Rupal O'Quinn, MD, FACC, the Director of Cardio-Oncology at Penn Presbyterian Medical Center and Associate Professor of Clinical Medicine Perelman School of Medicine, takes a deep dive into the cardio-oncology field and the connection between cancer and heart disease. Dr. O'Quinn discusses how to identify clinical cardiotoxicity, therapeutics causing cardiotoxicity, and how to manage cardiotoxicity.
my name is linda Lafferty. I'm the liaison for penn medicine and I wanted to introduce dr Rupel O'Quinn Director of cardio oncology at Penn Presbyterian Medical center right nearby. She is an assistant professor of of clinic Clinical medicine at the University of Pennsylvania and the Director of the Cardio Oncology Program and Presbyterian since July of 2020. Uh Dr Quinn joined our faculty in 2015 and specializes in cardio oncology with the clinical work and research centered on patients who have had cancer and now have cardiovascular issues. So I will turn it over to Dr O'Quinn and please note there is a chat box, feel free to answer to put any questions there. Um and then after the lecture um Dr Oaklyn can address any questions that you may have. Thank you linda and thank you everyone for having me. Honestly it's a saturday morning, it's early and I'm sure all of you have money many things you should be doing instead and rather would be rather would be doing so. I appreciate your time right now. So I'm just gonna get started on the interest of time. So why what is first of all cardio oncology and why has it become its own niche, especially since cardio toxic chemotherapeutic have been around for a long time. So right now there are many more targeted agents that are coming out that have cardiovascular effects that are both on as well as off target and it's getting very difficult to keep track of all of them even for cardiologists. So people in general also living longer. There's been developments in cancer treatment and care that have improved survival for cancer patients as well. But often their hearts have sustained damage that are meant for the malignant cells. And so nowadays cancer has actually become more of a chronic disease. So the goals in this field include recognizing which therapies can cause an increase the risk of cardiac damage, preventing and mitigating that cardiac damage, whether it be via medications or early detection and then also eliminating cardiac disease as a barrier to effective cancer therapy, monitoring these patients with baseline cardiac issues and then risk factors for worsening are also important as well as development of new cardiac problems. Research is important to find out why certain patients are more susceptible to cardio toxicity to defend, discovers ways to mitigate that damage and then also to find better ways to detect this damage earlier, the goal is ultimately to ensure better outcomes for our patients and then also that have both cancer as well as heart disease. So, um, why should we even care? And so, learning about cardio oncology is important because heart disease and cancer were the top two causes of death in the United States in 2017 to 2018, that has been the case for many years. Although now, covid maybe changing these numbers. So multiple studies have shown that there is likely a link between cancer and heart disease. So hasten and always show that heart failure patients are at increased risk of cancer with the worst prognosis while bank at all demonstrated that cancer increases mortality and heart failure. They have similar risk factors such as age, obesity, diabetes and tobacco use chronic inflammation and oxidative stress likely play a role in both the pathogenesis as well as progression of both heart disease and cancer. So patients are going to be seeing articles about cancer therapeutics affecting their heart and they're gonna come to you as their primary care providers or their physicians. And so you'll see in the mainstream media there's going to be many many articles and they're going to continue to come out. So the most common type of cardio toxicity from oncological agents is left ventricular dysfunction. So there are many definitions of cancer therapy related cardiac dysfunction. It's often called CTR C. D. One of the more widely used one is a decline in the left ventricular ejection fraction by a baseline from baseline by a greater than 10% to a value of less than 53%. And that baseline left ventricular ejection fraction is that E. F. prior to any therapy. Other groups also use a 10% drop from baseline to an EF of less than 50%. There have also been multiple. Other definitions used there in the trial setting and then C. TR Cd can be symptomatic or asymptomatic and it can be reversible or irreversible. Some people believe that C. R. A. C. T. R. C. D. Can be further broken down into a Type one cardio toxicity which is what an three cyclones can cause. And type two which consists of trust you so mad. And some of the terrorist in chinese inhibitors will talk about among some others. So type one toxicity is thought to be due to irreversible damage and cellular apoptosis death with changes actually seen on biopsy. And I have this picture here is because patients will often have a history of chemotherapy and they won't be able to remember what they actually got. And you should try to ask them if you're curious about whether they received and recycling. If the color of that chemotherapy was read um it's actually docks iridescent uh and recycling is called the red devil. And it's at least partially due to the fact that it's actually bright red in color and almost looks like Kool Aid. And it's so we you know it's hard to know if it's the color versus the side effects that causes to have the nickname of red double. And then type two co toxicity is thought to be mostly reversible with more cellular dysfunction but not actual death. There should be no changes if you were to look on the pathology sides from agents that cause the type to dysfunction. But the story is actually much more complicated nowadays because we have newer agents such as immunotherapy that can cause a different type of cardio toxicity that's very difficult to see which one it is. And so now in terms of monitoring. Historically, multi gated acquisition or market scans were used to monitor the left ventricular ejection fraction during chemotherapy. The limitations that method included problems with accuracy and reproducibility. There was a radiation exposure and many of these patients already have a lot of radiation exposure and then there was also limited information on some of the other cardiac structures other than just the ejection fraction. So right now, the most common imaging modality to evaluate for C. T. R. C. D. Is actually two dimensional trans drastic echocardiogram is probably many of, you know, the advantages include the fact that it is widely available, especially the United States. It does not expose patients to additional radiation, which is important as I mentioned earlier. Since many of these patients already have both cancer imaging as well as testing and treatment that exposes them to radiation. And then Echo also offers the ability to view other aspects of the heart such as the great vessels and the valves. However many of us probably already know this, but sometimes those images, that image quality is very challenging and it can be the body habits or certain positions that patients aren't able to do. And that will obviously affect the image quality and because of that there can be significant differences in the l the left ventricular ejection fraction evaluation From one reader and to the next. And given that the definition of cancer therapy related cardio texas is a 10% change. It can be difficult to detect an echocardiogram if that image quality is especially poor and it's also important to keep in mind that loading conditions may be variable. These patients due to cancer therapy so many patients are very dehydrated because of nausea and vomiting or they're getting a lot of fluids in the form of chemotherapy and so their volume expanding and this can also affect the ejection fraction. And so in terms of monitoring the expert consensus of the american society of echocardiography and the european association of cardiovascular imaging has actually recommended three dimensional echocardiogram or cardiac MRI. Which is actually the gold standard. When we are evaluating for cancer therapy related cardiac dysfunction. And studies have shown that three D. Echocardiogram has better reproducibility and accuracy due to less geometric assumptions, especially when that left ventricular ejection fraction is low normal or borderline. There's also lower temporal variability with three D. But three D. Echo might not be available everywhere and it's also more costly, expertise is important to obtain reproducible and accurate values. So the expert consensus says that if three D. Is not available, modified biplane Simpson's techniques should be used to calculate that left ventricular ejection fraction and most places are able to do this and then something called strain should also be done. So what strain is is there is a technique it's called. It actually measures myocardial deformation. So our left ventricular wall can be subdivided into three layers. You