Cynthia St. Hilaire, PhD & Milka Koupenova, PhD

April 2020 CircRes

April 2020 CircRes

  This month on Episode 111 of the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from the March 27 issue of Circulation Research and talks with Dr. Matthias Nahrendorf  and Dr. Maximilian Schloss about their article Modifiable Cardiovascular Risk, Hematopoiesis and Innate Immunity.   Article highlights:   Liu et al. Genetics of Transposition of the Great Arteries   Park et al. Mild Lipid Abnormalities and ASCVD in the Young Yan, et al. Gut Flora Adjusts Blood Pressure By Corticosterone Transcript Cindy St. Hilaire:              Hello and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh. Today, I'm going to share with you articles selected from the March 27th issue of Circulation Research, as well as give you a hint of the cutting-edge ideas in the Compendium on atherosclerosis. We'll also have a discussion with Dr Maximilian Schloss and Matthias Nahrendorf about their article On Modifiable Cardiovascular Risk, Hematopoiesis And Innate Immunity. So, first the highlights.                                            The first article I'm sharing with you is titled Exome-Based Case Control Analysis Highlights the Pathogenic Role of Ciliary genes and Transposition of the Great Arteries Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries. The first authors are Xuanyu Liu and Wen Chen and the corresponding author is Zhou Zhou from Peking Union Medical College in Beijing, China. In normal healthy hearts, the aorta develops from the left ventricle and the pulmonary arteries from the right ventricle, but in the common congenital heart malformation called transposition of the great arteries or TGA, the plumbing of these two major vessels is switched. Thus, the pulmonary arteries arise from the left ventricle and the aorta from the right.                                            This is a life-threatening condition, requires surgery in the earliest days of life and currently, the genetic etiology of this congenital disease is largely unknown. To identify the genetic drivers of transposition of the great arteries, the authors of this study performed whole exome sequencing of 249 TGA patients and, in 66 cases, they were actually able to do exome sequencing on their parents as well. The analysis identified 82 candidate genes in which the allele variant or mutation that was found in TGA patients was predicted to alter protein function.                                            Interestingly, a quarter of these mutations or variants were found to be in genes that are involved in cilia function. So, the cilium is an organelle that's found on all eukaryotic cells and is in the shape of a slender protuberance that projects from the much larger cell body. Recently, cilia have been identified as playing a central role in the pathogenesis of congenital heart diseases, and it has been suggested that congenital heart disease may be a new class of ciliopathy. Transposition of the great arteries has been hypothesized to arise from disturbances in the left right patterning during embryo development, and cilia are required cellular organelles and they are essential for left-right axis determination in early development. These findings add to the growing body of evidence that has identified a role of cilia genes and congenital heart disease and may lead to future prenatal diagnostic screenings.                                            The next article I want to highlight is titled Mildly Abnormal Lipid Levels, but Not High Lipid Variability, Are Associated with Increased Risk of Myocardial Infarction and Stroke in ‘Statin-Naive’ Young Population: A Nationwide Cohort Study. The first author is Jun-Bean Park and the corresponding author is Hyung-Kwan Kim from Seoul National University Hospital in Seoul in the Republic of Korea. High levels of lipids in the blood increase a person's risk of cardiovascular disease, and evidence suggests that this risk builds over lifetime. However, in young adults, and in this case, young adult means any individual between 20 and 39 years of age. In young adults, relatively little evidence is available that identifies individuals at high risk for atherosclerotic cardiovascular diseases, except for very high LDLC levels.                                            Variability in lipid levels has recently emerged as a predictor of adverse clinical outcomes and lipid level variability may be causally linked with the atherosclerotic cardiovascular disease risk. This is because theoretically, high lipid levels can induce fluctuations in the atherosclerotic plaque composition. These fluctuations result in plaque instability and rupture and ultimately, plaque related clinical events, such as myocardial infarction. However, high lipid level variability may merely reflect other risk factors or confounders for atherosclerotic cardiovascular diseases, including unhealthy lifestyle and unrecognized comorbidities. This study therefore examined health data of close to two million Korean individuals aged 20 to 39. None of them had ever been treated for high cholesterol with statins nor had any of them suffered any myocardial infarctions or stroke.                                            