophic cardiomyopathy may further unravel and reveal causes of other more common idiopathic congenital disorders and hypertrophic diseases.

Dr Greg Hundley:             Oh, very good. Well, I'm going to switch gears and talk a little bit about infective endocarditis prophylaxis and this article comes from Pallavi Garg at the London Health Scientist Center. Carolyn, as you may recall, given the lack of proven efficacy and concerns about the perceived risks of antibiotic prophylaxis like development of antibiotic resistance, the American Heart Association in 2007 and the European Society of Cardiology in 2009 published revised guidelines recommending cessation of antibiotic prophylaxis prior to dental procedures for patients at moderate risk of infective endocarditis while continuing the practice in high risk patients. This Canadian study was conducted from 2002 to 2014 among all adults and those at high and moderate risk for infective endocarditis and they were stratified by age. Prescriptions for antibiotic prophylaxis were obtained from the Ontario Drug Benefit Database for adults 65 and older and outcomes regarding antibiotic prophylaxis prescription rates and the incidents of infective endocarditis related hospitalization were assessed.

Dr Carolyn Lam:                 Ooh, interesting. What did they find?

Dr Greg Hundley:             The authors found a sustained reduction in antibiotic prophylaxis prescriptions among individuals at moderate risk for infective endocarditis that coincided with the change in guidelines. In contrast, while there was a decreasing trend in antibiotic prophylaxis among individuals at high risk of infective endocarditis and a minimal drop following the guidelines released, the overall rates of prophylaxis prescribing in this group continued to climb since early 2007, and collectively, these findings suggest that appropriate uptake of the revised AHA guidelines occurred.

                                                Furthermore, over the thirteen-year study period, the authors identified an increase in hospitalizations for new episodes of endocarditis approximately three years after the AHA guidelines were revised. This timeline along with the rise of endocarditis incidents in both the high and moderate risk groups suggests that this observed increase in endocarditis is likely unrelated to the change in the prescribing practice of antibiotic prophylaxis. This conclusion is further supported by the overall decrease in endocarditis cases attributable to streptococcal infections over time, a finding contrary to what might be expected as a result of the reduction in antibiotic prophylaxis.

Dr Carolyn Lam:                Oh, very interesting, Greg. At first a little bit scary and then after when you described it more, it does seem a little bit more reassuring. Very interesting. Well, thank you. My next paper deals with functional tricuspid regurgitation, which as you know is really common in heart failure with reduced ejection fraction or HFrEF and mostly consequent to pulmonary hypertension. However, what is the access mortality associate with functional tricuspid regurgitation in HFrEF? Well, this paper from Dr Maurice Serrano from Mayo Clinic and colleagues looked at all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B and C and an ejection fraction less than 50% who had functional tricuspid regurgitation grading and systolic pulmonary artery pressure measured by Doppler echocardiography.

                                                Now among more than 13,000 patients meeting these inclusion criteria, functional tricuspid regurgitation was detected in 88%. Functional tricuspid regurgitation was independently associated with more dyspnea, more impaired kidney function, and lower cardiac output. For the long term outcomes, the higher the degree of functional tricuspid regurgitation compared with a group with trivial tricuspid regurgitation was independently associated with a higher mortality hazard. The five year survival was substantially lower with increasing severity of tricuspid regurgitation so it was 68% on average for trivial functional tricuspid regurgitation versus 34% for severe functional tricuspid regurgitation.

                                                Importantly, this access mortality observed with moderate or severe functional tricuspid regurgitation was independent of pulmonary hypertension and any other clinical characteristics.

Dr Greg Hundley:             Hmm, interesting but Carolyn, wouldn't we expect this?

Dr Carolyn Lam:                You know what, you may expect it, but this is really the largest series, I think, that has shown this and shown this in the systematic way that functional tricuspid regurgitation in and of itself may play an important pathophysiologic role and thus, may represent a potential therapeutic target in HFrEF. In other words, the present study really advocates for a trial to test treating functional tricuspid regurgitation in patients with HFrEF.

Dr Greg Hundley:             Oh wow, you really put that in great perspective, Carolyn. Well, your reward is   going to be a quiz.

Dr Carolyn Lam:                 Oh my gosh, Greg.

Dr Greg Hundley:             We're going to talk about ...

Dr Carolyn Lam:                 What now?