have the endo cardi um the myocardial and then the epic Rd um as well. And what stream does is it looks at myocardial lengthening, shortening and thickening at the various dimensions. And most commonly we call it the longitudinal circumferential and radio. And so what global longitudinal strain has been shown is that it can be actually be the most reliable and reproducible versus circumvention radio. And that's so this is the constraint parameter that's most commonly used and reported. And then although Echo can be helpful in detecting cancer therapy related cardiac dysfunction. But by the time it's noted on echo the damage actually can had already been has already been done. So. And ideally we would like to be able to detect the card of toxicity before it actually results in a change or decline in the left ventricular ejection fraction. And so because of this there have been numerous studies that have looked into using G. Ls. Or global longitudinal strain in cardio oncology with most of them being done in patients who are undergoing treatment and recycling and or two rescues and mad. They have shown that G. L. S. Can actually detect the political left ventricular dysfunction earlier and that these findings can be more reproducible than two dimensional echocardiogram. It's actually also better than ejection fraction and predicting mortality from all causes. As well as providing better risk stratification and patients with heart failure but as you imagine there are caveats because it's not as widely used. It's important to remember that strain is also dependent on image quality and is also influenced by the same loading conditions as ejection fraction. And so this can change based on the volume status of the patient. There was both also intra and inter intra and inter observer variability as well as test and retest variability. And then to make things more complicated there's also inter vendor and software variability that makes accurate comparison of studies difficult when using different kinds for serial patients on this seriously from the same patient. And often most eco labs have different kinds of machines right? Obviously different texts and so there's a lot of variability that comes into this. And then other things that have looked at besides strain has been biomarkers such as proponent and anti pro Bmp. And I'm actually going to discuss them further in the next slide. The american society of Echocardiography and the european society of Echo of cardiology has strongly recommended that we obtained global longitudinal strain in addition to the ejection fraction as well as the proponent. And they ideally we you know people to try to use the same vendor and software but I'll be very honest that this is very difficult to do. And in busy echo lab. And then what happens is that the G. L. S. Values that people get on serial echocardiograms can be compared to the baseline and to the prior values as well. And in regards to what it means like what that G. L. S. And when it's abnormal versus normal. So a relative G. Ls reduction of greater than 15% from baseline is considered to be clinically significant and concerning for subclinical cardiomyopathy. And those who have received cardio toxic chemotherapy. If you have a relative reduction in G. L. S. of less than 8%. It's considered to be clinically insignificant and a change between 8-15% is indeterminant. I'm just gonna give an example and I know most of you won't be doing this. But just to kind of understand if you see these numbers on patient what that means. So an example would be of a patient that has A G. L. S. Baseline of 22%. It's often reported as a negative number. So you may see negative 22% and then she undergoes an echocardiogram after getting three cycles of trustees, some of which is Herceptin. And I'll talk about that more later as well. And her G. Ls then is noted to be 17%. So a question that may come up is whether this is clinically significant. And so the calculation we would do would be that the change in GLS is actually calculated to be 23% reduction from baseline. So you would consider this relevant and significant. And then so this patient was referred to cardio oncology and she had been on antihypertensive consisting of hydrochlorothiazide and Amadu pe. So I ended up switching them to carvedilol in the center for additional cardio protection. But you know to be honest there's no clear data to support what we're doing. There was actually a large multi center trial called Souk or that actually looked at prophylactically treating patients who had to drop in just global longitudinal strain and nothing else. And they actually at one year really didn't find any benefit to overall E. F. At the end of the trial. So I think if they're now considering looking at different endpoints but for the time being dropped in just G. Ls restraint is not enough for someone to stop their chemotherapy or even hold it. And so the night of alluded to the fact that biomarkers are another tool that offer hope and potentially identifying subclinical cardiac toxicity. So there have been numerous studies that have shown that certain biomarkers are elevated in certain therapies. And the most common biomarker studies so far has been troponin and as many of you know, troponin i is both sensitive as well specific for myocardial injury. And then as although both proponents I N. T. Have been looked at, it's actually been a proponent. I has that has been studied the most in patients receiving and recycling trust and interest in chinese inhibitors. And many studies have found a possible relationship between troponin elevation and then current or future cardiac dysfunction. Although some have not, it seems that high sensitivity Troponin has a very high negative predictive value of ef decline. It may help us identify those that are at low risk for having cancer therapy related cardiac dysfunction. More research is needed to find out the best timing of that. Troponin draw the optimal cut off values and then ways to increase the specificity of the high sensitivity troponin values and then BNP and NT PRO BNP have also been looked at in multiple studies but there have been some conflicting results. Many of us, what we end up doing is we checked proponents and NT PRO BNP at baseline for patients that are high risk and then we have young college is just check them at every other time that they're getting blood work done and if they are starting to go up that may have us start viewing them a little bit more closely and potentially getting an echocardiogram student or and asking questions about volume overload as well. And so then now I'm going to switch gears and talk about some of the newer agents that can cause cardiac toxicity. So, and three cyclones are the class that most people are familiar with and so I will not be talking about these specifically moving forward nor five F you what I will be concentrating on will be some of the newer, more commonly seen targeted agents that you will all see in practice in many of your patients that can cause cardiac toxicity. So specifically I'm going to be speaking about Trust you so mad. Um the vast vascular signaling pathway inhibitors also called that Jeff inhibitors, the newer tires in genesis for chronic myelogenous leukemia, uh Bhutan's tyrosine kinase inhibitors for cll or chronic lymphocytic leukemia and then finally the checkpoint inhibitors. And then even though this list seems like it's very exhausted, exhausted. It's actually really not. There's a huge number of drugs that I will not be getting to today. So I'm gonna make this case based. So we have a 60 year old woman with a past medical history of hypertension, Hyperloop anemia and then left side of breast cancer who undergoes four cycles of chemotherapy consisting of Dr. Robinson and cyclophosphamide. That results in remission. She is then subsequently diagnosed with metastatic right sided estrogen receptor negative progesterone receptor negative and her two positive breast cancer. And she started on trust using mad. So our baseline ejection fraction was normal at 60%. But then she undergoes a repeat echocardiogram after two cycles because she's experiencing new symptoms of waking Indus mia. And this reveals an ejection fraction of 35%. So trust us map has which is also known as Herceptin was approved back in 1998 as the first FADA approved targeted anticancer agent for her two positive breast cancer. The over expression of this epidermal growth factor receptor subunit was previously associated with more poorly differentiated tumors, higher rates of metastases and an overall poor patient survival. So her two positive breast cancer was the kind you did not want to get. But nowadays with the addition of trust you cement to standard chemotherapy this has resulted in a 20% decrease in debt that one year in the therapy with the standard prior standard was always docks Robinson and cyclophosphamide. And then the first pivotal study was unfortunately notable for symptomatic heart failure or asymptomatic cardiac dysfunction. And over a quarter of the patients who were receiving an anthropoid cycling based regimen along with trust using that and it was thought that maybe it might be because her two is also important for self survival including bio