Over a four-year period, the subjects had undergone at least three lipid measurements as part of their general health assessments and then they were followed for a further four years or until death. The data showed that high baseline lipid levels was linked with an increased risk of adverse cardiovascular events, and in particular, myocardial infarctions. They also found that individuals who exhibited high lipid variability, so sometimes getting high readings, sometimes getting low readings, these individuals who exhibited high variability and lipid level measurements were not at any greater risk of such cardiovascular events. While such up and downs have previously been linked to cardiovascular disease, this study argues that perhaps statin use in other cohorts may have contributed to the variability and thus confounded research interpretation, an issue that was specifically avoided in this study. Together the results indicate that lipid in young adults can indeed indicate future cardiovascular risk and therefore suggest lipid-lowering strategies could be beneficial for this age group.                                            The next article I want to share with you is titled Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension. The first author is Xuefang Yan and the corresponding authors are Zhe Wang and Qunye Zhang from Shandong University in China. Hypertension is highly prevalent in the adult population all over the world and it is a major risk factor for heart disease and stroke. A high salt diet can help to drive hypertension pathogenesis, but complete details about the mechanisms by which high salt intake shapes vascular pathology are lacking.                                            Recent studies show that fecal transfer from salt hypertensive to salt normotensive animals can lead to hypertension in the recipients, and this suggests that perhaps gut flora may play a role in hypertension. In the article by Yan and colleagues, they show that rats on a high salt diet have altered gut flora profiles and in particular that levels of the bacterium, Bacteroides fragilis, was reduced. Analysis of intestinal metabolites and substrates in high salt diet fed rats also showed that levels of arachidonic acid, which is produced by this bacterium, were low and levels of the stress hormone, corticosterone, which regulates blood pressure, were elevated.                                            The team went on to show that supernatants from this bacterial culture could prevent corticosterone production in the intestinal tissue of high salt fed mice as could direct treatment with arachidonic acid. Moreover, both B. fragilis and arachidonic acid were found to be lower in the feces of humans with hypertension compared to that of healthy controls. The results suggest B. fragilis and arachidonic acid normally curb corticosterone production and could therefore be novel targets for hypertension treatment strategies.                                            The last thing I want to mention before we switch to our interview is the Circulation Research Compendium on Atherosclerosis. The last compendium on this topic was back in 2016 and this new compendium provides the most cutting-edge ideas in the field. The topics highlighted in this compendium are polygenic scores to assess atherosclerotic risk, clinical perspectives, and basic implications, epigenetic reader proteins and cardiovascular transcriptional programs, sex as a biological variable in atherosclerosis, neutrophil extracellular traps in cardiovascular diseases, CD31 as a therapeutic target in athero, interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease, non-coding RNAs in vascular diseases, intracellular aspects of macrophage immunometabolism in atherosclerosis, single cell RNA sequencing in atherosclerosis, vaccination strategies and immune modulation in atherosclerosis and we have an update from the group leading the One Brave Idea. Please check out this compendium.                                            All right. So, now we're going to switch over to our interview portion of the podcast. I have with me today Dr. Matthias Nahrendorf, who is a professor at the Center of Systems Biology at Massachusetts General Hospital Research Institute and Harvard Medical School and his research fellow, Dr. Maximilian Schloss. Today, we're going to be discussing the article Modifiable Cardiovascular Risk, Hematopoiesis, Innate Immunity, which is part of our Compendium on Atherosclerosis. Circulation Research puts together two to three compendiums annually and this current one is the Compendium on Atherosclerosis. We will have two additional compendiums planned for 2020. One on Obesity, Metabolic Syndrome and Cardiovascular Disease and that should come out in late May and another on Atrial Fibrillation scheduled for June. So stay tuned.                                            