Dr. Carolyn Lam: 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.
Our feature paper this week provides important mechanistic insights into oxidative stress and inflammation with aging. More of that soon right after the summary of this week's journal.
The first paper contributes to our understanding of the genetic and functional relevance of soluble guanylyl cyclase activity for coronary artery disease. As background, a chromosomal locus at 4q32.1 has been associated with coronary artery disease risk with genome wide significance. The locus encompasses GUCY1A3, which encodes the alpha one subunit of the soluble guanylyl cyclase, a key enzyme of the nitric oxide cyclic GMP signaling pathway.
In today's study from co-corresponding authors Dr. Kessler, and Dr. Schunkert from Munich, Germany and colleagues the authors showed that the GUCY1A3 locus has regulatory properties with the risk allele leading to reduced expression of GUCY1A3. The lead snip modulated finding of the transcription factor ZEB1 resulting in reduced expression of GUCY1A3 in carriers of the risk allele. As a consequence risk allele carriers demonstrated impaired inhibition of vascular smooth muscle cell migration and platelet aggregation after stimulation of the soluble guanylyl cyclase.
In summary, this study suggest that modulating soluble guanylyl cyclase activity or inhibiting the effects of reduced expression of GUCY1A3 may be promising therapeutic strategies for individuals with the high risk alleles of GUCY1A3.
The next paper reports the outcome associations between adding a radial arterial graft to single and bilateral internal thoracic artery grafts in the arterial revascularization trial or ART. As a reminder, ART was designed to compare survival after bilateral internal thoracic artery over single left internal thoracic artery bypass with about 20% also receiving a radial artery graft instead of a saphenous vein graft.
In the current paper, first author Dr. Taggert from University of Oxford and corresponding author Dr. Benedetto from University of Bristol in the United Kingdom and colleagues showed that the primary endpoint of ART which was a composite of myocardial infarction, cardiovascular death and repeat revascularization at five years was significantly lower in the radial artery group when compared to the saphenous vein graft group. This association was present when the radial artery graft was used to supplement both the single internal thoracic artery as well as the bilateral internal thoracic artery grafts.
In summary this post-hoc ART analysis showed that an additional radial artery was associated with lower risk for mid-term major adverse cardiac events when used to supplement single or bilateral internal thoracic artery grafts.
The next study addresses the questions of whether intensive blood pressure lowering beyond usual targets recommended by guidelines would lead to more lowering of left ventricular hypertrophy in patients with hypertension and whether reducing the risk of left ventricular hypertrophy explains the reported cardiovascular benefits of intensive blood pressure lowering.
To answer this question Dr. Soliman from Wake Forest School of Medicine in North Carolina and colleagues studied the 8,164 participants with hypertension but no diabetes from the Systolic Blood Pressure Intervention or SPRINT Trial. They showed that among SPRINT participants without baseline left ventricular hypertrophy, intensive blood pressure lowering was associated with a 46% lower risk of developing left ventricular hypertrophy compared to standard therapy. Similarly, among SPRINT participants with baseline left ventricular hypertrophy blood pressure lowering intensively was associated with a 66% greater likelihood for regression or improvement of their left ventricular hypertrophy. Furthermore, adjusting for left ventricular hypertrophy as a time-varying covariate did not substantially attenuate the effect of intensive blood pressure therapy on cardiovascular disease events.
In summary these findings add further evidence of the benefits of the intensive blood pressure lowering in patients with hypertension and suggest that these benefits go beyond reducing the hemodynamic stress on the cardiac structure. Further research is needed to understand the mediating factors and mechanisms by which intensive blood pressure lowering impacts the cardiovascular system.
Well that wraps it up for our summaries, now for our feature discussion.
We are going to talking about aging, oxidative stress and inflammation today and really taking a deep dive into potential mechanisms. I am so pleased to be here with the corresponding author of our feature paper in this week's issue. And that is Dr. Mustapha Rouis from INSERM University Paris six in France as well associate editor from University of Rochester Dr. Charlie Lowenstein.
Dr. Charlie Lowenstein: Thank you for having us.
Dr. Mustapha Rouis: Thank you very much.
Dr. Carolyn Lam: Mustapha, what inspired you to actually look at the Thioredoxin system in looking at this aging question? What were your hypotheses?
Dr. Mustapha Rouis: Actually our laboratories working on cardiovascular diseases for several years. We have been trying to understand why oxidative stress and inflammation increase with age despite the presence of a variety of antioxidant proteins in the body. So among the antioxidant proteins the Thioredoxin-1, isoform one which is a small ubiquitous incytocylic protein called our attention because it's a multi functional protein. It can exert an antioxidant role, anti-inflammatory and anti-apositic role. So therefore we wanted to know whether the increase in the oxidative stress and inflammation with age is it due or at least in part to a deficiency of Thioredoxin-1. If so is there increases due to a decrease in protein synthesis or to increase in its degradation.
For this purpose we have constituted a cohort of young and old subject, male and female. They want to focus on this particular point because this is very important point it has not been easy to achieve and we took a lot of time to sort and to keep only subject meeting our criteria. Those who we wanted to enroll consisting of people free from any history of diseases such as cardiovascular diseases, diabetes, obesity, inflammation, any kind of inflammation, cancer et cetera. In addition we wanted subject without any risk factor for cardiovascular disease except of course the age. No smoking, no hyperlipidemia and no taking any medication.
This really very hard to achieve. Then once we have enough subject we evaluate the Thioredoxin-1 using commercially available very specific kit, ELISA kit and showed that the plasma level of Thioredoxin-1 decreased significantly with age. Since it has been described for several years that Thioredoxin-1 can be cleaved at the C terminal level, the cleavage has been described to be occur after lysine at position eight. This will generate a truncated called Thioredoxin-80. We measured the plasma concentration of Thioredoxin-80 in this sample, in this same sample of the selected subject using an ELISA method developed in our laboratory because there is no commercially kit for Thioredoxin-80.
The result showed that Thioredoxin-80 increased with age therefore the decrease in the plasma concentration of the full length Thioredoxin-1 observed in the old, in the elderly is probably due to an increase in its cleavage and not to a decrease in its synthesis. Of note we observed an increase of the expression and activity of two alpha secretases ADAM-10 and ADAM-17 two enzyme responsible for the cleavage process in the peripheral blood mononuclear cells of the old subject. Our results consolidate our interpretation.
Dr. Carolyn Lam: Wow, what a beautiful set of studies that included human samples and then also included some very elegant mouse experiments. I remember the excitement among the editors when we discussed this paper. Charlie could you just share a little bit of what went on when we looked at this?
Dr. Charlie Lowenstein: First I'd like to put this study into context which is that oxidants increase during aging and it's been known for a long time that animals that have high metabolic rates have short life spans and one of the things that goes along with high metabolic rate is a lot of radical production. And since the 1950's there's been this theory, the free radical theory of aging that radicals damage cells. And so the question is, are radicals bad? What do they do in aging? And what defenses do we have against them? So that's one of the contexts of this article.
Secondly we also know that oxidants are associated with diseases. Increased oxidants during cancer, during inflammatory diseases and during atherosclerosis so that's why this study is important. It's important for two reasons. First of all there's a theory that as you age there's more radicals and radicals might actually cause part of the problem in aging. Secondly radicals are also associated with inflammatory diseases like atherosclerosis.
When the editors got this article, it was very exciting for several reasons. First of all, the short form of Thioredoxin, TRX-80 might explain why older people have more oxidative stress. Secondly this short form TRX, TRX-80 might be a new bio-marker for aging. And thirdly, the short form of Thioredoxin might help us monitor different antioxidant therapies when people have too many radicals. So for a number of important clinical reasons our editors were very excited when we received this important manuscript.
Dr. Carolyn Lam: Mustapha, what are your next steps when it comes to this?