sites and then subsequent trials and clinical experience with trust issues. Not sure to lower incidence of cardiomyopathy. But it was also thought that that might be because people were looking for and monitoring patients much more carefully and also interviewing early. And I also suspect that many of these trials subsequently excluded patients with a history of cardiac disease and heart failure. And so that was why the incident was lower as well. And then certain factors have been associated with a higher risk of trustees and then party of toxicity. So these include older age obesity baseline hypertension. Those who have previously been treated are also being treated with anti Cyclones and those that have a low ejection fraction of baseline as well as a prior history of radiation exposure. The C. T. R. C. D. That usually manifests during active therapy. Um And and then actually you can improve when you hold therapy and or you initiate some cardio protective medications such as beta blockers and neural neural hormonal blockers such as ancient inhibitors, arbs or interest. Oh the toxicity to the trust using map is not thought to be related to total cumulative juice which is different than an three cyclones but one is more likely to get LV dysfunction were longer there on trust using maps and then L. B. We know that LV dysfunction has been found to be twice the rate and those that were treated for 24 months of trust using map versus only 12 months. And then there are some newer agents um that are also target hurt too that can cause cardiac dysfunction but the incident has been noted to be lower so far. There was a study that we did find that nations that were aged over 65 years that this age was a risk factor for cardio toxicity. And those receiving trust News Mad and Sandy and Tansy but that the overall that rate was low and that most patients remain asymptomatic with ejection fraction improvement after it was stopped. And then this is the algorithm that is suggested by the american society of echocardiography. They recommend in terms of monitoring that we obtain a baseline LVF with three D. Preferred or two dimensional if not available. And they also recommend that you obtain a global longitudinal strain if possible. As well as the Troponin I. And then in this algorithm if the ejection fraction is less than 53% at baseline particularized should be considered for verification. And it also notes that the baseline EF is not normal and or you know the proponents are elevated and the global longitudinal strands of good quality and decreased then consider a cardiology council. And if all of those are fine that an echo or A G. Ls search components can be checked every three months with therapy and if the patient has previously received and recycling and ECO should actually be done six months after it is completed. And that's because some studies have suggested that most of the cardio toxicity after and recycling containing therapy occurs without that first year and that recovery is more likely the earlier that treatment is initiated. So as primary care you may see these patients that have completed therapy and then are coming to you and maybe having symptoms and an echo might be the right first thing to do. And so one of the reasons that I talked about every three months and one of the reasons that patients on trust using map get echoes every three months is because FDA package actually insert for trust use magnets recommending it and the Canadian consensus guidelines also recognized it. And then so these echoes right if there is any evidence of cardio toxicity, what I normally have patients do is hold the trust using math. And then we normally initiate guideline directed medical therapy with beta blockers. Ace inhibitors and arbs or arms and then or trapped and presto and then we usually remain image after 3-4 weeks. And then one thing to also note is that the breast cancer clinical practice guidelines recommend withholding and even considering discontinuation if that ejection fraction drops by more than 10-15% or below the lower limit of normal. That being said, there have been you know, trials that have been looking at this because in many of these patients trust using members of life saving throw B and we really do want to continue it. So there was this very small trial here that is looked at only 20 patients who are being treated and followed for one year. And during the study period 90% of the patients continued to receive trustees met even though they were noted to have mild left ventricular dysfunction, dysfunction with the drop in injection fraction 40-54% or a just droppin ejection fraction that 15% or more below baseline. None of these patients had any symptoms consistent with New York Heart Association. Class three or 4. So they were very mild. So that graph on the right actually shows that the EF was 60% of baseline and then subsequently decreased Right there so that enrollment. It was about 50, less than 50%. And then the graph on the left shows that a closer look at the E. F. Change over the subsequent one year study period in which these patients underwent through like a cardiogram fee as well as treatment with ace inhibitors and or beta blockers. And then although the EF dropped to less than 40% in about 10% of the patients for most of these patients, the symptoms improved in the cardio cardiomyopathy also improved after that transfusion was stopped at the completion of therapy. And so over the study period there was actually a mean increase in E. F. And the other treated patients from 49% to 55%. Despite the fact they were still getting dressed through Sinbad. And the thought was that that cardio protection agents actually helped. So these findings actually suggest that patients should and could be continued on trust using that in the setting of a very mild cardio toxicity. As long as they're followed closely and they get the appropriate of cardio protective therapy on board. Mhm. And there was also another study called say part that also enrolled only a small number of patients with 31 in this case that had mild cardiac dysfunction who were receiving her two targeted therapy. And they also found that a close collaboration with either cardio oncology or cardiologist that had some experience in this was important to ensure that treatment continued to be given And 90% of patients completed therapy with no significant decline in their E. F. subsequently at the end of treatment. And we clearly need more research in this area. So we needed to basically identify patients with the highest risk of irreversible disease and then also determine the best way to monitor these patients. Because I think many of us feel that getting echocardiograms in every three months and all patients is probably a waste of resources. We also need to find out which aspects or types of standard failure heart failure therapy are the best way to treat LV. Dysfunction is population. And then a popular question that often comes up is whether there are medications that can actually prevent the cardio toxicity. And they've actually had a few prospective randomized controlled trials that have looked at this so far. And the studies here um that I've listed include Trustees amount as one of the agents that has looked at. And then most of the studies unfortunately have been really small containing only about 100-200 patients. And the takeaway has been that actually meta brawl did not prevent carter from C. T. R. C. D. One trial showed a benefit of Canada starting but another one didn't and then protect skin at all in the manticore study found that one of the ace inhibitors as well as this Apollo actually attenuated ef decline but didn't actually prevent remodeling and then there was overcome trial, which I'll talk a little bit more in detail. So this one was the largest so far. It was a double blinded randomized controlled trial with almost 470 women, which was considered large and cardio oncology with her two positive breast cancer. And they either received carvedilol extended release of 10 mg or the center april 10 mg versus placebo. During while they were receiving trusted the mat based chemotherapy. So cardio toxicity was the primary outcome and they found that cardio toxicity was actually similar in all three groups and but higher compared to other trials because they almost had 30% of patients getting cardio toxicity. Interestingly though, if they did a pre specified analysis of patients would also receive and recycling. In addition to the trust using that. And here you can see that the Kaplan meier curves actually showed a protective benefit with both listen to pearl and carvedilol. And another thing to know in this tribe of the things that were, you know, people complained or you know, it's got next on was the fact that a lot of these, you know, they used a very broad definition of cardio toxicity. So many more patients were included and they also used mug and echo instead of cardiac M. R. I, which has been the gold standard in trials to really see if there is finished the change in the s So basically the jury is still out and the way I handle these patients that if they have hypertension at baseline, right? And they're already on medications that are not cardio protective. Like I like em