So, thank you very much for being with me here today, Matthias and Maximilian. Matthias Nahrendorf:    Thanks for having us. Maximilian Schloss:        Thanks for having us. Cindy St. Hilaire:              So, I really enjoyed this review article. I actually learned a lot. I also really liked your cartoons at the end, so maybe we can talk about those a little bit later, but what it's on is essentially the role of inflammation and cardiovascular disease and years of study, which have recently culminated in the completion of the CANTOS trial, have showed us that reducing inflammation can help reduce cardiovascular events. When we look at the factors that we know drive cardiovascular disease, it's things like bad diet choices, lack of exercise, stress, and inadequate or disrupted sleep and in this article you make the more nuanced argument that these modifiable factors are in fact influenced by the innate immunity. So, before we dig too deep into what you are really discussing in this article, could you maybe give us a brief introduction to the role of innate immunity and cardiovascular disease initiation and progression? Matthias Nahrendorf:    Sure. Yeah. So, I think one very instructive experiment that had been done by more than one lab actually almost two decades ago, is stopping innate immune cells from migrating to atherosclerotic plaque by deleting the chemokine MCP-1 or the chemokine receptor CCR2 in mice that have a propensity to develop atherosclerosis. What became apparent is that these mice, despite having very high blood cholesterol levels, they don't really develop atherosclerosis. This really led the whole field now almost 20 years ago, to the insight that it's not only the hypercholesterolemia, it's also the immune system that contributes to the disease. So, innate immune cells, most numerous neutrophils and monocytes then in tissue also macrophages and they're meant to defend us against infections and they support healing. In this particular setting, they are probably doing more harm than good because they promote inflammation in areas where inflammation shouldn't be i.e., in the vessel wall. Maximilian Schloss:        Yeah, I would add that what Matthias said is that basically it's all about a balance between necessary inflammation and too much inflammation. If we take, for instance, myocardial infarction as an example, we need a certain amount of inflammation, local inflammation. We need a recruitment of innate immune cells like neutrophils and monocytes and eventually macrophages, to do their job. For instance, phagocytizing a dying cardiomyocytes or inducing fibrosis. So in this example, we need inflammation, but what we see in different models where we can manipulate inflammation being at reducing or increasing inflammation, we can see that if we do either/or then wound healing and scar formation is impaired. I think that's all we are interested in studying not only the mechanisms, how inflammation can be increased or decreased, but also what is actually the perfect balance in view also of finding ways of improving outcomes in cardiovascular patients. Cindy St. Hilaire:              One of the things in my research, so I focus on cardiovascular calcification, which is very hard to do in a mouse. They don't like to calcify similarly like they don't like to make plaque without a proper genetic background. Are there aspects of the mouse versus the human innate immune system that are very different? I mean I know specific receptors are slightly different, but in general, are they matched up pretty well or is there things that are quite different about them? Matthias Nahrendorf:    I think the answer is both and there are very important parallels and then there are very important differences. So, one important difference is just if you look at sheer numbers and the contribution of immune cells in the blood and, possibly also in the plaque, can be quite different. So, recent studies that use unbiased profiling in human plaques, for instance, say that there's quite a lot of lymphocytes and we still have to understand whether this is due to the retrieval or if it says species difference or the situation, but I think there are important differences. On the other hand, I think that it really make sense to study mice because a lot of the important discoveries about the immune system in the setting have translated to humans. Cindy St. Hilaire:              Like the IL-1 beta story. Matthias Nahrendorf:    That's right. Yeah. Cindy St. Hilaire:              So, actually one of the topics that you started out with in your article is on the role of hematopoiesis in cardiovascular disease. You had a beautiful paper years ago actually with my colleague at University of Pittsburgh, Partha Dutta, who's right down the hall from me, where you guys showed that myocardial infarction itself further exacerbates atherosclerotic plaques mid part through recruiting monocytes from the spleen and mobilizing the immune system. So, I'm wondering, what are the role of the cells when they get mobilized? You talk about these modifiable risk factors of stress and sleep interruption, unhealthy diet. So, how can these risk factors help or promote this mobilization of hematopoietic cells? Matthias Nahrendorf:    Yeah. So, I think that early on when we thought about going down this road and studying these risk factors, even before going there, you realize that the cells that we're interested in, innate immune cells are very short lived. So they live on the order of hours or days. So, they're really produced just in time. That's different to lymphocytes and resident macrophages, which have much longer lifespans. So, this really triggered the insight that we should look at production and release because it's a just in time supply situation. So, what we were wondering is whether in the setting of cardiovascular disease, whether production rates are increased and we now know and a number of labs have studied hematopoiesis in this setting including Fil Swirski, Alan Tall, and some others.                                            