Dr. Mustapha Rouis: Well several studies have shown that Thioredoxin-1 can reduce inflammation and can protect the body against several pathologies which has an increased interest in its use for therapeutic purpose. However its cleavage in the generation of the Thioredoxin-80, limited research work in this direction so I just remember you that the Thioredoxin-80, the truncated form in contrast to the full length Thioredoxin-1 exerts a pro-oxidant, pro-inflammatory angiogenic and carcinogenic effect. So nevertheless in order to counter these difficulties we plan to synthesize some Thioredoxin limited peptides such as catalytic site containing peptides and these peptide used it in therapy could show significant biologic activity. This peptide could lose constitute maybe an alternative to the full length Thioredoxin.
Dr. Carolyn Lam: Wow, that is exciting. Charlie, what do think is the take home message for clinicians listening to this?
Dr. Charlie Lowenstein: Scientists and clinicians all agree that an excess of radicals is bad. But there's an antioxidant paradox which is when patients take antioxidants like vitamin E, those antioxidants don't help. In a large clinical trial suggesting that vitamin E and other antioxidants don't help. So the question is, maybe antioxidant therapy helps some patients but doesn't help others. One of the interesting aspects of this study that maybe the presence or absence of TRX-80 might determine whether antioxidant therapies will help. Furthermore, maybe TRX-80 levels might be able to guide patients as to whether or not they should take antioxidant therapy. There are many important aspects of this study that point toward future studies.
Dr. Mustapha Rouis: We thought about inhibiting the ADAM-10, ADAM-17 alpha secretase enzyme to prevent the cleavage process and I know that many drug companies are trying to find the specific inhibitors but the problem is these two enzyme are benefit in brain for enzymatic disease. So waiting to have a specific inhibitor for this enzyme that do not cross the hematoencephalic barrier to use it in humans but until that we may be the use or conceive the peptides it's better approach.
Dr. Carolyn Lam: I'm just loving this discussion because it's really bringing out a lot more to this paper than I realized as a clinician. Charlie could you end by just saying a few words about how we look at basic science papers in Circulation and the importance of the clinical translation element that we keep saying is our primary focus.
Dr. Charlie Lowenstein: Circulation is a great journal that covers important clinical topics. There's a lot of basic science that underlies some of these clinical topics so whenever we get a paper that gives us insight into a disease or reveals a new therapy and it's at the basic level we look very carefully at it. We want to know, will it help our readers understand something about the clinical process, clinical disease, diagnostics [inaudible 00:16:00] So when we get a paper we look at it very carefully and emphasize it has to be a basic paper that reveals a mechanism that's important to clinicians. That clinicians can understand and appreciate and gain insight about what's going on with their patients. I'm both a clinician and a scientist, I am charged with trying to figure out what basic concepts are relevant to our clinical audience.
Dr. Carolyn Lam: Thank you Mustapha, thank you Charlie and thank you listeners for tuning in this week. Don't forget to tune in again next week.
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. Our journal this week features an in-depth review on transcatheter therapy for mitral regurgitation, a very, very hot and interesting topic. You have to listen on, coming up right after these summaries.
Our first original paper this week sheds light on the influence of aging on aldosterone secretion and physiology. First author Dr. Nanba, corresponding author Dr. Rainey and colleagues from the University of Michigan in United States, examine the relationship between age and adrenal aldosterone synthase in 127 normal adrenals from deceased kidney donors. The donors' ages ranged from nine months to 68 years. The authors found that adrenals from older individuals displayed less normal aldosterone synthase expression and zona glomerulosa, and greater content of abnormal foci of aldosterone synthase expressing cells.
Furthermore, older age was independently associated with dysregulated and autonomous aldosterone physiology, in an ancillary clinical study of subjects without primary aldosteronism. This study therefore suggests that aging may be associated with a sub-clinical form of aldosterone excess and provides at least one potential explanation for age related cardiovascular risk.
The next study shows, for the first time, that the chemokine receptor, CXCR4, in vascular cells, limits atherosclerosis. The CXCL12 and CXCR4 chemokine ligand receptor axis is known to control cell homeostasis and trafficking. However, its specific in atheroprotection has thus far been unclear. This is addressed in today's study by first author Dr. During, corresponding author Dr. Weber, and colleagues of The Institute for Cardiovascular Prevention in Munich, Germany. In hyperlipidemic mice, the authors showed that cell-specific deletion of CXCR4 in arterial endothelial cells, or smooth muscle cells, marked the increase atherosclerotic lesion formation. Mechanistically, CXCR4 axis promoted endothelial barrier function through VE-cadherin expression and a stabilization of junctional VE-cadherin complexes. In arterial smooth muscle cells, CXCR4 sustained vascular reactivity responses, and a contractile smooth muscle cell phenotype. Whereas, CXCR4 deficiency favored the occurrence of macrophage-like smooth muscle cells in atherosclerotic plaques and impaired cholesterol efflux.
Finally, in humans, the authors identified a common allele variant within the CXCR4 locus that was associated with reduced CXCR4 expression in carotid RG plaques, and increased risk for coronary heart disease. Thus, the study suggests that enhancing the atheroprotective effect of arterial CXCR4 by selective modulators may open normal therapeutic options in atherosclerosis.
The next paper is the first to study the effects of rosuvastatin on carotid intima-media thickness in children, with heterozygous familial hypercholesterolemia. First author Dr. Braamskamp, corresponding author Dr. Hutten, and colleagues from Academic Medical Center Amsterdam in the Netherlands, study children with heterozygous familial hypercholesterolemia aged 6 to less than 18 years, with LDL cholesterol more than 4.9, or more than 4.1 millimoles per liter in combination with other risk factors, who received rosuvastatin for 2 years, starting at 5 milligrams once daily, with uptitration to 10 milligrams for children aged 6 to 10 years old, or 20 milligrams daily for those aged 10 to 18 years old.
Carotid intima-media thickness was assessed by ultrasonography at baseline, 12 months and 24 months in all patients and in age-matched, unaffected siblings. Carotid intima-media thickness was measured at 3 locations, the common carotid artery, the carotid ball, and the internal carotid artery in both the left and right carotid arteries. At baseline, the mean carotid intima-media thickness was significantly greater for the 197 children with heterozygous familial hypercholesterolemia compared with the 65 unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid intima-media thickness in children with heterozygous familial hypercholesterolemia than in the untreated, or unaffected siblings. As a result, there was no difference in carotid intima-media thickness between the two groups after two years of rosuvastatin. These findings, therefore, support the value of early initiation of statin treatment for LDL cholesterol reduction in children with heterozygous familial hypercholesterolemia.
The final study highlights the therapeutic potential of a novel alpha calcitonin gene-related peptide for the treatment of heart failure. First author Dr. Aubdool, corresponding author Dr. Brain, and colleagues from King's College London in United Kingdom, tested the stable alpha analog of calcitonin gene-related peptide in 2 models ... First, an angiotensin 2 infused mouse, and secondly, pressure overload cardiac hypertrophy mouse model using suprarenal aortic ligation. They showed that systemic colon injection of the alpha analog blunted the angiotensin 2 induced rise in blood pressure, as well as the vascular and cardiac remodeling, changes in water consumption, and renal injury, that are normally associated with angiotensin 2 infusion. Furthermore, protective effects were also seen when starting the alpha analog treatment, only during the last week of the 2-week angiotensin 2 infusion, in other words, when hypertension was already established. Finally, the alpha analog preserved heart function, and diminished the degree of hypertrophy and fibrosis in the aortic ligation model.
Thus, these results demonstrate the therapeutic potential of the alpha calcitonin gene-related peptide pathway, and the possibility that this injectable alpha analog may be effective in cardiac disease.
Well, that wraps it up for this week's summaries! Now, for our featured discussion.
For our feature discussion this week, we're talking about trans-catheter therapy for mitral regurgitation, a very hot field and a field in which there have been a lot of advances. To help us break it down, and get right into the insights, the challenges, and potential solutions, I am so pleased to have the first author of this in-depth review paper, Dr. Paul Sorajja from Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital, as well as Dr. Manos Brilakis, associate editor from UT Southwestern, here with us today!