loaded peeing or hydra for these. I would I would recommend in these patients would be to switch them to a beta blocker and or ace inhibitor since this will also offer some cardio protection in the future. And then now I'm going to be doing a few cases of its harassing Chinese inhibitors. So the purpose of this slide is to actually make you feel overwhelmed. So don't worry. So I'm actually trying to show it to highlight the fact that there are over 60 receptor tyrosine kindnesses and over 30 side of plastic ones. And so when you hear about these in the oncology oncology world, just realized that, You know, tyrosine kinase inhibitors, it's like a very broad term and then targeting one ax aspect um to manage one type of cancer um can also cause a downstream effect in many different side effects and multiple organ systems. And it's one of the reasons that many of these these medications have such a diverse group of side effects. And so I'm going to be specifically talking about two classes inhibitors. So he was 63, a man with a history of metastatic renal cell cancer and hypertension hydrocortisone. And he comes to see oncology, he started on a bad jak inhibitor called serotonin and his baseline blood pressure was more well controlled at one twenty's over seventies And then he ends up going up to 190/102 in the next 10 days. So the veggies singling pathway is also called the sp. It leads to activation of the jAK inhibitors among others. And this leads to downstream activation of multiple pathways. And this includes Basta title in a Seattle three kindness which results in release of nitric oxide synthesis which then increases nitric oxide production as well as increased process cycling production. What then ends up happening is that nitric oxide goes into the adjacent vascular smooth muscle cells. And so basically the gist of it is it leads to facilitation. All of this leads to angiogenesis, endothelial cell survival facilitation and normal cardio contract. I'll function which is necessary for cardiovascular homeostasis. But unfortunately it can also contribute to tumor growth since the same pathways are used by tumor cells. And so what happens is is that the veg texting like pathway inhibitors actually suppressed this to our growth. And when when as a result nitric oxide pathway suppressed. So then you have that endothelial one pathway that stimulated um press the cyclone and production decreases and all of this leads to oxidative stress cell injury. Endothelial dysfunction, nasal constriction and then all of this leads to hypertension. And then also in addition um veggies inhibitor targeted therapies are associated with a threefold increase in this for party arterial from bolic events that includes stroke. Transient ischemic attacks, myocardial infarction, angina and other also arterial events. The platelet activation is like actually accompanied by the release of veggies. And this seems to regulate endothelial cell survival and also repair of the vascular service. So when you inhibit this pathway, you likely get microvascular injury and thrombosis as well. And so as I noted earlier that hypertension is the most common side effect with these. By Jeff inhibitors and risk factors include preexisting hypertension age greater than 60 years and a body mass index of over 25. The effect is also thought to be dose related and more frequent in patients treated with higher doses and then polymorphisms and Jeff are thought to be associated with the risk of hypertension as well as efficacy against the tumor. So this is important because hypertension is actually thought to be a marker of treatment response and we get a little bit excited when we see it because it means it's working In a trial that was done in 2015. The overall survival was higher at 25.5 months in patients who experienced a hypertensive response versus only 12 months and those who didn't when they received a vet Geoff inhibitor. So again the hypertension can actually be a very beneficial and a good sign. But it's also important to know, as we all know that control of hypertension is especially important because uncontrolled blood pressures can lead to myocardial ischemia as well as heart failure. It's also thought that I a transgenic imbalances between that range and angiotensin little dust alone system and contributes to the hypertension as well. So there's been some thought that maybe using X inhibitors and arbs especially in these patients with elevated baseline blood pressures or switching their current agents to these can attenuate the increases and also protect against protein area which is dealing with these agents. And then this class was also associated with improved improved overall progression free survival and renal cell cancer. And so if I had to pick a drug I would be thinking about these for blood pressure control. So the di hydro puritan calcium channel blockers such as am loaded pin and that pin are effective. But the non di hydro puritans like BLTs and verapamil should be avoided because they inhibit um the cytochrome P 4 50 system which can then cause higher levels of budget inhibitors. And then finally if there is severe resistant hypertension you should actually interrupt therapy briefly until you can get the better blood pressure under better control and next slide. So next case is a 70 year old four year old man with a history of hypertension. Hyper lipid e mia diabetes obstructive sleep apnea who then presents with new chronic myelogenous leukemia. He started on a therapy called a magnet. He unfortunately progresses on a magnet and is thus switched to dissect nib but then he begins to experience new dysthymia. So an Echocardiogram is ordered and it is notable for a newly elevated pulmonary artery systolic pressure of 98 mm of Mercury. His pulmonary pressures were normal at baseline. So chronic myelogenous leukemia is most commonly due to the dis regular dis regulated tires in chinese called beast are able, as many of us remember from med school Prior to 2001, only 33% of patients diagnosed with CML were alive five years later. But nowadays given the advent of these multi targeted tyrosine kinase inhibitors like a magnet, the five year survival is actually over 90% which is amazing. So manu of itself is actually pretty well tolerated. It can cause fluid retention and rarely chf. But out of these newer all of the newer tires in Chinese inhibitors for CML, the Saturn, it has actually been associated with pulmonary hypertension and up to 11% of patients and Maine and unfortunately may not be reversible with drug discontinuation. So one possible mechanism is that the Saturn it can cause pulmonary vascular endothelial cell damage. And then management includes um stopping the disadvantage, treating with standard and pulmonary arterial hypertension therapy including like calcium channel blockers, Preston noise and ophelia receptor antagonists and then pd in mid rivers as well and then deciding it can also increase the risk of vascular events such as myocardial infarction and stroke. QT prolongation as well as pleural and pericardial effusions manila and it was another newer generation TK for CML. And it can also cause vascular events such as AM I. And stroke and also peripheral vascular events. It can also um cause hyperglycemia and prolong the QT interval. It's also rarely been associated with sudden cardiac death. And if that's it's unclear whether this is due to that prolonged Q. T. That it can cause And then is actually special in that it is a multi targeted agent with potent activity against something called the able one Chinese mutation. And what this boils down to in this with this medication is that hypertension is very common along with coronary cerebral and peripheral vascular events. Uh There was a study done that I'm showing you here by MD. Anderson that reviewed the charts of over 500 patients. And they looked at the events as the types of cardiovascular anti r truth robotic events in patients that had CML during the course of therapy with these terrorists and chinese inhibitors. And this included both the 400 or 800 mg of Imatinib as well as a relatively sensitive and reactive. And what they found that was almost half it was 45% developed cardiovascular events with hypertension being the most common. 