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Circulation on the Run

Apr 15, 2019

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 in Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also associate editor of Circulation and director of the Poly Heart Center at BCU Health in Richmond. Carolyn, we've got a really exciting interview to follow our coffee chat and it's evaluating individuals with low complexity congenital heart disease. We often think of those with high complexity congenital heart disease and looking at their cardiovascular events. We're going to hear a little bit about low complexity congenital heart disease.

                                                Now you've got a paper you wanted to talk about first.

Dr Carolyn Lam:                Absolutely. You've got to hang on for that because I'm going to delve into chromatin architecture in heart failure, and it's in this paper from corresponding author Dr Foo from Genome Institute of Singapore.

                                                So, as background, the human genome actually folds in 3D to form thousands of chromatin loops within the nucleus encasing the genes and assists regulatory elements for accurate gene expression control. Now, these physical tethers of loops are anchored by the DNA binding protein CTCF, also known as the weaver of the genome and the cohesion ring complex. Now, the role of CTC in binding and changes in chromatin structure in heart failure are not well understood. Well, until today's paper.

                                                What the author said is they undertook an independent analysis of chromatin organization with mouse pressure overload model of myocardial stress or transverse aortic constriction, and a cardiomyocyte specific knockout of CTCF. So, interestingly, they found that the cardiac chromatin architectural in adult terminally differentiated cardiomyocytes was unchanged in pressure overload from transverse aortic constriction. Now this was completely unlike the CTCF knockout model where they verified that there was generation of vast genome-wide loss of genomic insulation and near complete abolition of the CTCF chromatin loops.

                                                Instead of chromatin rewiring on the scale of that knockout, the myocardial stress response appeared to proceed through enhancer H3K27 acetylation epigenetic changes and gene network co-regulation driven largely by fixed cardiac 3D chromatin architecture. In other words, a stable chromatin architecture really set the stage for accurate enhancer promoter interactions required for basal gene expression control and induction of the classical myocardial stress gene response.

Dr Greg Hundley:             So Carolyn, are there therapeutic implications here for this?

Dr Carolyn Lam:                Now of course, that was preclinical work, but it really opens the door to consider these epigenetic regulators that control disease expression changes and interacting gene sets in heart as potential future targets for novel heart failure therapy.

Dr Greg Hundley:             Very interesting. So, I'm going to review and switch gears a little bit and focus on diabetic cardiomyopathy and mitochondria associated endoplasmic reticulin membranes. And this paper is from Shengnan Wu from the Center for Molecular and Translational Medicine at Georgia State University here in the US in Atlanta, Georgia. So as we all know, mitochondria are essential for cellular energy production, but when they're damaged, they become a major source of reactive oxygen species and pro-apoptotic factors. In particular, increasing evidence suggests that mitochondrial dysfunction is a central event in diabetic cardiomyopathy.

                                                Well, the mitochondria and the endoplasmic reticulum are key players that regulate many cellular functions and their structural and functional interactions are essential for cellular homeostasis. The contact points, however, through which the endoplasmic reticulum communicates with mitochondria, they're known as mitochondria associated endoplasmic reticulum membranes, or MAMS. Importantly, MAMS play a pivotal role in calcium signaling, lipid transport, energy metabolism and cell survival, and they've been implicated in a variety of diseases, including Alzheimer's Disease, cancer, lysosomal storage diseases, diabetes, obesity induced mitochondrial dysfunction and other metabolic disorders.

                                                But the role of these MAMS in the initiation and progression of Diabetic Cardiomyopathy is really unknown. So now, FUNDC1 is a highly conserved protein that's exclusively localized to the mitochondria. And this group had previously demonstrated that FUNDC1 was essential for maintaining the structure of MAMS and ensuring appropriate calcium transfer from the endoplasmic reticulum to the mitochondria normal hearts. Moreover, cardiac specific deletion of FUNDC1 induced cardiac dysfunction by inhibiting MAM formation.

Dr Carolyn Lam:                Interesting. So that was their prior work? What did the current study show?