Paul, could I start with you, and just ask you first to give us an idea of what we're talking about here when we talk about mitral regurgitation ... There are different kinds, which are we referring to, and what are the challenges involved in a trans-catheter therapy for mitral regurgitation?
Dr. Paul Sorajja: I think there are a number of challenges, I think the first thing is that MR is often thought of as one disease, but it's really an incredibly heterogeneous disease ... Broadly, we talk about primary versus secondary MR, but the mitral valve is so complex, with multiple different components, any one of which can disrupt and cause MR. When we're talking about trans-catheter therapy, it's often very easy, again, to think we could have one therapy that could treat a simply insufficient valve, but it's way more complex than that, and as a result, there have been many different approaches that have been developed, adding to the complexity of how we manage these patients.
Dr. Carolyn Lam: Right, and in your paper, I loved the way you grouped them, very logically, under those from mitral valve repair, and that for mitral valve replacement ... And then, under repair, you grouped it into leaflet versus targeting the LV ... Could you maybe give us some top-line insights on these techniques?
Dr. Paul Sorajja: Yeah, there are a number of different approaches that have mechanistically gone after the different components through the pathophysiology of MR, where there is leaflets, where there's analysts, cords, or ventricular approach ... I think it's somewhat simplistic to think of it that way, but as catheter-based technology, we are technically limited by what we can do from a catheter standpoint. I think it's inevitable to think about these catheter technologies as eventually being combined, rather than singular, in order to approach what surgeons do in the OR.
Dr. Carolyn Lam: Right, but then even going further, you spent quite a bit of the paper talking about trans-catheter mitral valve implantation ... So, replacing the mitral valve, that's really cool, could you tell us a bit about that, and about that important issue brought up about patient selection.
Dr. Paul Sorajja: Yes, it's a very good point, I think in terms of trans-catheter mitral replacement, I think that that's really where the future is going to go ... The simple analogy is that people think that it will follow the route of TAVR, but I think it will follow the route of TAVR more quickly so, because when you look at how the mitral valve is currently treated in the OR, sometimes, a lot of the times, patients can end up worse. Whereas, a trans-catheter solution actually, I think in terms of the safety margin, actually will equate a degree of safety relative to surgery, if it's done and developed correctly, as opposed to how TAVR's done. I think for TAVR, it's been a number of years for our field to be equivalent or superior to surgery, whereas I think with mitral, I think there's a lot of potential for mitral to have equated a degree of safety. As an example, in the Tendine Feasibility Study, it was published this past January ... A high-risk population, there was not a single procedure death, out of 30 patients ... And for these patients who would go to the OR with an eject fraction of 30 to 40 percent, I think that's quite remarkable.
Dr. Carolyn Lam: Wow, that's really exciting indeed! Manos, you handled this paper, and it's just so beautifully laid out ... That flow chart, I just want to refer all our listeners to the flow chart in Figure 7, that talks about maybe an approach that can be considered. Manos, could you share some thoughts on how this developed?
Dr. Manos Brilakis: Yeah, absolutely, and obviously Paul is the expert on this, but I think it's very important about this paper, and through discussions with Paul and through the development of the paper, is that there's more of a collaboration between the surgeons and the interventionists. So instead, if it's additional style of ... Or the interventionists are doing one thing and the surgeon is doing another, I think the key to success in the mitral field is working very closely together ... Many of those valves right now, the percutaneous valves, are done through a cut down and a typical approach, so working very closely to addressing the anatomic components of the mitral valve problem is a big plus.
The other thing I think that is very important is the new emergence of imaging, trying to understand whether the new mitral valve is going to create issues with LVOT obstruction or not. I think that's leading to a whole new understanding of when and how patients are even candidates for this approach, and I think Paul can elaborate more on this, but as things evolve, fewer and fewer patients are going to be excluded from these new technologies.
Dr. Carolyn Lam: Paul, would you like to take that? What do you think is happening and will happen with patient selection?
Dr. Paul Sorajja: There has been a challenge in current feasibility studies, in terms of getting patients in, the anatomical restraints are exactly what Dr. Brilakis has outlined. There's a certain bulkiness and size to the valve, which essentially poses risk for LVOT obstruction if the valve is too big ... As a feasibility study that's still early, or a field that's still early in its development, there's been a really conservative approach in terms of patient selection to ensure that LVOT obstruction doesn't happen. I think we're pushing the boundaries for that, and I think we've learned a lot from CT imaging, in terms of predicting LVOT obstruction, and I think the valves are also getting to be shorter in profile, which makes it less likely ... But that is definitely one of the limitations, and it's a limitation that exists, not just for trans-cat therapy but also for surgical therapy.
Dr. Carolyn Lam: Right, and then maybe a question for both of you ... What do you think the future is going to hold? What do we need to make this more mainstream, and where do you think this will leave surgical approaches? I know you said a combined approach, but maybe you could elaborate a little bit more?
Dr. Paul Sorajja: I do think, and I agree, I think Manos' point is spot on about that ... This will have to be multidisciplinary, the surgeons and cardiologists absolutely need to continue to work together, that's what's led to the successful development of TAVR, and I think that will be even more so for mitral, because the mitral valve is just infinitely more complex, and we have a lot to learn from the surgeons. But I think going forward, the collaboration is going to be a requirement, and then the training is also going to be a significant portion ... Putting in a mitral valve is much more complex than putting in an aortic valve ... I think if there's a safety margin that's demonstrated, I still think that it will be more appealing and more rapidly adopted than aortic disease.
Dr. Carolyn Lam: Well, Manos?
Dr. Manos Brilakis: No, I completely agree with Paul on that respect. I think, in my mind, at least, an again, this is from an early standpoint, the next big step would be to make it completely percutaneous, right now, you still have to do the cut down, and it's a little more invasive, although still safer than the completely open surgery, but maybe having a complete percutaneous system would be the next big step ... There's no question in my mind, as well ... And watching very closely how Paul and the surgical team are handling this, I think this is definitely the way for the future. Sometimes, in TAVR, it's not as technically demanding, and you don't really need to have too many people in the room, but for this procedure, it's definitely more important to have everyone in the room, and benefit from everyone's expertise.
Dr. Carolyn Lam: Manos, could I switch tracks for a moment now, and ask you to comment on the question that I get a lot ... You're an Interventionist, you handle a lot of the interventional papers for Circulation, and a lot of people are wondering, what makes papers like Paul's ... What makes interventional papers something that we would want to publish in Circulation? Could you share some thoughts?
Dr. Manos Brilakis: Absolutely, thanks Carolyn ... That's a big part, I think, of the appeal of Circulation right now. We're really trying to communicate to people that cutting-edge, clinical science is actually at the heart and the core of Circulation, and clinical content is what drives a lot of editorial ... Especially in intervention, where particularly interesting and new, cutting-edge technologies, new trials, observational studies ... But essentially, things that are cutting-edge, and are going to have a specific implication and impact in the way the field is going ... And this is part of Dr. Sorajja's paper, showing where the future lies in terms of trans-catheter mitral technologies, but along the same lines, we love to have cutting-edge papers on various aspects ... Coronary, peripheral, all aspects of interventional cardiologies, as well as interventional imaging ... The goal, again is to make the submission easy, there are not many honors requirements for submitting the papers, it's very simple to submit, and there's an answer going out very quick, so we're looking forward to receiving more and more interventional papers on cutting-edge science.
Dr. Carolyn Lam: Thank you so much for joining us today, and don't forget to tune in again next week.
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.
Now, the SGLT2 inhibitor, empagliflozin, has been shown to improve outcomes in the EMPA-REG OUTCOMES trial. But do these benefits also apply in the real world, and to other SGLT2 inhibitors as a class? Well, we may just have some answers this week in the CVD-REAL study. More soon right after these summaries.
The first original paper this week uncovers the mechanism of beneficial action of T-cells for proper healing after myocardial infarction. Now, the pro-inflammatory danger signal, adenosine triphosphate or ATP, is released from damaged cells, and degraded by the ectonucleotidase CD73 to the anti-inflammatory mediator, adenosine.