9% developed artur anthropic events. These events were also noted to be in the high highs in the early years of T. K. I. Therapy and then also varied among the different kinds of targeting chinese inhibitors. So in this slide the top row highlights that the monotony of therapy was associated with the highest risk of cardiovascular events. The middle road shows that overall hypertension and new hypertension was also the highest in platinum group. And then the bottom row shows that patients that had the greatest number of risk factors had the greatest number of risk especially with catnip. So management here includes treatment of the complication according to guidelines and then consideration of those reduction after weighing the versus versus benefits Putin and it was actually briefly pulled from the United States back in 2014. But given the fact that has so many targets it's often effective when patients develop resistance to the other agents. And so it's being used now with this you know black box warning And then case # four is a 65 year old man with a history of controlled hypertension. On hydro for thighs side. He also has diabetes. He then presents with progressive chronic lymphocytic leukemia. He started on Uprooting him and he's initially tolerating it well. But then developed competitions. He presents to the emergency department where his ejection where his E. C. G. Shows asia fibrillation with the rapid ventricular rate. So basically tobacco for a second chronic lymphocytic leukemia is actually one of the most common B cell malignancies in the western world and primarily affects the elderly which we you know as we all know can have more comorbidities. The course of CLL can be indolent so that management is often just observation or it can be rapidly progressive. So inhibitors of this B cell receptor pathway represent an attractive target for Cll. So Bruton's tyrosine kinase, which is often called B T K, is a cytoplasmic tyrosine kinase that's actually very essential to be cr signaling. So, by Britain, it was the first Britain Sarasin can be studied in clinical trials. It's been shown to improve progression free as well as overall survival and relapse refractory CLL. Um in the initial studies that were done in the new England Journal of Medicine back in 2014, I wouldn't be talking about it if it didn't have cardiovascular side effects. So H revelation was found to be up to four times more likely in patients I received a broken hip. It may be due to that reduced Barcelona's 33 chinese hkt activity. No one is 100% sure, but that's what everyone is thinking right now. Also, almost 1/4 of these patients were noted to have hypertension at three year follow up and then this also is a risk factor for atrial fibrillation. There was also increased bleeding that was noted due to the downstream effects of this drug on glycoprotein and von Villagran factory sector and this is actually very important for all of us, you know, for a few reasons If patients are on this drug and they need a procedure. The drug should be held for about 3-7 days for minor procedures. We've been leaning towards three days, but for any major surgery, it should be held seven days prior. There's also new ruby TK inhibitors that have been approved for CLL and small lymphocytic lymphoma. A calibrated. It was approved in november of 2019 and more recently, daniel bryan it was approved. And right now studies had showed in their phase three clinical trials, they had said that HR fibrillation and bleeding was lower with a calibrated. But I do know that in the real world I've been hearing that a cal still causes a lot of atrial fibrillation and atrial flutter. So we'll just see what time, I guess as more and more patients get put on these drugs. And then we're also starting to see some of the other cardiovascular effects from Brittany. So there was a study that queried the vigil base, which is the international pharmacare vigilance database and they found that seven cardiovascular events were more common in patients who were taken at Brittany versus all other drugs. The seven events included Super ventricular tachycardia, hypertension, ventricular arrhythmias. Um cns hemorrhagic and ischemic events, heart failure and then also conduction disorders. And then they also, So this is really just for you guys to be aware that it might be something to think about if patients are having side effects or coming to you with these complaints and then treatment of atrial fibrillation when patients at on a group is a bit more complicated. Do the drug drug interactions as well. So I brought it is metabolized primarily by the cytochrome P 4 50 system. And so as a result of the use of multiple drugs including amphotericin and generally known as well as the taoism and verapamil can all cause increased levels of my brute name. And then I brought in. It can also inhibit peak like a protein which can then cause increased plasma levels of digoxin when used together. And then the other thing that becomes complicated is that often with these patients they have a high stroke risk based on their chats too vast for and so normally we would anti coagulate. But I mentioned that bleeding risk is also increased in these patients from my group in it. And so we also know that malignancy increases the robotic risk. So it's hard to know what to do in this situation in regards to whether these patients should be placed on anti coagulation. I know I've tried using the chest to bask and then also the has blood scoring system to kind of figure out the balance but it's very difficult to do because there aren't trials right now to help us to help guide us And then you can also increase factor 10 a levels such as in river rocks, even a picks abandoned docks even and it can also increase direct thrombin inhibitor levels such as the bigger trend included as well. So the bottom line is like what to do in these patients. And normally I use a factor 10 a. And most patients that have a high chance to bask for. But what I found to be beneficial is just to have a really good discussion with the patient. And many of them have very strong preferences because they have the fear of either bleeding versus having a stroke or clotting. And so that often will help us make that decision in terms of what the patient prefers. And then this is my last case. So we have a 53 year old woman with metastatic ovarian cancer who undergo surgery and then was started on paperless mad. She then presents to the emergency emergency department with exertion and chest pain. Her E. C. G. Shows what this is is an accelerated video ventricular rhythm which is slow ventricular tachycardia. And you can see on the left that the EC two is normal. But then on the right, she comes in with this slow Bt. So her labs are remarkable for an elevated troponin as well as the CK MB. Her transfer Isaac Echocardiogram shows a reduced ejection fraction of 35% along with RV Dysfunction. So she started an appropriate cardiac medications. She undergoes a cardiac catheterization that shows no obstructive corner artery disease. She subsequently undergoes a cardiac MRI that confirms myocarditis with delayed gadolinium enhancement predominantly in the typical septum as well as global T to elevation which means just global oedema. So she started on treatment stories at a dose of one mg per kilogram but she continues to have ventricular tachycardia. So what is this? Pebble is a map and it's a checkpoint inhibitor and what is the checkpoint inhibitor? So our immune system is very important, preventing as well as controlling cancer as we all know, the T cells are a major component and the process is regulated by a series of co stimulatory and inhibitory signals that serve as checkpoints. And so the C. T. L. A four and the pd one are two of the many checkpoint receptors. And so a simplistic way of thinking of this is that our T cell activation is turned off by tumor cells when they attach to these receptors. What immune checkpoint inhibitors do is they prevent this from occurring and they cause our T cells to continue to stay activated so that it in turn can attack the tumor cells. So these medications have essentially you know, they enhance our immune system. They have shown progression free and overall survival in a growing number of adult cancers that has been refractory, traditional traditional chemotherapeutic agents. But from what I've told you you can imagine that most of the side effects are party immune. So this was the slide I initially presented in 2015 which showed malignancies that checkpoint inhibitors short of promising and now when I had looked at this Last year this list has literally exploded off the page because over the past 5-6 years there were at least 57 more indications for immunotherapy that includes checkpoint inhibitors. Even just even the last three years approved by the FADA. So we're all going to be seeing these medications whether we want to or not. And so these checkpoint inhibitors have been associated with a four fold increased risk of major adverse cardiovascular events. Initially um cardio toxicity was thought to be rare. It was thought to occur also more likely with combination therapy, which still seems to be true. But we even in the initial trials, we see what they saw, I should say. We they saw that myocarditis, which is the most common cardio toxicity scene, was found to be highly fatal, with the mortality of up to 50%. Early case reports showed also this as well. And LV dysfunction was seen with both positive proponents as well as negative troponin. So it was thought that different path of physiology is likely exist with variable presentations. So, some of the clinical syndromes that have been seen have been tacos Hugo or stress cardiomyopathy, pericarditis, vasculitis, Bezos ASM and acute coronary syndrome and we don't actually even know the long term effects of the inflammation yet, because we imagine with the inflammation, it also leads to increased atherosclerosis in the vessels. And then these toxicities. What's concerning is that they can occur anytime, although most studies have shown that they usually occurs early within one or two cycles. And that toxicity is especially hard to diagnose since the ejection fraction can be normal and the troponin can be