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Circulation on the Run

Jun 10, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summery and backstage pass to the journal and it's editors. We're your co-hosts, I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Gregory Hundley:       And I'm Doctor Greg Hundley, Associate editor for Circulation and Director of the Pauley Heart Center at VCU of Health in Richmond, Virginia. Well Carolyn, in the second half of our feature we're going to discuss a randomized clinical trial in lower risked surgical patients related to, the five year clinical echocardiographic outcomes from aortic valve intervention. So Carolyn, do you want to go first this time and discuss on of your favorite papers?

Dr Carolyn Lam:                Absolutely! So, are Cardiac Troponin T and I equivalent measures of cardiovascular risk in the general population? Well that's the question Doctor Paul Welsh and colleagues from University of Glasgow aimed to look at. They wanted to compare and contrast the associations of Cardiac Troponin T and Cardiac Troponin I with cardiovascular disease and non-cardiovascular disease outcomes, and also determine their genetic determinants in a genome wide association study involving more than nineteen-thousand, five hundred individuals in generation Scotland, Scottish family health study.

Dr Gregory Hundley:       How about that. So this is kind of interesting. So most of us kind of use these two chests interchangeably Carolyn, and I think, I guess we'd consider them to be almost equivalent. So are you going to tell us that they are the same?

Dr Carolyn Lam:                Ah-hah! So this is what the authors found. Both Cardiac Troponins T and I were strongly associated with cardiovascular risk, however, Cardiac Troponin I but not T was associated with both myocardial infarction and coronary heart disease. Both Cardiac Troponins I and T had strong associations with cardiovascular death and heart failure, however, Cardiac Troponin T, but not I was associated with non-cardiovascular disease death. They also identified five genetic loci in fifty-three individuals snips that had GWAS significant associations with Cardiac Troponin I and a different set of four loci of four snips for Cardiac Troponin T.

                                                So, the upstream genetic causes of low-grade elevations of Cardiac Troponins I and Cardiac Troponin T appear to be distinct and their associations with outcomes also differ. Elevations of Cardiac Troponin I are more strongly associated with some cardiovascular disease outcomes whereas Cardiac Troponin T, is more strongly associated with the risk of non-cardiovascular disease death. These findings can help inform selection of an optimal Troponin essay for future clinical care and research in these settings.

Dr Gregory Hundley:       Very good! So, does sound like there could be a little bit of a difference, depending upon what outcome you're looking for. So, Carolyn I'm going to discuss a paper from Doctor Alison Wright and colleagues at the University of Manchester, and it involves cardiovascular risk and risk factor management in type two diabetes.

                                                So in this retrospective cohort study, using the clinical practice research data link, linked to hospital and death records for people in England, investigators identified 79,985 patients with incident type two diabetes, between the years 2006 and 2013, matched to three 386,547 patients without diabetes, and sex-stratified Cox models were used to assess cardiovascular risk.

Dr Carolyn Lam:                Oh I'm dying to know, what did they find?

Dr Gregory Hundley:       Well compared to women without type two diabetes mellitus, women with type two diabetes mellitus had a higher cardiovascular event risk than the adjusted hazard ratios 1.2, with similar corresponding data in men, so their hazard ratio is 1.1. And that lead to a nonsignificant relative risk in women with a risk ration of 1.07, however, some important sex differences in the management of risk factors were observed. Compared to men with type two diabetes, women with type two diabetes were more likely to be obese, hypertensive, and have hypercholesterolemia but were less likely to be described lipid lowering medication, ace inhibitors, especially if they had cardiovascular disease. So Carolyn, compared to men developing type two diabetes mellitus, women with type two diabetes mellitus do not have a significantly higher relative increase in cardiovascular risk, but, ongoing sex disparities in prescribing should prompt heightened efforts to improve the standard and equity of diabetes care in women as compared to men.

Dr Carolyn Lam:                Nice Greg. Important message. My next one has an important message too. Now it goes to the pediatric population now. We know that brain injury, impaired brain growth, and long term neuro development problems are common in children with transposition of the great arteries. Now does the age at arterial switch operation predict these neuro developmental outcomes in infants with transposition of the great arteries or TGA?

                                                Well Doctor Mike Seed from Hospital for Sick Children in Toronto, Canada and colleges addressed this question by imaging the brains of 45 infants with TGA, undergoing surgical repair, pre and post operatively using MRI. Their main finding was that surgery beyond two weeks of age is associated with impaired brain growth and slower language development in infants with TGA.

Dr Gregory Hundley:       Wow Carolyn, this seems like, this could have really important clinical implications for the management of these patients.

Dr Carolyn Lam:                Yeah, indeed. Expediting surgical repair could be neuro protective in newborns with Transposition. While the mechanisms underline this association are still unclear, extended periods of cyanosis and pulmonary over circulation maybe factors that inversely impact brain growth and subsequent neurodevelopment if the surgery's not done early. The timing of surgery may have an impact on neurodevelopment in other forms of congenital heart disease, too, therefore. So all of this is discussed in an editorial entitled Correction of TGA, "Sooner Rather than Later?", and this is by Doctors Rollins and Newburger, from Boston's Children's Hospital.