Using newly-generated CD4-CD73 null mice, first author, Dr. Borg, corresponding author, Dr. Schrader, and colleagues from Heinrich Heine University of Düsseldorf in Germany, showed that a lack of CD73 on T-cells enhanced tissue fibrosis and worsened myocardial function in the remodeling phase after myocardial infarction.
T-cells migrated into the injured heart and upregulated their enzymatic machinery to enhance the extracellular degradation of ATP to adenosine. T-cells lacking CD73 showed accelerated production of pro-inflammatory and profibrotic cytokines. Finally, the adenosine 2B receptor was upregulated on cardiac immune cells in the remodeling phase.
In summary, therefore, local adenosine formation by CD73 on T-cells appears to be the body's own defense mechanism to control inflammation induced by myocardial infarction. This is a mechanism that might be exploited to promote healing or remodeling by specifically targeting the adenosine 2B receptor in the infarcted heart.
The next paper provides insights on genetic determinants of susceptibility to peripheral artery disease, and specifically puts the spotlight on Bcl-2-associated athanogene-3, or Bag3, which is a cell chaperone protein previously identified in a genetic screen for determinants of tissue loss with hindlimb ischemia.
In the current study, Dr. McClung from East Carolina University, Brody School of Medicine in Greenville, North Carolina, and colleagues, used adeno-associated viruses to show that an isoleucine to methionine variant at position 81 in Bag3 was sufficient to confer susceptibility to ischemic tissue necrosis in BALB/c mice.
In a series of elegant experiments, they demonstrated that Bag3 was a modulator of ischemic muscle necrosis and blood flow. In summary, this study provides evidence that genetic variation in Bag3 plays an important role in the prevention of ischemic tissue necrosis, and highlights a pathway that preserves tissue survival and muscle function in the setting of ischemia.
The next study provides insights into inflammatory atherogenesis by studying psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction. First author, Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI, National Institutes of Health in Bethesda, United States, and colleagues, hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of non-calcified plaques with high-risk features.
To test this hypothesis, they compared total coronary plaque burden, non-calcified coronary plaque burden, and high-risk plaque prevalence between 105 psoriasis patients, 100 older hypolipidemic patients eligible for statin therapy, and 25 non-psoriasis healthy volunteers. All patients underwent CT coronary angiography, and a sample of the first 50 psoriasis patients were scanned again at one year following therapy.
The authors found that patients with psoriasis had greater non-coronary burden and increased high-risk plaque prevalence compared to healthy volunteers. Furthermore, compared to older hypolipidemic patients, patients with psoriasis had elevated non-calcified burden, and equivalent high-risk plaque prevalence. Finally, improvement in skin disease severity was associated with an improvement in non-calcified coronary burden at one year.
The clinical implications are that patients with psoriasis have similar coronary artery disease risk as hyperlipidemic patients one decade older, and these patients with psoriasis should be screened earlier for cardiovascular disease and educated about their elevated risks. Further investigations focus on the longitudinal impact of psoriasis treatment on high-risk plaque morphology, as well as on the extent of cardiovascular risk mitigation in randomized trials.
Well, those were your summaries. Now for our feature discussion. Now, we've heard of the EMPA-REG OUTCOME trial, that prospective randomized, controlled trial, showing a substantial reduction in cardiovascular death and hospitalization for heart failure with the sodium-glucose cotransporter 2, or SGLT2 inhibitor, empagliflozin, and that's, remember, that was in patients with type 2 diabetes and established atherosclerotic cardiovascular disease.
Well, our paper today really extends our knowledge and tells us a bit more about the role of SGLT2 inhibitors in real-world clinical care. And I'm so please to have with us the first and corresponding author, Dr. Mikhail Kosiborod from Saint Luke's, Mid America Heart Institute, as well as Dr. Gabriel Steg, associate editor from Paris, France, joining us today. Hello, gentlemen.
Dr. Gabriel Steg: Hello.
Dr. Mikhail Kosiborod: Hi. Good morning, Carolyn.
Dr. Carolyn Lam: Mikhail, I am going to say what I said to you at the ACC and at the ESC Heart Failure: Congratulations on CVD-REAL. Please tell us about CVD-REAL.
Dr. Mikhail Kosiborod: Right, well, we know, as you just mentioned, that the EMPA-REG OUTCOME trial showed substantial reduction in cardiovascular death, and hospitalizations for heart failure in patients with type 2 diabetes and established cardiovascular disease. We were all very excited once that data got presented in September of 2015 in Stockholm, but there were several very important questions that weren't really addressed, and truly, could not be addressed, in EMPA-REG's trial.
The first, actually, and probably the most important is, we all know that clinical trials, while we regard them as the gold standard of evidence, as we should, they do have their own set of limitations, the most important of which is that they examine a relatively small sliver of patients; and many patients we see in the clinic, in the hospital, don't look like patients in clinical trials. I think the most important questions we tried to address was, "Will this translate to real-world clinical practice?"
The second was, as you recall, again, all patients on EMPA-REG had established cardiovascular disease, so we wanted to know whether the benefits associated with the use of SGLT2 inhibitors could potentially extend to lower-risk patients with type 2 diabetes without established cardiovascular disease, a much broader spectrum of patients.
And finally, and also very importantly, I think, the third question was, "Is it an empagliflozin-specific effect or is it a class effect?" These are all the critical questions we tried to address in the CVD-REAL study.
Dr. Carolyn Lam: Great. Could you give us the topline results, please?
Dr. Mikhail Kosiborod: Right. So, just as a reminder, we collected data from well-established registries in six countries, so the United States and some five countries in Europe, Sweden, Norway, and Denmark, and also, the United Kingdom and Germany. And really, the inclusion/exclusion criteria for the study were quite broad, you just had to have type 2 diabetes and be newly started on either an SGLT2 inhibitor or any other glucose-lowering medications, which was the comparative group.
And after we did the one-to-one propensity match to make sure, comparable samples, we ended up with about 154,000 patients, and each treatment group, over 300,000 patients overall. What we actually observed was a marked and highly significant reduction in the risk of hospitalization for heart failure that was associated with use of SGLT2 inhibitors versus other glucose-lowering drugs.
In fact, the magnitude of reduction in risk that was associated with SGLT2 inhibitors, so that outcome was quite similar, about 39% relative risk reduction, quite similar to what we see in the EMPA-REG OUTCOME trial. But this, of course, was for the entire class of SGLT2 inhibitors, so patients in the study were treated primarily with canagliflozin and dapagliflozin, with a small proportion being treated with empagliflozin.
We also saw dramatic and highly significant associated reduction in the risk of all-cause death with SGLT2 inhibitors versus other glucose-lowering drugs, about a 51% relative risk reduction, and the composite of those two outcomes, obviously, there was significant associated reduction in risk as well.
So, again, the hazard ratio estimate that we saw for these outcomes were quite similar, and in some cases, almost identical to what we've seen in EMPA-REG, but for a patient population that was much broader, in fact, about 90% of patients, close to 90% of patients in our study did not have established, documented cardiovascular disease. And, of course, as I mentioned before, important implications to these findings, in my opinion.
Dr. Carolyn Lam: Yeah, that is just remarkable. Gabriel, could you share some of the discussions that happened among the editors about this paper?
Dr. Gabriel Steg: We were really excited by this paper. I think this is truly a landmark paper for a number of reasons. It's a very large, multinational study, but even more than the size, I think what's interesting here are a couple of key aspects. First of all is data on all-cause mortality, which is a highly reliable outcome when you look at many of the observational studies.
Non-fatal outcomes can easily be skewed or biased in ascertainment or assessment, but this is relatively reliable. And here, we have a very large multinational cohort that finds benefits on death, heart failure, and their composite, which are remarkably consistent internally, consistent across countries, and consistent with the randomized trial data evidence from the EMPA-REG OUTCOME trial.