negative and not in the non inflammatory LV dysfunction. So we clearly have a lot more to learn. And then management includes stopping the agent and it's also important to rule out other causes. And since myocarditis is the most common, the next step is often is to do it either a cardiac M. R. I. Or a biopsy to come from myocarditis. And if there is myocarditis we normally initiate steroids and there is currently no consensus in regards to the steroid dozing. But there has been a few studies that have shown that lower risk of maize has been found to have has been found with higher doses and earlier initiation of steroids. Unfortunately, almost 50% of patients may not respond to steroids and so then we need to consider other immuno suppressive therapy. There have been a numerous, as I mentioned right over here in flex mob micro fennel, it plasmapheresis I. D. I. G 80 G. Um They've all been used to try to help with these cases if steroids don't work, interestingly, we append we ended up using inflicts map a few years back and we've been pretty lucky with it, which I can't say has been the uh the findings of other people. Um What's been interesting initially is that people are afraid to use inflicts map because there is this black box warning that there could be a development of heart failure in patients who used it for a rheumatoid arthritis. But we've actually had a few patients we've used it with cardiogenic shock and had pretty good outcomes. I think the drug that's showing the most promise right now is a bad except and that is A C. T. L. A. For excuse me agonist that's shown actually the most promise out of anything and then restarting that immune checkpoint inhibitor is very controversial as well. So people have done it when they have patients that come in with more benign presentations. I think it's really important to weigh the risk versus benefits because often this drug is the last ditch effort to control cancer in these patients and they really have no other option. I will say so, you know, for maybe for a benign presentation to consider it. But I think most of us are not comfortable if they present with full minute myocarditis at this time. And so that was really just a glimpse. Um The other thing is radiation wanted to bring up is that it can often cause long long terms of ballet. So something to remember that these patients should be screened with echocardiograms and stress test about at least five years from diagnosis onward. And then otherwise there's all these other agents that are also there in cardio oncology that you know honestly can cause some sort of party vascular side effects. And this slide is from 2013. So it's actually still just the tip of the iceberg. And since 2013 we've seen many more therapeutics that have some form of impact on the cardiovascular system. But I have run out of time for today. So the take heart points. Um there's been no overwhelming benefit for prophylactic based on beta blockers. Ace inhibitors and A. R. Bs in an three cyclones interest to cement. And then there's also to monitor cardio god cancer therapy related cardiac dysfunction with echo as three D. Performed over two D. As well as global longitudinal strain. Your troponin levels. Veggie of inhibitors can cause hypertension which can actually be a good thing and is a marker of efficacy but needs to be controlled. Some of the new retire seeing chinese inhibitors for CML can cause pulmonary hypertension, increased risk of cardiovascular and vascular events as well as hypertension. I brewed in it has a tendency to cause a defibrillation but there are many many drug drug interactions as well as an increased bleeding risk. And so if you see this beta blockers are the first line and also you need to raise the risk versus benefits for anti coagulation and then finally just make sure you remember to stop it before any procedures and then recognizing immune checkpoint inhibitor toxicity is actually the most important thing I hopefully I have you walk away with because it's often very difficult to diagnose and if you do see it um initiate higher doses of steroids early and then also consider a bad except for other agents if steroids aren't working. And then finally um really the goal is to optimize care in these patients who have cancer so that they can have a more fulfilling higher quality and hopefully prolonged life as well. And so thank you. I really again, saturday, I very much appreciate all of your attention. If I'm happy to answer any questions, I'm going to try to pull up the check here. So everyone is muted. If you'd like to add, ask a question please unmute yourself. Yeah, I'm having go ahead. Okay thanks. Um just a very um kind of pedestrian question in your in your CML patients with risk of atrial fibrillation. Do you follow any of them with um uh the uh cardio mobile technology where they're actually monitoring their own a fib and sending you EKGs over the net. Absolutely, yeah. Because especially because right, these drugs are there gonna be honored for years and to your point, a lot of the cardiac event monitoring. Right? Most of the ones we have are 30 days and so a few of the types I've done have been Apple Watch which is probably a more expensive option. But if patients already have series fiber above they can detect a tribulation that way. Um I cardia are alive. I think. I don't know if you guys have heard it's an amazon but cardio is the company for a live core. But that is well they can honestly they have symptoms. They can monitor themselves to you know the risk. It's hard to know there sometimes it's earlier on but I've definitely seen patients that didn't have a choice fibrillation history and didn't have it and then years later developed it. And one thought is also is that the longer patients are on these drugs I end up having longer you know hypertension. Right? And so that's a respect for each of the relation as well. So many of these agents can lead to that too. So just a quick follow up question um in that balance between um atrial fibrillation and clotting risk. Um What what data points do you use to help the patient in that conversation you said was so important. So if you know what's been interesting um they will tell you right away. So since Uprooting it thins the blood, many of them actually already have a lot of easing. Easy bruising as well as bleeding on a prudent. So when if they develop a tribulation and we have this conversation they often will tell you I'm already bruising or bleeding too much. I don't want it. Others don't and they will usually do is try I usually use a pick Stephen by milligrams bay I. D. And then and or some river rocks even 20 mg a day. And if they tolerated great. If not then it depends on how badly they don't tolerate it. It's hard for us to stay in between doses right? Unless they have other criteria since unless you have right abnormal kidney function if you're older or your weight is low there really isn't any other indication to decrease those medications to have does but what we've done is like basically it's a conversation but it's usually what ends up happening pre starting the no act right and then afterwards how they tolerated too. Hopefully that's helpful. It's it's very it ends up being a very nuanced conversation back and forth and they ultimately the patient will decide what they want. Great thanks so much appreciate that. Thank you for the question. So doc I have a question um a lot of these drugs all these things are just so brand new that you know in every in every month there's new things new direct consumer advertising that I go back and look up stuff because and I think several of us and are certain of a certain age are in this point. So a lot of these a lot of these medicines you talk was aimed at oncology but a lot of these type drugs like jak inhibitors and things like that um are also used for rheumatology and a couple other specialties. So are you personally seeing people for like rheumatoid logic patients to or are you just doing the cardiology? I do cardiology. It's a great question. I do, yeah I do cardiology but I think what ends ends up often happening is you know, if they're on these agents, I know I've been referred to these patients because I probably have more experience with some of them than some of the other cardiologist. But my primary field is cardiology. And even honestly patients if they start asking me about a lot of the side effects like uncle and other side effects that are outside the heart. I know some of them just because I've seen patients with them but I often will tell them like that's not my area of expertise and probably the best person asks the oncologist who knows of all of these potential side effects. Got it. But I'm thank you but I miss phase I miss phrased my question but I didn't mean cardiology because I know you're a cardiologist. But are you seeing a lot of people referred from the rheumatologists? I'm sorry I said it wrong. No. So yeah, so as a cardiologist by pharmacological, I haven't but I think like I mentioned, you know, I wonder if that will start happening. I know in some of our case conferences like it'll be a rheumatologist disorder and people will be like well do you know what that drug is? If you've heard of it, you know, just because there may