Dr Greg Hundley:             Right, so what the investigator showed in this study is that high glucose driven inactivation of AMP-activated protein kinase increased FUNDC1 stability, but resulted in aberrant MAM formation, impaired mitochondrial calcium increase, mitochondria dysfunction and then cardiac dysfunction. And additionally, AMP-K activation reverses Diabetic Cardiomyopathy by suppressing high glucose induced MAM formation, mitochondrial calcium increase and mitochondrial dysfunction.

                                                And interestingly, Metformin, an AMP-K activator, used exclusively for Type 2 Diabetes, might be effective in treating Diabetic Cardiomyopathy in individuals with Type 1 Diabetes. So a very interesting mechanistic study providing some information of how MAMS, mitochondrial function and endoplasmic reticulum could be important in understanding how to prevent Diabetic Cardiomyopathy.

Dr Carolyn Lam:                Indeed. And you know, that last note that you made on Type 1 Diabetes, also links very well with the next paper that I chose. Which really asks the question, in Type 1 Diabetes, what are the relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes? And this comes from Dr Rawshani and colleagues from the Swedish National Diabetes register who studied more than 32,600 patients with Type 1 Diabetes in their national observational cohort study from the Swedish National Diabetes register, with a mean follow-up of 10.4 years and a mean duration of diabetes of 17.9 years.

                                                They found that the most important predictors for outcomes were HP-A1C, albuminuria, duration of diabetes, systolic blood pressure and low-density lipoprotein cholesterol, or LDL cholesterol. Now, the lower levels of HP-A1C, systolic blood pressure and LDL cholesterol than contemporary target levels were associated with lower risk for outcomes. Albuminuria was associated with a two to four times greater risk of cardiovascular disease and death. And each millimole increase of LDL cholesterol was associated with 35 to 50% higher risk for outcomes.

Dr Greg Hundley:             Boy, Carolyn, those are interesting results. So, what do we take away from this in clinical management of patients?

Dr Carolyn Lam:                The take home message is that in patients with Type 1 Diabetes, the strongest predictors for mortality and cardiovascular disease, with the exception of age, were mostly conventional and modifiable cardio-metabolic risk factors. And this in turn suggests that increased clinical focus on these risk factors, particularly in primary prevention, may result in the largest relative risk reduction for mortality and cardiovascular disease, even in Type 1 Diabetes. So, future clinical trials may be designed to test these findings.

Dr Greg Hundley:             Very good. Well, Carolyn, my next paper, I'm going to talk about five year outcomes after off-pump versus on-pump coronary artery bypass grafting in those over the age of 75 years. And this paper comes from Anno Diegeler from Bad Neustadt in Germany. From June of 2008 to September of 2011, they evaluated a total of 2,539 patients that were 75 years or older, who had been randomly assigned to undergo off-pump or on-pump coronary artery bypass grafting across 12 centers in Germany.

                                                And the primary outcome was all cause mortality at five years, and the secondary outcome included a composite of death, myocardial infarction and repeat revascularization. What did they show in this study? Well, after a median follow up of five years, the hazard ratio for off-pump versus on-pump coronary artery bypass grafting was 1.03, confidence interval 0.81 to 1.19, no difference. The composite outcome of death, myocardial infarction and repeat revascularization, the same. Hazard ratio 1.03, confidence interval 0.89 to 1.18, P-value 0.7.

                                                So, first take-home message, no difference if you had your surgery off-pump or on-pump, if you're over the age of 75. Now, another outcome related to incomplete revascularization. And what was striking I this study is whether you underwent on-pump or off-pump bypass, if you were incompletely revascularized, that was associated with both the primary as well as the secondary outcomes. So, in elderly patients, in summary, greater than or equal to 75 years, the five year survival rates as well as the combined outcome of death, MI and repeat revascularization, was similar for on-pump versus off-pump CABG. And incomplete revascularization was associated with a lower five year survival rate, irrespective of the type of surgery that was performed.