Dr Gregory Hundley:       Fantastic Carolyn, well I'm going to discuss a paper from the World of Basic Science from the Ohio State University, Wexner Medical Center from Doctor Douglas Lewandowski. And it involves the preservation of Acyl-CoA and how that attenuates pathological and metabolic cardiac remodeling through selective lipid trafficking. So Carolyn, it has been shown that metabolic remodeling in heart failure contributes to dysfunctional lipid trafficking, and lipotoxicity. Acyl-Coenzyme A Synthase One, or ACLACSL1 facilitates long chain fatty acid uptake an activation with coenzyme A, mediating the fate of the long chain fatty acids. The authors tested wither cardiac Acyl coenzymes A synthase One over-expression aided long chain fatty acid oxidation and reduced lipotoxicity under the pathologic stress of transverse aortic constriction or TAC.

Dr Carolyn Lam:                Interesting, I like that concept of metabolic remodeling. So what did they find?

Dr Gregory Hundley:       So Carolyn, the studies were performed in both mice and in human subjects, and in mice at 14 weeks, TAC induced cardiac hypertrophy and disfunction was mitigated in MHCACSL1 hearts compared to nontransgenic hearts. This was manifest by retain greater rejection fraction, 65.8 percent versus the nontransgenic hearts of 45.9 percent. An improvement in diastolic E over E prime. Also, functional improvements were mediated by ACSL1 changes to cardiac long chain fatty acid trafficking. In humans, long chain Acyl-CoA was reduced in human failing myocardium and restored to control levels by mechanical unloading.

                                                So, Carolyn, this is the first demonstration on reduced Acyl-Co-A in failing hearts of humans and mice, and suggest possible mechanisms for maintaining mitochondrial oxidative energy metabolism by restoring long chain Acyl-CoA through ASCL1 activation and mechanical unloading.

Dr Carolyn Lam:                Awesome Greg! Thanks so much for sharing that paper. Let's go on to our feature discussion.

Dr Gregory Hundley:       You bet.

Dr Carolyn Lam:                Our feature discussion today is about transcatheter aortic-valve replacement. Could this be the new gold standard for the treatment of aortic stenosis? And yes, I am borrowing from the title of the editorial that accompanies our feature paper. With the editorialists right here with us, Dr Bernard Prendergast, from Saint Thomas' Hospital in London, and we are talking about the wonderful paper for the notion trial and that's a Nordic aortic valve intervention randomized clinical trial, and we're here with the first and corresponding author of that paper Dr Hans Gustav Thyregod from Copenhagen University Hospital, and we also have our associate editor Dr Dharam Kumbhani from UT Southwestern. So welcome gentlemen! And for a start could I ask Hans to please describe the results of the notion trial.

Dr Hans Thyregod:           The notion trial as you said is the Nordic aortic valve intervention trial. Designed to compare transcatheter therapy and surgical therapy and patients with severe aortic valve stenosis, patients have to be thirteen years old or older and we didn't really specify any risk profile, as in previous trials. So all patients eligible for both procedures would be enrolled in the trial. And the main result of the trial was that we couldn't find a difference when looking at the composite outcome, which was all-cause mortality, stroke American infraction.

                                                The primary outcome was after one year, in this paper it's up to five years and we could not see any difference. So the range was, in my estimate was 38 percent for transcatheter therapy versus 36.3 percent for surgery. And when looking at the different components of this composite outcome, all-cause mortality, stroke American infraction. We couldn't find any surgically significant difference for any of those outcomes either.

Dr Carolyn Lam:                Wow, Bernard, could I ask you to place these results into context for us, I mean the notion trial is after all the first to compare TAVR and SAVR in patients with severe isolated valve stenosis at lower surgical risk, and really has the longest follow-up doesn't it? So please tell us, what are your thoughts?

Dr Bernard Prendergast:               So this is yet another notch the remarkable success story of TAVI or TAVR, as you call it in the U.S. We pass our congratulations from the community to Dr Thyregod and the team in Copenhagen for such a ground-breaking study. The wider context is he say is the TAVR have demonstrated remarkable efficacy and safety, initially in operable and high-risk patients, but, more recently randomized control trials in intermediates and lower risk patients. And the important perspective of this study provides is the longer term follow up, because for a number of years we've perhaps considered TAVI or TAVR as a, let’s say a shorter-term treatment for patients in their eighty's and older, who perhaps have a shorter life expectancy. But what the five-year data demonstrates to us is that TAVI or TAVR is as good as surgery, at five years of follow up. With very reassuring outcomes, they maintain durability of the transcatheter heart valve, that's highlighted in the companion paper, which, is published very recently in JACC.