We now know that this is really the case, so hematopoiesis increases in chronic atherosclerosis. It increases in acute myocardial infarction and increases in heart failure. What we don't know is what mechanisms actually ramp up blood cell production and we're beginning to understand that the sympathetic nervous system is involved. But I think we only see the tip of the iceberg here. That's why we wanted to study modifiable risk factors, because if you look at others such as high cholesterol, once the insight was gained that lowering cholesterol is helpful, we had the statins which make a huge change. So, we hope to repeat that. Cindy St. Hilaire:              Maximilian, one of the things that you brought up is this balance. The inflammation's a little bit good and then it's a little bit bad or a lot bad. So, where is that good and bad spectrum in terms of mobilizing hematopoiesis or hematopoietic cells? Maximilian Schloss:        Yeah. I think that depends a bit on the disease type or we're talking about a chronic disease or an acute disease? For instance, to stay at the example of myocardial infarction, once cardiomyocytes become ischemic, they will release certain chemokines and cytokines into the blood, which then circulate to the bone marrow and tell the cells that leukocytes need to leave the bone marrow to enter the blood circulation system and then go to the heart to fulfill their very important functions there. Once the cells leave the bone marrow, the bone marrow need to reproduce themselves, then this process starts of hematopoiesis and there we can go back again to the concept of a balance. Of course, there is a certain beneficial physiological need of cell production, but one sees mechanisms so to say maybe go out of control and too many leukocytes are produced and released to the blood.                                            Then that again impairs patient outcome. There are very many papers, clinical papers, who have shown that leukocyte counts after myocardial infarction have a certain U shape relationship with the outcome. That I think is best described that if leukocyte counts are very high, that they actually negatively correlate with the outcome of MI patients. If you look at the bone marrow specifically, there are certain mechanisms, which we know, and what we are more closely looking at now, what are actually the modifier of this process, what are the signals which tell these cells to secrete more hematopoietic factors or quiescence factors? I think that's what also the Review is a little bit about. Cindy St. Hilaire:              Yeah, it's great. So, you were speaking about that kind of U-shaped curve in the release of these cells. Do we know based on some of the other things you spoke about, I guess I'm thinking about like diet or exercise or sleep in contributing to that release after an event like myocardial infarction. Is that known yet or has anyone looked into that? Matthias Nahrendorf:    Yeah. So, I think we're in the very beginning of understanding what's happening acutely. There's more knowledge on the chronic side and this is what we've been working on. Often the things that influenced the chronic situation can be quite different from what happens acutely. So I think in general, we're just beginning to understand what happens in acute myocardial infarction. Well, we know for instance is that exercise doesn't compromise the release and supply of leukocytes that's necessary in acute infection or acute myocardial infarction. So, if the mouse or the individual was exercising before the event, that may reduce overall leukocyte levels, but not to a degree that it's harmful. Cindy St. Hilaire:              Yeah. You can't exercise your way beyond a certain point. Matthias Nahrendorf:    Maybe that's also possible. If you run more than one marathon a day, I'm sure that's… Cindy St. Hilaire:              That will do something else. Matthias Nahrendorf:    Yeah. Cindy St. Hilaire:              Actually, so one of the interesting things that I saw in the article was when you were talking about diet and the role of diet in innate immunity, which is something I really never thought about, and you did bring up things like intermittent fasting. Can you discuss what's known at least scientifically about how that kind of diet timing can impact the immune system and therefore maybe cardiovascular disease? Matthias Nahrendorf:    So, that's a very emerging field. There's very little known about this. I think it's very interesting because very relevant and a lot of