So that is striking, and this is consistent across six countries using a very large sample size. But again, the size of the sample is not the most important thing, because in observational studies, you often have very large sample sizes, but if you have bias in your observational study, the bias is just replicated times the size of the study.
The consistency here between the treatment effects across the various countries, the consistency with the efficacy assessed in randomized clinical trials is really a crux in the quality of the data and how believable the results are. Another key aspect that got us really excited is the fact that only a minute fraction of the data is related to use of empagliflozin.
Most of the data was acquired using other SGLT2, and we still only have results now with empagliflozin, we don't have outcome trial data with the other agents. They are pending, but pending the availability of these trials, the fact that this large study sees a consistent benefit, in terms of heart failure and mortality, of the other agents in the class suggests that this is a class effect.
And likewise, the fact that we're seeing these benefits in a population that is much, much broader than the population of EMPA-REG OUTCOMES is also very, very intriguing, and exciting, and makes us really want to see more data not only from the randomized trials that are upcoming, but also from this study.
Because now, what we would like to see is, see the detailed cardiovascular outcomes in these cohorts, and I know that Mikhail and his colleagues are working very, very actively on preparing these analyses. I think this is going to be exciting. This is the first of a series of landmark papers from a model observational study.
There are many issues with observational studies. This is almost as good as it can ever get, and I want to compliment Mikhail and the consortium that's with him, because this is a tremendous effort, across several countries, on achieving this. I think it's very exciting for our readership and for clinicians around the world.
Dr. Carolyn Lam: I couldn't agree more, and I share your compliments for Mikhail. Perhaps, Mikhail, could you give us a sneak peek at the future and the ongoing work?
Dr. Mikhail Kosiborod: We frequently think of, and I think perhaps mistakenly at times, think of clinical trials and observational real-world data as competing with one another. In many cases, they're really complementary, and I think if you really, kind of, think of interventions that we consider as those gold standards enshrined in clinical guidelines, or something we absolutely should be doing for our patients.
Just to pick one example, statins for secondary prevention after a cardiovascular event, for example, there is data from both sources suggesting that these drugs are highly beneficial, right? So it is very important to have data from both sides, and I think, as Gabriel mentioned, I look at CVD-REAL as a model, in many ways, of how compelling the data from non-randomized, large, real-world observational studies can be when done well.
In terms of a sneak peek for the future, there are many, many things going on. We are carefully examining the outcomes that we are reporting in circulation, including heart failure and all-cause mortality in various subgroups. We are, of course, as Gabriel mentioned, intently looking at other outcomes, including myocardial infarction, stroke, cardiovascular death, and a composite of major adverse cardiac events.
We're also examining some of the diabetes, one could argue, maybe, diabetes-specific outcomes, such as hypoglycemia rates. We, of course, as cardiologists tend to concentrate on cardiovascular outcomes, but it's also important to remember that there are other important outcomes that could be associated benefits.
So these medications may be associated with marked reduction of cardiovascular events, such as death and heart failure, but they may also reduce hypoglycemia rates and, of course, that's important from a quality-of-life standpoint for patients with diabetes, so some of that work is ongoing.
And I would say, importantly, one of the other things that we're hoping to be able to do in the future is to go beyond cardiovascular outcomes, and perhaps blood glucose-specific outcomes, such as hypoglycemia, and start looking at events such as renal disease events, which I think are very important, of course. Interact quite a bit with, I suspect, in many ways, with some of the cardiovascular benefits that we're observing with those agents, both in the clinical trials and, now, in large observational studies.
And that's just the beginning. I mean, I think it's fair to say that, as Gabriel mentioned, a huge amount of work went into putting this together, right? And we're actually not only expanding things from a standpoint of outcomes. We're also expanding things from a standpoint of countries that will be participating in CVD-REAL consortium.
So we're actually planning to add at least two or three more countries from Europe, Middle East, and Asia in the coming months, and more so in the future. And of course, once you have a resource like this, there are additional questions that can be addressed, actually, both with SGLT2 inhibitors as a class, but also with other classes of type 2 diabetes medication. So that's, I think, as much of a sneak peek as I can give you right now. Just definitely promise you that there is a lot more coming.
In addition to ADA, we're going to have abstracts being presented at ESC in August, and also the European Association for the Study of Diabetes meeting in Lisbon, in September, and there's going to be a lot more afterwards as well. So just stay tuned, I would say. This is definitely just the beginning. There's going to be a lot more coming.
Dr. Carolyn Lam: You took the words right out of my mouth. Listeners, stay tuned, and don't forget to tune in next week as well.
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 Youth National University of Singapore. Coming right up, we will be discussing fascinating new data on the prevalence of subclinical coronary artery disease in masters endurance athletes but first, here's your summary of this week's journal. The first paper provides insight into ischemic cellular post conditioning. Now, we know that cardiosphere derived cell therapy has been utilized as a strategy to treat ischemic heart disease and reduce chronic scar burden when administered months after myocardial infarction. In the current study, by first author Dr. de Couto, corresponding authors Dr. Marban and Berman from Cedars-Sinai Heart Institute in Los Angeles, California, the authors used rat and pig models of myocardial infarction to show that exosomes, which are nanosize lipid bi-layer vesicles, actually mediate the cardio protective effects of cardiosphere derived cells when administered after reperfusion of myocardial infarction.
They further show that treatment with either cardiosphere-derived cells or their secreted exosomes reduce infarct size and improved functional recovery. Using RNA sequencing to determine exosome content and alterations in gene expression profiles on macrophages from cardiac tissue or bone marrow, they found that a specific micro RNA species miR 181-B within the exosomes, acted on macrophages and was implicated as a key mediator of the cardio-protective benefits. Thus, this study gives new reason to test the idea that allogeneic cardiosphere-derived cells may be efficacious in preventing scar formation and improving cardiac function, when given in the earlier reperfusion period. The data further support that exosomal transfer of miR 181-B from these cardiospheric-derived cells into macrophages underlie the cardio-protective effects after reperfusion.
The next study describes a potential new therapeutic strategy for vasoproliferative retinopathy which can underlie age-related macular degeneration, the leading cause of blindness in industrialized nations. First author, Dr. Bucher, corresponding authors Dr. Yea and Friedlander, from the Scripps Research Institute in La Jolla, California used rodent models of retinal neo-vascular disease to show that Tspan-12, beta-catenin signaling plays an important role in the development of vasoproliferative retinopathy. As background, Tspan-12 belongs to the Tetraspanin family, which mainly includes cell surface proteins characterized by four transmembrane domains and two extra cellular domains.
Members of the Tspan family participate in a diverse cellular processes and act as signaling platforms by forming Tspan-enriched micro domains in plasma membranes. The authors went further to use a novel phage display combinatorial antibody library to specifically design a Tspan-12 blocking antibody which is capable of interacting with human and mouse Tspan-12 antigen. They then provided strong evidence that the Tspan-12 blocking antibody prevents developmental pathological neovascularization in murine models of vasoproliferative retinopathy. Combination therapy with a known anti-VEGF agent demonstrated significant synergy supporting the potential clinical use of the anti-Tspan-12 antibody as a novel angiomodulatory agent.
The next study addresses the paradox that blacks have higher coronary heart disease mortality compared with whites, but non-fatal coronary heart disease risks may be lower for black versus white men. To address this paradox, first author Dr. Colantonio, corresponding author, Dr. Safford and colleagues from Weill Cornell Medical College in New York, compared fatal and non-fatal coronary heart disease incidents and case fatality among blacks and whites in three studies. The Atherosclerosis Risk in Communities or ARIC study, cardiovascular health study, and reasons for geographic and racial differences in stroke or regards study, all stratified by gender.