be some overlap and I can't say except for you know, the big one was inflicts a map. For example, if the reason inflict cement was used for checkpoint inhibitor toxicity was that besides the fact that it's used for rheumatoid arthritis, is that the most common side effect in immune checkpoint inhibitor toxicity is colitis and colitis, right. Is often Remicade and inflicts map is used. And so that's how people started using it for that type of toxicity and then it kind of spilled over into other forms including cardiac. So I guess in that sense, um, I might be, but I haven't actually, no one's been referring rheumatology patients to me specifically and it and it very well might be, it's hard to say whether people haven't been thinking about it versus when they call the call center right there, it's not, you know, the call center doesn't know enough to actually check them in my direction and is that hopefully answered your question this time? Sorry, but I still have No, no, no, no, it does. I mean there is a rheumatologist on the call here too. And, and I'm just wondering as all these new medicines are coming out for psoriatic arthritis and you know, and yada yada if these newer medications for other things than oncology are going to start causing cardiac problems too. And you guys are going to start seeing a lot more of that. It's very possible so far. I think I have it in just general clinical practice, although like I mentioned, I'm not specifically getting referrals for this, I haven't And it's a little bit interesting because similar to, you know, I guess the one thing is is where audio immune disease right? And we definitely know there's a higher cardiovascular risk. So even forget the treatment the disease itself can cause a higher risk. And so often when I see my paper with general cardiology patients that have lupus or rheumatoid arthritis, I am usually pretty aggressive with statin therapy in terms of like starting it earlier because I think of it as it's an inflammatory disease, right? And it causes increased risk of cirrhosis. So for those patients forget about treatment, I do treat them, you know, as a higher risk. I think some of the agents are anti r immuno suppressed. So maybe that's why we don't see those as much. And then these are the agents were actually using a treat checkpoint inhibitor toxicity if that makes sense. What do you think? What do you think frank? Oh, I think it's a two way street. I think that he's a rheumatologist. Ha ha ha retire. But no, I think it's a two way street because if some of these drugs are going to be used as therapeutic agents there maybe cardiologists who might feel uncomfortable using agents and referred to a rheumatologist in the same way that dermatologists who treats psoriatic arthritis in the past at least anyway. Um you know, felt uncomfortable using some of the agents that were being used to treat, uh, sorry, attic arthritis. So, you know, it's it's just, you know, relates to the importance of good communication between the specialties. Um, but I had a question related to a little off the subject of the cancer, chemotherapy side effects is, you know, since we're in this era of covid and there have been issues with covid related cardiac disease and vaccine related cardiac disease. I wonder how much we really know about the path of physiology of the cardiac disease from covid and the cardiac disease from the vaccine. And how much of these methods. Methodologies are applicable to either of those categories. And you know, whether some of those conditions are temporary or um, you know, more permanent. And yeah, I can probably just answer from a clinical perspective we've seen. So we've definitely seen far more severe disease from the infection itself. At least if we're thinking about cardiac disease or myocardial, specifically, far more from the actual virus than the vaccine. I've had a few patients um, younger, usually Like the few I'm thinking about have been in their 20's that have come in after the vaccine. I know there's this trend that more men may get this, but I've seen actually the two I have are women. And interestingly they've done fine. We've done, you know, we've ruled out other causes. Although at a 20 year old. They're really, most of the time we've considered it being cardio toxicity or myocarditis is because there's nothing else. And they honestly, it's been after the second vaccine. Usually that's where we've seen it. What I've done is treated with usually I don't, I try to avoid steroids that's been mostly culturally we've tried the most and said in the may be short term and most of them have done pretty well. The ones with that have actually gotten illness from the virus. They often have not done well. We've seen, you know, drops in the s and they don't get better. Some of these patients have been on ECMO and I always think it's interesting and actually you could probably help with this question as a rheumatologist more than I even can. But you know, the vaccine, you're not getting the virus, your body thinks it is, it's your body. And so obviously the immune response. And I've been I've been curious is whether people with rheumatology disorders since they have such a robust robust immune system, have you seen more significant pathology from either the vaccine or virus in your patients? Because I was wondering since it's often the immune response that's causing many of these effects, right? We're seeing that the patients are being hospitalized for the immune system is going haywire. And so I always wondered if patients who are not being adequately treated on municipal presents for their rheumatology disease, Are they often going to do worse with either the vaccine versus actual covid virus? Yeah. I can't answer that clinically because I've retired. But that's it's a good question. Um I don't have an answer for it. Yeah we were still recommending even I've gotten a lot of questions from patients with a prior history of pericarditis myocarditis. Like should I not get the vaccine? And I tell them the mechanism is very likely different. And I'd be more worried that if you got covid honestly. So I still recommend it. And I think the people who have had you know it's mostly the M. RNA vaccines, Advisor and Moderna. If they've gotten reactions I say that J and J. Is different. So I would get the johnson and johnson and I would still continue to be vaccinated. And I think most people have listened to some people have not and I'm sure that's the case for everyone's seen have a question for the major the major concern with the rumen illogical patients is you know, certain groups of immuno suppressants that will predispose patients to a greater risk for covid. So it's probably better that they get vaccinated than and not. Yeah. Yeah. Have a question. You hear me? Hello, go ahead in there. What do you want to ask a question? I can hear you about using the intra cycling's and the high incidence of the cardio toxicity and the availability of the new biologicals is that you do. We still I know probably this is for oncology but is still the intro cycling is the first line of treatment of certain cancers taking into consideration the high cardio toxicity. Yes. So I think in breast cancer it's actually less now. Right. They use a lot of other agents for breast cancer. But for lymphoma and leukemia it's still you know, one of the first line agents I think A. C. Um I'm so sorry art shop for lymphoma right. Which includes ants recycling. And then also IDa Robison is part of for leukemia acute aml leukemia. They often use it as well. So it's mostly for leukemia lymphoma that I've been seeing more and three cyclones uh for breast cancer. I think in certain types they still use A. C. And that's what I was saying and recycling cyclophosphamide. And then often depending they'll often also use Herceptin later if it's her two positive. That being said there are also using a lot of um Pirjeta and some of the other ones as well. Tax on Pirjeta along with Herceptin. So it's something that we're going to continue seeing for a very long time I think still and you know I had alluded to this earlier is that and the recycling cardio toxicity. I think you can see even your speed. I think initially we think that you know there were that one trial that showed within the first year is probably the greatest. And so if we screen these patients with 62 months, 6 to 12 months after they've completed and recycling we might catch that cardio toxicity and a good number of people. But we've all seen patients who have come in you know they've had a normal E. F. For years and then coming years later with a drop. And is it something else? Of course it can be. But I will also say that I think anthro cycling's decreased cardiac reserve in patients. Right. And as a result all stressors that subsequently occur have more of a likelihood of affecting that ejection fraction and LV function. That's why I think that even later a lot of these patients can drop their ejection fractions. We usually see when they come in the hospital with some other illness whether it's sepsis I think aging probably also contributes. Right. And then ultimately it's going to be the genes that we don't know yet that people have rights some genetic predisposition and we have not