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Circulation on the Run

Aug 13, 2018

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. I'm the one you usually hear chatting about all the papers in your weekly issue, however I am so delighted to be handing over the mic this week to two beloved colleagues, and they are Dr Greg Hundley and Dr Vlad Zaha, who will be taking us through this week's very special issue centered around cardio-oncology. Here they are.

Dr Greg Hundley:             My name is Greg Hundley. I'm a professor at VCU Health Sciences in Richmond, Virginia. We also have Vlad Zaha, who is an assistant professor at University of Texas Southwestern in Dallas.

Dr Vlad Zaha:                     Hello, everybody.

Dr Greg Hundley:             We're going to be talking about the field of cardio-oncology today. As we all know, there have been many advances in the treatment of cancer lately, such that cancer is now becoming in some regards almost a manageable disease or a chronic disease for many individuals. But unfortunately we're seeing the emergence of cardiovascular disease in many patients, so much so that for some cancers, for example breast cancer survivors, cardiovascular events have supplanted the occurrence of cancer-related morbidity and mortality overall.

                                                And so emerging today is this new field of cardio-oncology, which is really a bridging discipline between oncologists and cardiologists that have been focused almost on examining the relationship between chemotherapies, radiation therapies, newer targeted immunologic therapies on the development of cardiovascular events. We as cardiovascular medicine specialists often become involved and then we are consulted to see a patient that might be scheduled to receive a cardiotoxic therapy and what should we do. Maybe they've already received, they're in the middle of the therapy, and we're asked to provide guidance to help the patient move through that therapy successfully.

                                                We're examining survivors now, those that have gone on the therapy and are experiencing increased cardiovascular risk. And then finally, a new emerging field that examines the association of risk factors that seem to be common between cancer and cardiovascular disease.

                                                In this issue of Circulation there are theories, really a miniseries of manuscripts, that are at this interface between cardiovascular and oncologic science and medicine. Following a similar miniseries that we published in 2015, this new block of manuscripts looks on some of the risk factors and mechanisms that may be common between these disorders.

                                                We're going to start today and look at this particular issue and examine the original manuscripts, look at the letters, and then talk a little bit about the review articles. I will walk through some of the introduction and then Vlad Zaha, who is working in cardio-oncology at University of Texas Southwestern, will help interpret for us some of the results and the meaning.

                                                The first study, an original manuscript by Simes et. al that's a subanalysis of the lipid study, and that's the Long-Term Intervention with Pravastatin in Ischemic Disease. The study is going to examine the relationship between D-dimer and the future development of cardiovascular events, but also importantly, cancer-related events. Remember, D-dimer is the degradation product of cross-linked fibrin markers of hypercoagulation and thrombosis. We use this a lot in the emergency department as an identifier of those at risk when we're suspecting one of CVT, pulmonary emboli, etc.

                                                This particular study focused on individuals aged 31 to 75 years that had experienced previously a myocardial infarction. The patients were randomized to receive 40 mg of pravastatin versus a placebo and as part of the study they were followed for six years to identify cardiovascular events. But at the end of the study another examination, an extended review, was enabled so that the patients or participants could be followed for another ten more years and in addition to looking at cardiovascular events, they also looked at all-cause mortality and etiologies of that mortality and specifically cancer.

                                                Vlad, can you tell us a little bit about some of the results and what did D-dimer predict?

Dr Vlad Zaha:                     D-dimer has been considered a rather non-specific product that was first introduced in clinical practice in the 1970s for diagnosis of venous thromboembolisms. It is really interesting in this study that the others identified D-dimer that it is an independent predictor of not only long-term risk of arterial and venous events but all-cause mortality, cardiovascular disease mortality, cancer incidents and mortality and non-cardiovascular disease and non-cancer morality.

                                                It raises interesting questions that are further explored in an editorial in the same issue about what is a low and what is a high D-dimer and also what drives the D-dimer generation in these patients.

Dr Greg Hundley:             And so, it's interesting as well that one is identifying those at risk of cardiovascular disease but also cancer. Do the authors and the editorialists speculate on what that connection may be?

Dr Vlad Zaha:                     The question that is discussed is a common area of etiology that is being more and more discussed nowadays as bridging the domains of heart disease and cancer, and that is information. Information resulting then in alteration of the clotting cascade and hypercoagulability that may then influence downstream both atherosclerosis and cancer processes.

Dr Greg Hundley:             Very good. It's interesting that we're bringing up this whole area of thrombosis because that really follows in the next study, which is a large population cohort assessment that is collected from a Danish registry of 6600 subjects that had experienced a lower extremity arterial, not venous, but arterial thrombosis. In that study what did they uncover, Vlad, in terms of an association with cancer and previously experiencing a lower extremity arterial thrombosis?

Dr Vlad Zaha:                     Another interesting study where the patients uncovered an increased risk of cancer compared to the general population, especially during the first six months before, the investigators identified an association between lower limb arterial thrombosis and increased all-cause mortality in common especially for the smoking-related cancers. This is a very interesting study that brings up the possibility of opportunistic screening, again focused on cancer-related signs and symptoms during the diagnostic workup for lower limb arterial thrombosis.