They found that the incidents of non-fatal coronary heart disease was consistently lower among black versus white men, although black men have a higher burden of unfavorable social determinants of health and cardiovascular risk factors and a higher fatal coronary heart disease incidents. Following adjustment for social determinants of health and cardiovascular risk factors, black men and women had a similar risk of fatal coronary heart disease, but a lower risk of non-fatal coronary heart disease compared with white men and women respectively. Finally, blacks with incident coronary heart disease had a higher case fatality compared with whites and the difference remained similar after adjustment for social determinants of health and risk factors. Thus, there is an apparent lower risk for non-fatal coronary heart disease among black versus white men and women, which needs to be further studied. Blacks have a higher risk of their initial coronary heart disease event being fatal compared with whites, highlighting the need for reinforcing primary prevention in this population.
The next study provides important information on the burden of re-admissions after hospitalization for critical limb ischemia. First author, Dr. Kolte, corresponding Dr. Aronow and colleagues from Brown University in Providence, Rhode Island, used the 2013/2014 nationwide re-admissions databases to identify almost 61,0000 hospitalizations for primary diagnosis of critical limb ischemia during which patients underwent endovascular or surgical therapy. They found a 30-day re-admission rate of 20.4%. Independent predictors of 30-day re-admission included presentation with an ulcer or gangrene, age above 65 years, females, large hospital size teaching hospital status, known coronary artery disease, heart failure, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis. Interestingly, mode of revascularization was not independently associated with re-admissions.
The most common reasons for re-admissions included infections, persistent or recurrent manifestations of peripheral artery disease, cardiac conditions, procedural complications, and endocrine issues. Finally, the costs of 30-day re-admissions for critical limb ischemia during the study period were 624 million U.S. dollars. Thus, this study provide knowledge of independent predictors and reasons for re-admissions that will help clinicians and hospitals to identify, develop, and implement strategies to reduce re-hospitalizations and healthcare costs associated with critical limb ischemia.
The final study tells us that there may be a direct relationship between life-long exercise volume, and coronary atherosclerosis in athletes. Dr. Aengevaeren and colleagues from Radboud University Medical Center in the Netherlands, studied 284 middle-aged men engaged in competitive or recreational leisure supports, using contrast enhanced CT to assess coronary artery calcification and plaque characteristics.
Participants also reported life-long exercise history patterns and exercise volumes were quantified as metabolic equivalent of task or met minutes per week. They found that participants in the more than 2,000 met minutes per week group had a higher prevalence of coronary artery calcification and atherosclerotic plaques. The most active group did, however, have a more benign composition of plaques with fewer mixed plaques and more often, only calcified plaques. These observations may explain the increased longevity typical of endurance athletes, despite the presence of more coronary atherosclerotic plaques in the most active participants. Well, that wraps it up for your summaries. Now for our featured discussion.
Our current physical activity guidelines recommend 150 minutes of moderate exercise and that's supposed to protect against cardiovascular disease and increase longevity. However, what do we really know about the dose response relationships and the effects of exercises doses that exceed current recommendations. Well, recent data, including a paper in this week's issue, suggests that long-term, high volume endurance exercise may actually accelerate, rather than reduce coronary atherosclerosis. To discuss this exciting paper, we have the corresponding author, Dr. Sanjay Sharma, from Saint George's University of London, as well as editor of digital strategies and associate editor at UT Southwestern who handled this paper, Dr. Amit Khera. Welcome, gentleman.
Dr. Amit Khera: Good morning.
Dr. Sanjay Sharma: Thanks for having us.
Dr. Carolyn Lam: First, Sanjay, oh yikes! As a runner and as a person who strongly advocates regular exercise, please, please, put us out of our misery. Tell us what you've found and what you think are the possible explanations.
Dr. Sanjay Sharma: I'm a runner too, and I don't think anyone would argue that the benefits of exercise on the cardiovascular system are unrivaled. People who exercise regularly do reduce their risk of an adverse event from a heart attack by 50% when they're in their 5th and 6th decade and they live around three years longer than people who don't exercise at all. Now as you rightly point out, the current recommendation suggests 2 1/2 hours of moderate physical activity per week and by that I would mean, at maximum, a 15-minute mile pace. Clearly, our endurance athletes exercise much, much more than that. They exercise 10 to 20 times greater than that volume and in parallel with this has been the emergence of a large number of people participating in marathon runs. For example, in Europe, there were two million marathon runs per annum and that figure's going up by about 5%.
Coinciding with this burgeoning increase in endurance exercise, is the development of several reports that show that exercise may cause release of biomarkers of cardiac damage. Animal experiments have shown that exercise may cause scaring in the heart and human studies have shown that some marathon runners have more calcium in their coronary arteries compared to relatively sedentary individuals. One of the problems with these studies is firstly, the biomarker release is very transient, it goes away after about two days. Animal experiments cannot really reflect what goes on in human beings because they're artificial and animals are forced to exercise with electrical shocks, et cetera. The studies in human beings have been conducted in runners who have been former smokers.
In fact, the most commonly reported study or cited study, contained individuals of whom 50% had risk factors for coronary artery disease. What we decided to do was to do a clean study, where we took 150 individuals who had none of the risk factors for coronary artery disease and 92 relatively sedentary controls who exercise within the normal limits. We have to exclude a lot of people because we have to exclude anyone that had ever smoked, anyone that had high blood pressure, high cholesterol, or a family history of permanent cardiac disease. We actually subjected them to all sorts of investigations and we found that a small number of male runners had more calcium in their arteries compared to sedentary individuals.
Dr. Carolyn Lam: Wow! Please tell us that there's something good that you can say about that. First of all, I really want to congratulate you on this most elegant study and Amit, I'm sure you put in what the editor's thought but we're just so proud to be publishing such a high quality study here. Amit, is there anything you might want to add of what the editors thought?
Dr. Amit Khera: Sure, I first want to congratulate Dr. Sharma and his colleagues. This was a carefully done study and we've talked a bit about the coronary calcium but there was extensive investigation and I really think this advanced the field. Sounds like all three of us are runners, so this hit home to all of us and as he mentioned, this has been a very hot area and one that's been very controversial. I think here what we have is a manuscript that really helped move the field forward, helped us better understand the biology. The one thing I'll comment on that we found very interesting was the observation that those that were the masters athletes actually had more of a calcific phenotype, where as those that were not looked like a soft plaque phenotype, if you will. Actually, if you look, we have a companion article in circulation looking at sort of dose dependent finding a similar finding. My question, now turned back to Dr. Sharma is, what do you counsel your patients now with these findings? Has it changed now how you recommend exercise or your thoughts on how you counsel them?
Dr. Sanjay Sharma: Well, we examined 152 different athletes, or masters athletes in 92 controls. These athletes were aged 56 years old, who'd been training for 36 years and had immediate marathon number of 13. Now, what we've found in these individuals is that a small number of males, that's 11%, had a coronary artery calcium score of more than 300. Some men had more plaques than sedentary individuals and these plaques were distributed throughout all three coronary arteries. When we looked at the pathology of the plaques very carefully, we found that the plaques in the athletes were calcified. Indeed, 72% of athletes had very calcified plaques. We know that such calcified plaques are stable, they're less likely to fissure and are less likely to cause coronary thrombosis and therefore, acute myocardial infarction.
This led us to propose that although exercise may be causing some atherosclerosis through the sheering and stressful source during exercise of the bending and kicking of vessels, we believe that the repair mechanism here is different to that seen in people who smoke or who have high cholesterol or high blood pressure. The repair mechanism results in very calcified and stable plaques in athletes and this may actually mitigate the risk of acute myocardial infarction and may explain why the number of people who actually suffer an acute myocardial infarction during a marathon run is very small, around 1 in 50,000, and no different to the number of people who suffer a sudden cardiac arrest playing football or basketball, due to congenital or inherited abnormalities of the heart.
Dr. Carolyn Lam: Sanjay, those are just such important points to keep in mind as we read your paper. It did strike me as a significant minority, actually, of these long term endurance athletes who develop significant coronary artery calcification and it could potentially be a clinically benign phenotype. At the end of the day, this is a cross-sectional study, isn't it? We can't, I suppose, extrapolate into the clinical events. What are your postulations there and what could be future work that you're planning?