Dr Carolyn Lam:                Interesting. Beautifully summarized, Greg. Thank you.

Dr Greg Hundley:             Absolutely. And let's head on to that featured article.

                                                Well, welcome everyone to the second half of our program. We are very excited today to have Dr James Priest, from Stanford University School of Medicine. And also our associate editor Gerald Greil from University of Texas Southwestern School of Medicine in Dallas. And we're going to be discussing the article, Substantial Cardiovascular Morbidity in Adults with Lower Complexity Cardiovascular Disease.

                                                So, James, first could you tell us a little bit about what constitutes low complexity congenital heart disease? And then a little bit about your study population, your design, and the results that you found with your study?

Dr James Priest:                So, low complexity congenital heart disease really derives from definitions of congenital heart disease in adults that are grown up and have different complexity of lesions. And so high complexity congenital heart disease, you see things that, as people may remember, adult cardiologists may remember from their training. People remember from medical school, things like single ventricle disease, hypoplastic left heart, tetralogy of fallot, transposition of the great arteries. But, non-complex, so our low complexity disease, really constitutes a relatively simple malformation. Things like atrial septal defects, ventricular septal defects, patent ductus arteriosus. Things that are treatable with a single surgery.

                                                You close the hole, you ligate the vessels, you dilate the valve, and the patient is affectively cured. So relatively low complexity diseases that can be treated with typically, a single surgery or minimal interventions to restore completely, or essentially normal, cardiovascular physiology.

                                                So, the study was based upon a very large you know, volunteer data set, the UK Biobank. It comes from the United Kingdom where 500 thousand individuals enrolled, and from those individuals there is genetic information, medical histories dating back to the 1990s, self-reported history. A variety of functional and neuropsychiatric measures. And if you get a group of 500 thousand individuals from anywhere, there's going to be some congenital heart disease in there. And so, we looked to see what types of congenital heart disease were in there. And in fact, there was lower complexity individuals.

                                                And because I spent some time on the research side of things with my adult colleagues, the first thing we looked at were from the common adult cardiovascular outcomes, things people write about in Circulation all the time. Coronary artery disease, atrial fibrillation, heart failure. We know these things are problems in adults with complex cardiovascular disease, but nobody had really looked for the most part in adults with low complexity or non-complex disease. And we were surprised to see such high event rates for these common adult cardiovascular conditions.

Dr Greg Hundley:             So, what type of events did you appreciate in the population in follow up?

Dr James Priest:                So, we really appreciated about a two-fold rate of let's say, acute coronary syndrome relative to the general population. Up to almost 13 fold risk of atrial fibrillation and heart failure, relative to the general population. So, really substantial and very impactful event rates.

Dr Greg Hundley:             Very good. And so, just a couple points of clarification. Do you think that the events you observed, were they related to the congenital heart disease, per se? Or could it have been a result from the surgical procedure to treat that heart disease?

Dr James Priest:                So, that's a great question. I think, in some ways, that's the fundamental question that the paper leads to. So, we thought of it in two different ways. You know, one, were these events, and they're perioperative events, for individuals receiving some type of care for their congenital heart disease, during their adulthood? And we performed a sensitivity analysis where we basically looked at those events and then looked for events occurring within a year of adult interventions. And we saw no difference in those event rates. So, they weren't perioperative or postoperative events in adults receiving adult congenital heart disease care.

                                                The second part of the question is really more of an existential question in some ways. You know, is there some fundamental relationship between the care these people received as children? Or the genetic basis of congenital heart disease in the first place that is somehow put people at risk long term for adult cardiovascular disease, acquired adult cardiovascular disease? And I think there's indeed a lot of different ways to try and get at that question and explore that more, which we're currently working on.

Dr Greg Hundley:             So, Gerald, I wanted to turn over to you now and, in your practice that encompasses those that are young adults that have this low complexity congenital heart disease, how do you manage them now? And how might the results of this study suggest, potentially, a different management strategy?