Dr Greg Hundley:             Caveolin-1, an atherogenesis and nitric oxide and this is from Professor Carlos Fernandez Hernando at the Yale University School of Medicine. Okay, multiple choice. What are caveolae? Now I'm going to give you some choices, you get to pick A. Are they crypts within the walls of vessels. B. Crypts within the membranes of endothelial cells. Or C. Crypts within the border zones of infarcts.

Dr Carolyn Lam:                Wait a minute, Greg. I'm not even sure we're pronouncing it the same. You're asking about caveolae like ... Potato potata. They're invaginations of cell membranes, that's all I know.

Dr Greg Hundley:             Oh wow, fantastic. This study focused on the effect of Caveolin-1, a protein integral to the formation of caveolae. The investigators found in a series of mouse experiments that A. The athero-protection observed in mice lacking Caveolin-1 is independent of endothelial nitric oxide synthase activation and nitric oxide production. B. Endothelial Caveolin-1 controls lipoprotein infiltration in vascular inflammation in early stage atherosclerotic lesion. C. Endothelial Caveolin-1 promotes pro-atherogenic matrix deposition leading to endothelial cell activation in atheroprone regions of the aorta and finally, D. Atheroprone regions of the aorta are characterized by increased intracellular and basolateral caveolae distribution in endothelial cells compared to athero-resistant areas.

Dr Carolyn Lam:                Wow, I like the way you broke that down into four points, but could you summarize what it means clinically?

Dr Greg Hundley:             Yeah, so I think if you had to summarize all of this in a sentence, perhaps the suppression of Caveolin-1 expression in endothelial cells might prevent the progression and promote the regression of atherosclerosis so in the future perhaps an interesting target to treat atherosclerosis. Well, now Carolyn, I guess we should proceed to that talk with our featured discussion.

Dr Carolyn Lam:                 Absolutely. Thanks, Greg.

                                                Hypertrophic cardiomyopathy is an inheritable myocardial disease with age-related penetrance. Current guidelines recommend that clinical screening of relatives start from the age of ten years onwards by the European Society of Cardiology and twelve years onwards by the American College of Cardiology or American Heart Association. There are of course caveats for earlier screening but the clinical value of this approach has really not been systematically evaluated. That is until today's feature paper and we are so pleased to be here discussing it. This is Greg Hundley and Carolyn Lam and we're your co-hosts for Circulation on the Run. So happy to welcome Dr Juan Pablo Kaski who's the corresponding author of today's feature paper from Great Ormand Street Hospital in London and we also have Dr Gerald Greil, Associate Editor from UT Southwestern.

                                                Welcome, everyone. Juan, if you don't mind, could you start by summarizing this very important study of yours?

Dr Juan Pablo Kaski:        Thank you very much. Hypertrophic cardiomyopathy is a genetic muscle condition that is characterized by hypertrophy and is most commonly inherited as a dominant trait. Previous studies have suggested that in familial disease at least ventricular hypertrophy doesn't usually present until adolescence and this has led to the current guidelines which do not recommend routine screening of children below the age of twelve according to the American guidelines below the age of ten and the European guidelines for hypertrophy cardiomyopathy but own clinical experience was different and suggested that perhaps sarcomeric disease and familial disease could present in younger children, so what we aimed to do with this study was to assess the validity of this approach and tried to assess the yield of clinical screening in children from families of hypertrophic cardiomyopathy.

Dr Juan Pablo Kaski:        We took our collective experience in our institution over a period of many years and recruited just on the 1,200 consecutive children all aged less than eighteen years at the time of initial assessment coming from just under 600 families and these were children who were referred for clinical screenings because a first degree relative had been diagnosed with hypertrophic cardiomyopathy. What we found was that in 5% of these children and in fact, in 8% of the families that we screened, we were able to pick up early phenotypic features of hypertrophic cardiomyopathy. In 72% of patients, we made a diagnosis before the age of twelve, so before current clinical screening guidelines we'd recommend and importantly, a third of these patients during follow up had a change in their management as a result of the diagnosis. Their medication was commenced, they underwent procedures or implantations of defibrillators.

Dr Greg Hundley:             Juan, this is Greg Hundley and I was wondering when did the participants that were enrolled experience events? Did those that were say under fourteen or even under twelve, did they experience events relative to those that were a little older?

Dr Juan Pablo Kaski:        The events that our participants experienced were relatively few. Many of these occurred during the childhood age but some occurred once the children had transitioned into the adult age. We did look to see whether there was any difference in terms of early diagnosis and subsequent events, but we didn't find anything, we didn't identify two separate populations in that respect.