Dr Greg Hundley:             And so, in these first two studies, both large in number, were identifying issues related to thromboembolic events and cardiovascular disease that also appear related or associated with the future development of cancer. The next couple of studies now switch and address issues related to mechanism. The first is a relatively large complex translational study by Meijers and associates that were examining the relationships between heart and vascular injury and the future development of colon cancer.

                                                In this particular study there were two separate experiments, one group performed in mice and the other performed in analyses of serum and plasma that were collected from human subjects that had experienced colon cancer. In the first series of experiments in mice, the mice were induced myocardial infarction and then they were a strain that were somewhat predisposed to development of colon cancer. What the investigators did is they examined in this strain predisposed to the development of colon cancer, the impact of inducing a myocardial infarction and promoting heart failure versus those that were not and they identified what looks to be some sort of association between an increased risk of development of colon cancer.

                                                Vlad, what were your observations and thoughts in terms of these particular findings and results?

Dr Vlad Zaha:                     This is an interesting paradigm of bringing basic science observations and testing them in a translational fashion. It is a combination of really elegant studies in a mouse model that identifies potential targets of clinical relevance in a model of myocardial infarction. The authors evaluate the fact that such molecules in human cell line models and test the proliferation in that environment. The question is then: How does this reflect in a cohort of patients? That, I think, is really the strength of the study to be able to show that some of the biomarkers identified which events can have an implication at the bedside.

Dr Greg Hundley:             It was really interesting in that in the animals, independent of the hemodynamic compromise, so the hypotension, the reductions in EF, these circulating biomarkers that you identified seemed more associated with the development of colon cancer and then in the human study, examining similar factors were observed in patients with colon cancer and heart failure from the circulating blood of those individuals. Very interesting relationship identified in a very elegant translational study that involved both animal models and human subjects.

                                                The second mechanistic paper is by Li and associates and it's really addressing the issue of anthracycline-related cardiovascular injury. Remember, we still utilize anthracycline chemotherapy today as a fundamental curative component of the therapeutic regimen for lymphoma, leukemia and sarcoma, also in those with triple-negative breast cancer as an important component of that regimen for adjuvant treatment. In this particular study, the investigators were examining the implication of phosphoinositide 3-kinase. That is an important enzymatic regulator of tumorigenesis, but it also when it's expressed is up-regulated during cardiac stress and really impacts adverse remodeling and promotion of heart failure.

                                                In this particular study, the investigators in a mouse model were looking at blocking this particular enzyme and they had some really interesting results pertaining to the development of heart failure and cancer. Vlad, what did you see in this study that looked unique in that perspective?

Dr Vlad Zaha:                     This is an especially interesting study for the perspective of the oncologists who still have to prescribe anthracycline, given the uncertainty of early toxicity that can manifest in some studies in five to ten percent of patients. Also, related to the late toxicity of anthracycline treatment in survivors of childhood cancer. What is particularly interesting about this isoform of phosphoinositide 3-kinase, the gamma isoforms, is that at the same time blocking this enzyme in macrophages increases the anti-tumor, I think it's the anthracycline therapy, and blocking it in the cardiomyocytes, suggests a potential cardioprotective mechanism.

                                                Having a target that can be used both to enhance the anti-cancer effect of anthracycline and to enhance the cardioprotective mechanism is really a potential ideal intervention that would help maximize the anti-cancer treatment and at the same time protect the heart.

Dr Greg Hundley:             Fantastic. Again, new research helping to come up with ways for those that continue to need anthracycline therapy that we may be able to attenuate some of the untoward cardiovascular effects, all the while preserving the antagonistic features associated with the treatment for cancer.

                                                Let's switch to the other sort of prospective original research format that we have in Circulation, and that's our letter format. Remember, our letters are addressing a specific point that can be readily appreciated in 800 words or less. The first is a letter by Anquetil et al that examines individuals recorded in the VigiBase World Health Organization database. This is basically a database organized around treatment of cancer and cancer therapeutics and it is examining those individuals that received sort of a newer class of agents called immune checkpoint inhibitors. Remember, that is modulation of our immune system to help attack cancer.

                                                In some rare circumstances, relatively infrequent, when these agents have been administered, the immune system has been unlocked and attacks the heart, promoting a myocarditis that if not recognized can be fulminant and lead to death. This particular group identified a new phenomenon that we need to be aware of and that's just frank myositis.

                                                Vlad, what are your thoughts on now perhaps these agents being associated with the development of myositis in the skeletal muscle?

Dr Vlad Zaha:                     Often when adverse events, as you mentioned Greg, are an important concern for these new powerful tools for the oncologists and it has been pretty early in the process where some of the cases have demonstrated severe cardiovascular events. Fortunately it is a very low percentage, less than 1% of cases that can manifest with fulminant myocarditis, but this raises again a question of expanding the view towards other systems when we are applying one of these early novel molecular interventions.