                                                                So really takes TAVI into a new territory, which is patients who have at least five years or longer to live and allows us to extend the indication for the procedure into younger patients. Alongside lower risk patients, who have supported by the recent landmark studies published in the New England Journal from Partner Three, and the Core Valve Low Risk trial. So, the information is very reassuring and it's another very positive notch in the journey of TAVI across the spectrum of surgical risk.

Dr Carolyn Lam:                Thank you! Beautifully put and Dharam could I just ask you I mean what more do we need? Do you think this is guideline defining stuff now? Or do you have questions?

Dr Dharam Kumbhani:   I really want to congratulate the investigators of the NOTION trial, as far as providing us with this longer term follow up in a lower risk population, and so, you know the field is moving incredibly, incredibly quickly and you know as we just mentioned TAVR has now gone from being something that's done in patients that are too high risk to level convention surgery, to now perhaps becoming either one of the main stream options, or the main stream option. And you know time will tell, so I think what this study really helps us is, provide us with a five-year time horizon on follow up, but, to be fair, you know this trial is very helpful in certain ways because it was designed a few years ago. You know it was done with the generation of a valve that is not used much right now for the most part, and you know so it's some of the things like pacemaker et cetera, may not translate to current practice.

                                                Even though the clinical outcomes were similar, it's probably some issues with power as well, but, again not in a clinical way, but, just to kind of say that this trial definitely helps us in moving the field forward and it kind of adds to the growing body of literature that supports that. Going forward I guess one question I would have for this group is, you know as we think about TAVR and surgical aortic replacement, it would seem that we would need even longer term data, based off of detonators to be able to confidently tell patients, there are fairly similar therapies.

                                                And then the other question is, this construct of surgical risk is that we applied telegraphically based on how the evolution of TAVR has occurred, but one wonder, you know with NOTION and other trials we should be thinking about this perhaps from an age perspective as a sort of NOTION trial—those would be my two comments.

Dr Bernard Prendergast:               I think that's a very valuable comment, and of course there are other ongoing trials, which, will help to address many of these questions. One important deficit of notion is that it didn't enroll, for example, patients with bicuspid aortic valves. And we know that bicuspid aortic stenosis is far more common in younger patients. So, Hans a few comments regarding the protocol for notion two maybe helpful for our listeners.

Dr Hans Thyregod:           Well this was mentioned, the follow up of five years is obviously not a very long time in younger patients with a lower risk profile. We are planning to follow these patients for at least 10 years. And the other comment about the risk profile of the risk certification of patients is also very interesting because the SDS and your scores have been developed for surgical patients and not for transcatheter patients. So we need a whole new transcatheter risk scoring system to help our team determining what treatment would be the best suited for each patient.

                                                And as Dr Prendergast mentioned we are in Copenhagen, and Scandinavia conducting a NOTION II trial, which, will enroll patients younger than the previous low risk trials and also the notion trial. Which, at a mean age, at least for the patient of around 80 years and in notion two patients must be younger than 75 years old. And we are also including patients with bicuspid valve stenosis, and also patients which were not included in the NOTION I trial. Patients with a coronary artery disease, so these patients are obviously also a different patient category and will maybe require a different approach regarding the timing of the revascularization and so forth so there is more research to be done in those areas.

Dr Carolyn Lam:                Well exciting. Thank you for sharing that Hans. Dharam could I ask you to just wrap us up with the take home message, it's for our audience right now.

Dr Dharam Kumbhani:   For me one of the most interesting findings was that in five years, the clinical performance between TAVR and SAVR were similar, but, more importantly the valve performance, the hemodynamic performance was the same, and perhaps slightly better with the self-expanding design. They are so proud of the self-expanding design that was studied in the study. So that is helpful because as we discussed earlier, I think a lot of the controversy discussions centers around the long-term durability of TAVR compared with surgically aortic valve replacement, so that is a step in the right direction. The same investigators have published that hemodynamic performance elsewhere as well, sot that's I think the number one take home message that, that's very, very reassuring. The second thing is you know this study shows us it adds to the growing body of literature, in lower risk patients so all of this was not strictly a lower risk trial based on contemporary definition.

                                                It was definitely a lower risk population and so, this is the largest pool of patients where they aortic stenosis about 50 percent will have low risk aortic stenosis, low surgical risk aortic stenosis and so this is very helpful in that space and then third you know that this is very exciting that NOTION investigators indeed are the low risk trial investigators, will be extending their follow up with 10 years. So I think in this next decade, most people expect as Dr Prendergast also mentioned, we'll see a gradual change perhaps in how patients with aortic stenosis manage. But, I will add a word of caution, I think in the current era, the way things stand right now, it's probably best in favor to appeal to what the guideline indicates. And for the low risk patients, surgical aorta valve replacement is still the center of choice.

Dr Carolyn Lam:                Thank you so much Dharam and thank you Hans for the beautiful paper, and Bernard for that excellent editorial!

                                                Thank you audience for joining us today, 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.