figured out what they are. And i in a perfect world, will be able to identify those genes and know which patients are at risk before it even happens. Thank you very much. Yeah. I think someone in the chat had or actually can't even talk about against G. L. S. And then determination and measurements again. And so what global longitudinal strain is. It's something that's in our eco party graphics software most places have and you basically are attracting that. Myocardial and the thought is that the computer and software can pick up these changes before our eyes can. Right? So we detect cardiac toxicity before we even see the drop actually in ejection fraction. And so the thought has been is like we do it at baseline and then often these patients get serial measurements either during therapy or afterwards. And the thought is like is it consistent? This is G. L. Is the same or is there a drop? I still think the biggest issue like what what the studies are done have shown is that in a study environment you can be very controlled. You can have one reader one ultra sonography for one machine one software. And so you can actually I think it makes when you track it the data means something I will say in the real world like that never happens in a clinical echocardiogram lab right? Like there's different machines. There's often different software there's definitely different texts and readers each day that is reading this. And so I think that's one caveat but in terms of what we've been doing is we'll get a baseline G. L. S. And all these patients. And then every time like for example with trespassing every single time they get an echocardiogram in three months we repeated if that drop is greater than 15% from prior then it's considered clinically significant if it's less than 8% it's stable. That being said again I mentioned that suk or just recently came out right. And they even used strained to determine whether patients should start getting cardio protective therapy and they really found no benefit in one year. And so right now I feel like we're doing this and strain has been shown to be helpful in other diseases like heart failure, hypertrophic cardiomyopathy even aortic stenosis. People have been looking at but I think right now we use it to maybe um tell us we need to pay more attention if anything else. Like if someone strained drops like in the echocardiogram would I end up And it's a significant drop. I usually reach out to the patient and say hey how are you feeling? Any symptoms? Any side of any issues at all. And then like I mentioned earlier one of the other things I like doing and we could all be doing this is that if you know someone's going to get cancer therapy and they have a baseline history of hypertension is to change those antihypertensive. Two more cardio protective therapy because at least that way you're adding a little bit of extra. That could be helping them in the long term. But definitely not any data to support us for prophylactically treating patients with beta blockers. Ace inhibitors or arbs just on a lower G. Ls based on that? Only if they drop their, yes it's very different than than I would initiate those. I hope I answered the question. Okay Any other questions. Excellent talk dr thank you. Okay it's been very informative. Thank you. I hope so. I know it's not oncology is not cardiology but I I really do think, you know, primary care is it's going to be seeing a lot of these patients. Um I'm hoping that don could something that sometimes can get us a lecture on. Just an overall view of immunology and how these immunology is changing exponentially. And we're learning so much new meds. So, I mean, that would be great for us. Old timers to get an overview. We never had this in in pharmacology classes because I know that's very important. Mm hmm. I had I have a master's background in pharmacology. This stuff. This stuff never existed way back when. And you would have been like an expert back then when this came out then. You would have been the expert people would go to since you had this background of understanding how some of these drugs work. But but it's changed so much. The understanding. That was 40 years ago. I have one final question. Dr O'Quinn uh, is Don powers. Does radiation therapy have the same uh, complications induced? Yeah. So, yes, So, radiation is just one of the things I've only very briefly touched on at the end. So radiation um, definitely causes cardio toxicity for sure. So, what we used to think it was only with time. But there have been studies that show that even in acute when they receive radiation that there are some changes clinically speaking, what we normally have been doing is that I always ask them, did you get radiation? Often patients have little tattoos you can look for to figure out exactly where the radiation field was. Nowadays. The radiation oncologists are very careful about trying to minimize cardiac exposure. A lot of them if they have less cited lung cancer for example and the heart is in the field here and then they often use proton therapy because they can actually control where that radiation goes and minimize the cardiac exposure. That being said sometimes you can't help it. And what I normally do in those patients is we get a baseline studies consisting of MT PRO BMP as well as troponin. And then mostly I get an echo too. Subsequent follow up includes in many of the guidelines now. But even if patients are asymptomatic to do a stress test in five years after radiation exposure. And the reason for that is is even if patients aren't having symptoms you never know if the nerves were damaged and they they may still have corner artery disease but they're just not manifesting. And so I usually stress them every five years after exposure. I usually also if they've had carotid artery radiation right for head and neck cancer and sometimes with certain lymphomas it goes up higher. I usually get credit ultrasound as well in five years and then echocardiogram because radiation can really affect the valves, it can affect the arteries. It can affect the myocardial and that can also affect the pericardium. One of the really um I still remember I found this super interesting. Which is why I think hopefully it will stick with you as well is one of the surgeons and I think he he was at Mayo Clinic who does did a lot of these patients with radiation history. So prior people would get blasted with radiation because people used to think that the radio the pericardium protected your heart against radiation. So that's why you see a lot of these patients survivors from the 1970s. They have so much corn they usually aortic and mitral valve replacement, coronary artery disease and diastolic dysfunction as well as LV dysfunction. And a lot of them can have constrictive pericarditis right as well because of that radiation affecting that pericardium. But it's very hard to tell the difference between pericardium being affected versus the myocardial being stiff from the actual radiation as well. And so what the surgeon told us was he would get all these referrals for you know, para cardiac to me to strip the pericardium because this patient had constrictive pericarditis. And often all the studies we had in cardiology. Sometimes we can't tell whether it's that thick and myocardial and a restrictive picture versus true constrictive pericarditis. Pericarditis is requiring removal of that pericardium. So what he would do in the O. R. Is he would make a slit in the pericardium. If the LV bulged out right then he would strip the pericardium because he said that clearly showed that it was that constrictive pericardium that needed to be removed. But if that didn't happen he would close the patient and then they would be treated for restrictive cardiomyopathy instead because the muscle itself as well or the damage had occurred. So hopefully I don't know that that has stuck with me for years and years in terms of thinking about how to look at for certain side effects and also to think about this. But I think for you I would say if you see these patients who had radiation I would stress them if they haven't gotten the stresses in the last five years. And then I would also get an echocardiogram as well linda. Can you hear me? Yes I can. Um We're over nine we're over the nine p.m. So I just want to assure our audience if you use E. D. S. I don't know if you're familiar with seeds. Um for credit. I have set it up where the conference is one hour and a half so we're okay just to let let the audience know. Great thank you. Well I will follow up I'll send a recording and some other information on dr O'Quinn um I have the grand rounds distribution list you had given me before Dr powers and if there's feel free to pass it on to anyone that I may have missed on there. Well, thank you Everyone really appreciate you. I really appreciate your time again on a saturday morning. You guys are troopers. So thank you so much. Thank you very much. Really, really informative, very informative talk that you don't usually hear about. Oh good. I'm glad. I hope it wasn't, it was relevant and that's really the most important thing. Absolutely. Very good. Thank you. Thank you all have the rest of your weekend. Thank you everyone else as well. Take care. Bye bye. But by