                                                In this context, the recognition of myositis in another small percentage of patients is an important observation and increasing awareness of both cardiologists and oncologists towards this side effect is important as not all fatigue is equal and sometimes that can be due to manifestations of cardiomyopathy and sometimes it can be a manifestation of oxygen extraction in the peripheral tissue than muscle contractility. It is an important hypothesis-generating piece that will allow people to appreciate more of the complexity of addressing the intrinsic molecular mechanisms in cancer and heart disease.

Dr Greg Hundley:             It sounds that we need to be aware of another potential etiology of fatigue to put in an armamentarium of differential diagnoses for those patients that are not getting quite back to where they were from an exercise and activity level after treatment. The second research letter focuses on individuals that are receiving a Fontan procedure. Remember, Fontan procedures are surgical corrections for those primarily with single ventricles where we're diverting caval blood to the pulmonary circulation, since in some situations there's really no functional right ventricle. These patients over time experience chronic venous hypertension and have associations with liver disease.

                                                In this particular research letter, the authors are examining the relationship between really for the first report in an aggregate form of the relationship between undergoing a Fontan procedure and the development of hepatocellular carcinoma. Vlad, any quick comments to highlight on this particular procedure? I thought something that was interesting is that these individuals experienced these hepatocellular carcinomas in their 20s and 30s.

Dr Vlad Zaha:                     That's right, Greg. This study confirms observations from previous case reports and the early occurrence of hepatocellular carcinoma is raising still important hypotheses for future clinical trials. On one hand, either there is an increased risk of hepatocellular carcinoma development in patients with non-cirrhotic livers after a Fontan operation, or the current screening modalities using imaging are insufficiently sensitive to identify early signs of cirrhosis in such patients and this stratifies them effectively at an early stage in their disease post-op Fontan procedure.

Dr Greg Hundley:             Lastly, let's just briefly discuss here, Vlad, some of the other editorials and review article formats that we have in Circulation. A particular one, a perspective that was written by Peter Libby and Ebert and associates that highlights this phenomenon potentially implicating inflammation and the link between cancer and atherosclerotic cardiovascular disease. The topic of this perspective is really on something called CHIP, which stands for clonal hematopoiesis of indeterminate potential.

                                                What is this CHIP? As we age, basically what happens is we accumulate mutations of hematopoiesis stem cells in our bone marrow. Over time these little clones, they actually have within our bone marrow some survival advantages and they can spill out into the blood and actually can be associated with future leukemias. Those that have a large population of this particular clonal progeny, these CHIP-type cells, they have an increased risk of developing cancer, but also the levels of these are associated with increased overall mortality and it appears some risk of cardiovascular disease. How could that be? One characteristic of this particular cell line is they are associated with dysregulation of inflammatory genes that go on to produce, are associated with other inflammatory mediators.

                                                Vlad, this is calling in question and helping us to examine the relationship between inflammation, cancer and cardiovascular disease. What are your thoughts here about these very important insights provided by Libby and Ebert?

Dr Vlad Zaha:                     This is a fascinating perspective, Greg. It really brings, again, in the offline novel molecular mechanisms that have been discovered recently and that are becoming a turning point into the molecular interventions, not only in cancer but potentially soon in cardiovascular disease prevention and treatment. Having a common root for a problem set involving such a prevalent cardiovascular problem as atherosclerosis and cancers reveals the connection between the different systems and the fact that integrating our understanding of the molecular regulation of cell proliferation results in an effective translation of leading to new targets and new approaches to treat disease.

                                                It is striking that there are multiple areas where cancer and inflammation are interacting, one of them being at the cellular level and other ones at humoral levels, in a way reproducing other complex mechanisms that we see in regulation of inter-system interactions within the body.

Dr Greg Hundley:             And so, summarizing this entire issue in Circulation, what a wonderful collection of a series of original manuscripts, both in the extended and the letter format as well as review articles, including a primer by Handy and associates that evaluates or draws attention to our screening tools that how we might examine the relationship between cardiology and the whole world or hematologic oncology related issues. And then this very unique perspective by Peter Libby and really is a continuation of the growth of this, as we called earlier, the bridging discipline of cardiovascular medicine and oncology as we work toward improving survivorship of all individuals with cardiovascular disease and cancer.

                                                I want to thank you for the opportunity to be with you today and encourage you to follow these issues further with the journal. I'll turn this over to Vlad for any closing remarks.

Dr Vlad Zaha:                     Thank you, Greg. This has been a really exciting overview of important points that are emerging now at this nexus between cardiology and oncology that give us a broader view of the complex interactions that the future will materialize for us, emerging from a molecular intervention on cancer, heart disease, immunologic disease and probably metabolic endocrinology disease.

                                                Thank you for listening.

Dr Carolyn Lam:                Thank you so much, Vlad and Greg. This is a tremendous issue and I'm sure, audience, you will be reaching for it right now, I would.

                                                Please let all your colleagues know about this podcast and tune in again next week.