Dr. Sanjay Sharma: Well, you make a good point. This is a cross-sectional study and the demonstration of an increased cardiopathy calcium does not necessarily reflect future cardiac events. We have followed these individuals up for the last 18 months. These masters athletes and have not demonstrated a single one to develop an acute event that would last 18 months. We really don't know what the meaning of these plaques is. I think the only thing to do now, being we've got the liberty of having so many people that do marathon runs and so many people who've been exercising for three or four decades, we can actually do a prolonged follow up study, so the answers will be a while coming. To follow these people up with high calcium, just to see whether they do go on to develop adverse events in the future. All our study has shown is that some male athletes who've exercised lifelong get an increasing number of plaques. These plaques appear to be calcified and stable and the long term effects of such plaques is unknown.
Dr. Carolyn Lam: Sanjay, just circling back to Amit's question earlier and maybe Amit, you could take it to after this. What do we recommend to our athletes who come in and have a high coronary artery calcium score? Do we tell them to stop?
Dr. Sanjay Sharma: I certainly wouldn't and I'm much less worried about an increase coronary calcium score in a lifelong runner or cyclist than I was 10 years ago. It appears that these plaques are there in some individuals, they are calcified, they appear stable. Given the fact that we know that coronary events during marathon running in experienced runners are very, very low indeed. I don't think I would be keen to do anything about it, not even consider stacking therapy based on our findings at present. As I said before, we do need longitudinal follow up to really identify all ascertain the precise implications of these plaques in masters athletes.
Dr. Carolyn Lam: Right, and this is again recognizing that your particular population was free of traditional cardiovascular disease. Of course, if we were to find these risk factors in our athletes, we would most certainly treat the traditional risk factors. Amit, anything to add there?
Dr. Amit Khera: I think that was an excellent point about his approach to counseling patients. I will mention on the editorial staff, we felt like this was such an interesting area with emerging data and fast moving, that it was warranting of an editorial. I recommend people to look at the one by Aaron Baggish and Ben Levine. I think they had a very similar conclusion and that was that they don't necessarily proscribe exercise in patients with high coronary calcium but rather, focus on risk mitigation strategy, focusing on risk factors as we normally would do. I think the conclusions are similar and the thoughts in that editorial were insightful, pairing both of these papers and helping us make sense out of this really evolving field.
Dr. Carolyn Lam: Well, thank you Sanjay and Amit for this wonderful discussion. I learned so much as I'm sure our listeners did. You've been listening to Circulation On The Run. Tune in next week.
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. What is the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy? We will be discussing new data in this area in just a moment, following these summaries.
The first paper describes the effect of long-term metformin and lifestyle measures on coronary artery calcium. This is a paper from Dr. Goldberg of George Washington University Biostatistics Center and colleagues of the Diabetes Prevention Program Research Group. The Diabetes Prevention Program and its outcome study is a long-term intervention study in subjects with prediabetes, which showed reduced diabetes risk with lifestyle and metformin compared to placebo.
In the current study, the authors looked at subclinical atherosclerosis, which was assessed in 2,029 participants using coronary artery calcium measurements after 14 years of average follow-up. They found that men but not women with prediabetes treated with metformin for an average duration of 14 years had lower coronary calcium scores than their placebo counterparts. No difference in coronary calcium scores was observed in the group receiving a lifestyle intervention as compared to the placebo group.
These findings provide the first evidence that metformin may protect against coronary atherosclerosis in men with prediabetes, although demonstration that metformin reduces cardiovascular disease events in these subjects is still needed before firm therapeutic implications of these findings can be made. The reason for an absence of an effect in women is unclear and deserves further study.
The next study provides insights on the physiology of angina from invasive catheter laboratory measurements during exercise. Dr. Asrress of Royal North Shore Hospital in Sydney, Australia, and colleagues, studied 40 patients with exertional angina and coronary artery disease who underwent cardiac catheterization via radial axis and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual GTN was administered to half the patients and all patients continued to exercise for two minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity, and central aortic pressure were recorded using sensor wires.
Using this novel invasive approach, the authors showed that administration of GTN ameliorated angina by reducing myocardial oxygen demand as well as increasing supply with a key component being the reversal of exercise-induced coronary lesion vasoconstriction. This was evidenced by the fact that there was a relationship between the diastolic velocity pressure gradient with significant increase in relative stenosis severity. In keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilation of normal segments, with trends towards reversal with GTN.
Thus, this study describes the development of a paradigm where patients with coronary artery disease can exercise while simultaneously having coronary and central aortic hemodynamics measured invasively, and has shown that this provides a unique opportunity to study mechanisms underlying the physiology of angina. In treating patients with exercise-induced angina, the results highlight the importance of after-load reduction and the use of agents that reduce arterial wave reflection and promote coronary artery vasodilation.
The next study provides mechanistic insights into reverse cholesterol transport, where excess cholesterol is removed from macrophage-derived foam cells in atherosclerotic plaques. It suggests that melanocortin receptor-1, or MC1-R, may play a role. As background, the melanocortin system, consisting of melanocyte-stimulating hormones and their receptors, regulate a variety of physiological functions, ranging from skin pigmentation to centrally-mediated energy balance control. At the cellular level, the biological actions are mediated by G protein-coupled melanocortin receptors, such as MC1-R. MC1-R not only affects melanogenesis in the skin but also has immunomodulatory effects through its wide expression in the cells of the immune system.
In the current study from Dr. Rinne of University of Turku in Finland, and colleagues, human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was further assessed in apolipoprotein E deficient mice. Their findings identified a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R conferred protection against macrophage foam cell formation through a dual mechanism. It prevented cholesterol uptake while it concomitantly promoted reverse cholesterol transport by increasing the expression of ATP-binding cassette transporters, ABCA1 and ABCG1.
Thus, the identification of MC1-R in lesional macrophages, demonstration of its role in regulating reverse cholesterol transport, combined with its established anti-inflammatory effects, suggests that MC1-R could be a novel new therapeutic target for preventing atherosclerosis.
The next study suggests that obesity-related heart failure with preserved ejection fraction, or HFpEF, is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments. First author, Dr. Obokata, corresponding author, Dr. Borlaug, and colleagues from Mayo Clinic Rochester and Minnesota studied 99 patients with obese HFpEF with a BMI above 35, with 96 non-obese HFpEF with a BMI less than 30, and 71 non-obese controls without heart failure. All subjects underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.
The authors found that, compared to non-obese HFpEF, obese HFpEF patients displayed greater volume overload, more biventricular remodeling, greater right ventricular dysfunction, worse exercise capacity, more impaired pulmonary vasodilation, and more profound hemodynamic arrangements, despite a lower NT-proBNP level. Obese HFpEF patients displayed other important contributors to high left ventricular filling pressures, including greater dependence on plasma volume expansion, increased pericardial restraint, and enhanced ventricular interaction, which was exaggerated as pulmonary pressure load increased.
These data provide compelling evidence that patients with the obese HFpEF phenotype have real heart failure and display several pathophysiological mechanisms that differ from non-obese patients with HFpEF. These and other issues are discussed in an accompanying editorial by Dr. Dalane Kitzman and myself. We hope you enjoy it.
The final study identifies a novel long noncoding RNA that regulates angiogenesis. As background, although we know that the mammalian genome is pervasively transcribed, a large proportion of the transcripts do not encode a protein, and are thus regarded as noncoding RNAs. Based on their length, they can be divided into small or long noncoding RNAs, long being described as more than 200 nucleotides. Although their function is not fully understood, long noncoding RNAs have been increasingly reported to mediate the expression of other genes, affect the organization of the nucleus, and modify other RNAs.