Dr Greg Hundley:             And then did you perform genetic analyses? I know you described phenotypic characterization of the patient population but how about genetically? What results did you find there?

Dr Juan Pablo Kaski:        The main aim of the study really was to determine a yield of clinical screenings, so this is a reflection of a real-world practice where genetic testing may not necessarily be routinely available. Having said that, we did have genetic data in a third of our families and in fact, in maybe 70% of those children who made clinical diagnosis of hypertrophic cardiomyopathy was made and what we find in those individuals who have undergone genetic testing is that the vast majority of those had mutations in sarcomeric protein genes and pathogenic or likely pathogenic variants in sarcomeric genes in just under 70% and these were well characterized mutations that are very similar to those that are seen in adolescence or adult onset hypertrophic cardiomyopathy.

                                                I think what was interesting about these genetic results is that we seem to have identified a population of early onset sarcomeric disease that genetically appears to be indistinguishable from a sort of later onset adult disease but with the clinical presentation and natural history curve shifted somewhat to the left.

Dr Greg Hundley:             Gerald, just switching over, can you tell us some of your thoughts about how the results of this study will impact clinical practice, both in the European countries as well as U.S.?

Dr Gerald Greil:                 I mean, I was obviously delighted to see the study being submitted to circulation because there's a very important message particularly for pediatric cardiologists which is potentially influencing the guidelines and Dr Kaski may comment on this as well as the next step meaning that it seems like screening patients older than ten or twelve years and once again, there's a slight discrepancy between the European and U.S. guidelines, seems to be ... Can be questioned and potentially we should screen these patients earlier.

                                                Another amplification of this study is that we should think about how much genetic screening can be an essential tool in our methods in looking at these patients and I want to point out that because of these discrepancies we also initiated an editorial letter for this publication done by Dr Ommen and by Dr Mital kind of pointing out there needs a lot of work to be done maybe even including rewriting the current guidelines.

                                                There's another paper that came out recently in European Society Cardiology, the European Heart Journal about a similar topic so it's something which is very, very heavily discussed in our community. We think how we are looking at these patients and how we're following them up.

Dr Greg Hundley:             What would you suggest are next steps for the world community in this space in regards to modifying those guidelines?

Dr Gerald Greil:                 I think there's now enough literature around which suggests that we should look at these patients earlier and screen them earlier on both sides in European, in the U.S., in the Asian world, and ideally these two groups should sit together and write combined guidelines. It's still interesting that the European and U.S. guidelines are slightly different in that we're talking about a similar group of patients, so I'm very, very delighted to see that this is coming up in the national literature as a new topic and I think everything is open now to rethink this topic and rewrite these guidelines.

Dr Greg Hundley:             Do you think prospective studies would be necessary because I believe, and Dr Kaski please weigh in here, this was a retrospective review, and do you think there could have been triggering circumstances that prompted early screening? I mean, would a next step be some sort of prospective registry?

Dr Gerald Greil:                 I mean definitely that's the next step. I think we have enough data material around once again to rethink the strategy which age these patients should be looked at. A prospective registry and Dr Kaski can probably comment on it better than I can, I think that something which is a logical next step and there may be even something being on the way to make this happen.

Dr Juan Pablo Kaski:        I agree. I think further validation and confirmation of these data from prospective studies would be extremely helpful. I think one of the things that we need to bear in mind is the potential cost implications of expending screening to ever increasing populations and so perhaps an additional further step would be to try to refine the screening tools so that we are able to identify clinical by a chemical of those individuals who are more likely to present in childhood and perhaps set a target screening towards that population.

                                                I can just go back to one of your sort of previous points also about a potential bias and it is true that these patients were referred for clinical screening at a time when clinical recommendations do not suggest that this is necessary and although we didn't specifically in this cohort look at those that would have fulfilled current early screening criteria, the vast majority of the patients were asymptomatic at the time that they were referred. We also looked to see whether there was any link between those individuals who had a family history of early onset disease and an early diagnosis, and that was the only factor that came up as potentially significant so perhaps the current guidelines that do recommend considering earlier screenings if there's a family history of childhood disease are still applicable.

Dr Carolyn Lam:                That was just an amazing interview, by the way. I've learned so much and thank you so much for publishing this very important paper with us.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

This program is Copyright American Heart Association 2019.