Dr Gerald Greil:                 Usually these patients, they're kind of thought to be cured or only needed minimal follow up in the past. So, if you take a patient with a VSD, rarely during childhood, young adult or even kind of in 20s and 30s, you have any major difficulties. And as a pediatric cardiologist, you rarely experience any major follow up problems with these patients. I think, particularly in the US, and I work actually for more than 10 years in the UK, the problem in the US is how can you organize follow up in these patients?

                                                There're insurance issues, there're issues about moving into different areas, and since these patients were kind of labeled as being healthy and close to normal, they were lost for follow up, particularly in the US. I think this study raises some concerns, we should probably be more careful and cautious and follow these patients up kind of in a lifelong session. And take care of them. This is definitely something, which is a new finding, and what the cause is, how we are following up, that's the question. I guess it could be a good question for future studies.

Dr Greg Hundley:             You mentioned future studies. Specifically, what type of future studies do you think we need to perform next? This shows us that the events are occurring, are we ready yet for randomized trials to perform prevention? Do we need studies that have more frequent observation? What are your thoughts there? And I'll get your answer and then we'll come back to James and get his thoughts on the same question.

Dr Gerald Greil:                 Yeah, I think the major thing is we need close follow up of these patients. And it will be a combined effort between pediatric and specialized adult cardiologists, with a special interest in patients with congenital heart disease. Once again, coming back to it, a closer follow up is a little bit dependent on the medical system, which you have. If you take Canada and the UK, it may be easier in these patients are under close follow up. And this allows large multicenter studies, large data bases like UK Bio Bank are kind of exemplary. And we should try to get something similar within the US or in other countries.

                                                I think that's the lesson what we take from that, we need larger data bases, probably more granular than what we have right now. I mean, James probably can comment in a second about the shortcomings and what can be done better in the UK Bio Bank to allow more detailed conclusions than we have currently from his study.

Dr Greg Hundley:             James?

Dr James Priest:                I would agree with that. I think as a person who does not, clinically speaking, take care of adults with congenital heart disease, my colleagues and I, or I have the impression from my colleagues that for most of the time, in most of these patients in the Unites States adults who had VSD or ASD repair as a child, they were essentially said, oh, you're cured. And they perhaps had some follow up during childhood, but then were otherwise discharged to live the rest of their lives.

                                                And so, in many cases I'd say the first step before performing any studies is to simply identify who these patients are, and figure out you know, what their risk factors otherwise for cardiovascular disease might be. Now, that being said, I think that was one of the powerful things about the UK Bio Bank study is that there's a large population in which all these traditional cardiovascular risk factors you know, obesity, lipid levels, hypertension, smoking status, all these things were uniformly measured in both the individuals with congenital heart disease, the adults with congenital heart disease. And of course the control population.

                                                And so that allowed us to make some estimates about what proportion of disease was attributable to these traditional cardiovascular risk factors. And what was attributable to other factors related, potentially, to the congenital heart disease. But all those things being said, I think the first questions that I often to tend to receive about these studies from the pediatric cardiologists and the adult congenital heart disease doctors, reflects the sorts of data sets that we're used to looking at.

                                                Well, what sort of an intervention did this person have? Did they have a ventriculostomy? When did they receive their diagnosis and their repair? Details of the surgical care and the perioperative of course, are not available in this data set because it's not a particularly pediatric cardiology focused data set. It's a broad population based data set. And so the relationship specifically the details of their perioperative care and diagnosis are not able to be attained. And so we'll need larger data sets that include that information to fully start to develop those sorts of relationships over time.

Dr Greg Hundley:             So, we want to thank our lead author, Dr James Priest from Stanford University School of Medicine, and our associate editor, Gerald Greil from the University of Texas Southwestern Medical School in Dallas. And reviewing this very interesting article on lower complexity cardiovascular disease and its association with an increased risk of cardiovascular events. And thank you both so much for clarifying. It sounds like an opportunity to collect more data through registries, et cetera, that we may need to expand around the world.

                                                Thank you everyone for listening to Circulation on the Run. Remember that's your back stage pass to our journal. And we'll see you next week.