In the current study by first author, Dr. Leisegang, corresponding author, Dr. Brandes, and colleagues of Goethe University in Frankfurt, Germany, epigenetically controlled long noncoding RNAs in human umbilical vein endothelial cells were searched by axon array analysis following knockdown of the histone demethylase JARID1B. The authors discovered a novel noncoding RNA named MANTIS to be strongly upregulated. MANTIS is located in the antisense strand of an intronic region of the gene for annexin A4, calcium- and phospholipid-binding protein. MANTIS is a nuclear long noncoding RNA that is enriched in endothelial cells but also expressed in other cell types. Reducing MANTIS levels led to impaired endothelial sprouting, tube formation, attenuated endothelial migration, and inhibition of the alignment of endothelial cells in response to shear stress.
Brahma-like gene 1, or BRG-1, was identified as a direct interaction partner of MANTIS, implying a role of MANTIS in the formation of the switch/sucrose non-fermentable chromatin remodeling complex. MANTIS binding to BRG-1 was shown to stabilize the BRG-1 interaction, hence by inducing an open chromatin conformation, MANTIS was proposed to maintain the endothelial angiogenic potential. The implications of these findings are discussed in an accompanying editorial by Dr. Zampetaki and Mayr from Kings College London.
That brings us to the end of our summaries. Now for our feature discussion.
Today, we are going to be discussing the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. To discuss this, I have the first and corresponding author of our feature paper, Dr. Heather Boyd, from Statens Serum Institut in Copenhagen, and our familiar Dr. Sharon Reimold, content editor for special populations from UT Southwestern. Welcome, Heather and Sharon.
Dr. Heather Boyd: Thank you.
Dr. Sharon Reimold: Thank you.
Dr. Carolyn Lam: Heather, it's a topic that I can't say I'm very familiar with, association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. Could you start by sharing why would we think there would be a link? What was the hypothesis you were testing?
Dr. Heather Boyd: A couple years ago, there was a paper published in the European Heart Journal that reported evidence of angiogenic imbalance in women with fetuses with major congenital heart defects, so women who were pregnant with babies that had heart defects, and then in fetuses that were terminated because of this kind of defect. My research group focuses a lot of attention on preeclampsia. In the last decade or so, angiogenic imbalance in preeclampsia has been a really hot topic. Women with preeclampsia, particularly women with early-onset preeclampsia, have big angiogenic imbalances. When we saw the European Heart Journal paper, we immediately thought, "What's the connection between preeclampsia and heart defects in the offspring?"
Dr. Carolyn Lam: Oh!
Dr. Heather Boyd: Exactly. That was our entry point to it, was the term "angiogenic imbalance" in that paper sort of was a flag for us. It wasn't a completely new idea, but we in Denmark have one big advantage when considering research questions that involve either rare exposures and/or rare outcomes, and that's our National Health Registry. We have the ability to assemble these huge cohorts and study conditions like heart defects with good power, so we decided just to go for it.
Dr. Carolyn Lam: That makes a lot of sense now. Please, tell us what you did and what you found.
Dr. Heather Boyd: The first thing we did was look at the association between carrying a baby with a heart defect and then whether the mom had preeclampsia later in the same pregnancy. We had information on almost 2 million pregnancies for this part of the study. We found that women carrying a baby with a heart defect were seven times as likely as women with structurally normal babies to develop early preterm preeclampsia. We defined that as preeclampsia where the baby has to be delivered before 34 weeks, so the really severe form of preeclampsia. Then, women carrying a baby with a heart defect were almost three times as likely to develop late preterm preeclampsia as well. That's where they managed to carry it until 34 weeks but it has to be delivered some time before 37 weeks.
These findings were similar to those of other studies, but we were able to go a step further and look at individual heart defect subtypes. What we found there waws that these strong associations were similar across defect categories. Then we decided to see if we could shed any light on the origin of the problem, whether it was coming from the mom's side or the baby's side. To do this, we looked at women with at least two pregnancies in our study period to see whether preeclampsia in one pregnancy had any bearing on the chance of having a baby with a heart defect in another pregnancy or vice versa.
This part of the study included 700,000 women. We found very similar findings. We found that women with early preterm preeclampsia in one pregnancy had eight times the risk of having a baby with a heart defect in a subsequent pregnancy. Late-term preeclampsia in one pregnancy was associated with almost three times the risk of offspring heart defects in later pregnancies. Then, we found that it worked the other way around too. Women who had a baby with a heart defect were twice as likely to have preterm preeclampsia in subsequent pregnancies.
Those results were really, really exciting, because whatever mechanisms underlie the associations between preterm preeclampsia in moms and heart defects in the babies, they operate across pregnancies. Therefore, that pointed towards something maternal in origin.
Dr. Carolyn Lam: That is so fascinating. Sharon, please, share some of the thoughts, your own as well as those of the editors when we saw this paper.
Dr. Sharon Reimold: I think that there's a growing data about the links between hypertensive disorders of pregnancy and preeclampsia with subsequent abnormal maternal outcome. But this paper, I think, has implications for how we look at moms who are going to have offspring with congenital heart defects as well as those with preeclampsia. For instance, I would look at a patient now that has preeclampsia, especially in more than one pregnancy, to identify that they may be at risk to have offspring with congenital defects in the future if they have additional children. But the mom is also at risk based on other data for developing other cardiovascular risk factors and disease as she gets older. It was really the link going back and forth with the hypertensive disorders and the congenital defects that we found the most interesting.
Dr. Carolyn Lam: That struck me too, especially when you can look at multiple pregnancies and outcomes. That's amazing. You know what, Heather, could you share a little bit about what it's like working with these huge Danish databases? I think there must be a lot more than meets the eye.
Dr. Heather Boyd: It's an interesting question, because I'm a Canadian and I was trained in the US. I did my PhD in epidemiology at Emery, and then I moved to Copenhagen. When I first got here, I was absolutely floored at the possibility of doing studies with millions of women in them. It opens some amazing possibilities, like I said earlier, for certain outcomes and certain exposures. You just need to have a question where the information you want is registered.
Dr. Carolyn Lam: Yeah. But I think what I also want to put across is, having worked with big databases, and certainly not as big as that one, it's actually a lot of work. People might think, "Oh, it's just all sitting there." But, for example, how long did it take you to come to these observations and conclusions?
Dr. Heather Boyd: I have a fabulous statistician. I think she's the second author there, Saima Basit. She spends a lot of her time pulling together data from different registers. But yes, you're right. The data don't always just mesh nicely. The statisticians we have working with us are real pros at this sort of data slinging.
Dr. Carolyn Lam: Could I just pose one last question to both of you. What do you think are the remaining gaps?
Dr. Sharon Reimold: I think that this is a clinical link. Then, going back to figure more about what's going on biologically to set up this difference? Because right now there's really no intervention that's going to make a difference, it's just a risk going forward. This is sort of like medicine done backwards, that there's this association and now we need to figure out exactly why.
Dr. Heather Boyd: I can piggyback on what Sharon said a little bit, because I think one of the things we need to remember is that not all women with preeclampsia have babies with heart defects. Not by a long shot. What we need to do now is to figure out what distinguishes the women who do get this double whammy from the vast majority who don't.
One of the things that Denmark does really nicely is that there are large bio banks. One of the things we want to do is go back to bank first trimester maternal blood samples and see if we can identify biomarkers that are unique to the women with both preterm preeclampsia and babies with heart defects. That's one of the things we're thinking about to address this gap. Because, as Sharon says, we've got to figure out what the mechanism is.
The other thing we want to do is to see whether the association between preeclampsia and heart defects extends, for example, to other things, to cardiac functional deficits, for example, because it's probably not just severe structural defects. If there's an association, it's probably on a continuum. Are babies born to preeclamptic moms, do their cardiac outputs differ? Do their electrical parameters differ? Do they just have different hearts?
We're really lucky because right now the Copenhagen Baby Heart Study is offering to scan the hearts of all infants born at one of the three major university hospitals in the Copenhagen area. We're about to have echocardiography data on 30,000 newborn hearts to help us look at this. I'm really excited about that possibility.
Dr. Carolyn Lam: I've learnt so much from this conversation. I'm sure the listeners will agree with me. Thank you both very, very much.