people are excited about it, but it's basically, from what I know, it's mostly two papers that were published, I think both in Cell, and they say that intermittent fasting leads to a decline of cells that are in circulation. So, that's a very exciting observation. I think it's similar insight as to discovering that immune cell levels circulate the circadian rhythms, which had been discovered a while ago. So, I think there's definitely an impact and we're just beginning to understand why this is and what regulates it. Cindy St. Hilaire:              Yeah, that segues nicely into the next thing I was wondering about and that is we all know not enough sleep, you get tired, your brain's not focused and stuff like that, but it really does impact the inflammatory system and also cardiovascular disease. So how is sleep involved in this innate immunity cardiovascular disease progression? Matthias Nahrendorf:    The way we approached this was actually thinking about lifestyle factors and their impact on cardiovascular disease. Maybe a decade ago, Fil, who's our middle author on this Review, and I started thinking about lifestyle factors and what struck us is that the association of some of these risk cardiovascular events is really high. So, if you look at sleep or if you look at psychosocial stress, psychosocial stress has an odds ratio of 2.4 for premature myocardial infarction. That is right on scale with all these powerful risk factors that everybody knows about like hypertension, but then what isn't really clear or maybe not entirely, is whether or not these risk factors also act via the innate immune system and that's where we were coming from.                                            I think at this point it's pretty clear that they do have an influence via the immune system. What I think what we've done is we uncovered a couple mechanisms that lead to the activation or dampening of inflammation depending on what you look at, but we don't really understand the broader network. I think there's a lot of work to be done looking into these pathways, which is exciting because I think that we can learn from nature what's dangerous and what's helpful. That this is how humans learn to fly. So, I think that observing what leads to cardiovascular disease, which behaviors are really harmful, will maybe lead us to new ways of mitigating it. Cindy St. Hilaire:              Yeah. Also, I think all of this, it's interesting. We all went after smoking for decades, stop smoking, reduce cardiovascular risk and maybe it's stress and sleep is the next smoking. Matthias Nahrendorf:    Smoking was so successful, right? I mean if you look 50 years back, it was promoted as this healthy thing that you should do. Then people really started to learn how bad it is and now we're at a time where smoking is declining and has declined and we see the results. Lung cancer is really on the decline. So, I think that's a good example how understanding health effects of behavior can be really helpful. Maximilian Schloss:        I think one thing I would like to add is when you ask more general question about innate immunity and when we talk about sleep and sleeping habits, I think what's generally quite interesting to know is that the immune system or these leukocyte numbers in circulation, they oscillate quite dramatically over the course of a day in a healthy human being and also in mouse models. I think one aspect also among others to consider is when we have unhealthy steeping habits, like for example, going to bed late or being a shift worker, drinking for example before going to bed. Then this will also confuse a system on the circadian entrainment, which then subsequently will lead to other problems.                                            I also think another thing is that what you were mentioning with the fasting is what we learned from this similar to these extreme circadian patterns seen when we fast or when a mouse is fasting, then monocyte levels drop into extreme low levels and these monocytes hone back into the bone marrow. I think this is interesting because it shows how dynamic actually a system like innate immune cells actually is. So, it's a very delicate system which responds to sleep disruption, exercise, diets in a very dramatic way. Cindy St. Hilaire:              All right, I'm going to bed early tonight and eating a good dinner. Well, this was a wonderful Review. I really enjoyed reading it. I really do think it's introducing the next targets that we have to go after in modifying cardiovascular disease. Thank you so much for taking the time to speak with me today. Matthias Nahrendorf:    Thank you. Maximilian Schloss:        Thank you so much. Cindy St. Hilaire:              That's it for our highlights from the March 27th and Compendium issue of Circulation Research. Thank you so much for listening. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles was provided by Ruth Williams. Thank you to our guests, Max Schloss and Matthias Nahrendorf. I'm your host, Dr. Cindy St. Hilaire, and this is Discover CircRes, your on the go source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

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