In this webinar, Dr Rupal O’Quinn discusses the cardiovascular side effects of cancer and research surrounding cardio-toxicity. She elaborates on the links between cancer and heart disease and the options available to patients to decrease the cardio-toxicity of certain cancer treatments.
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All right. Good morning, everybody. For those of you that are logging in, we'll get started in just a couple of minutes At 7. 30 the CMI information is on the screen. Um, and that information will be also available in the chat box here. So we'll wait a few more minutes on like folks log in and then get started, right? Yeah. Yeah. All right. Good morning, everybody. Welcome to the cardiology grand round. Um, uh, the CMA information is on the screen for those of you that are claiming CMI credit, the code will also be available in the chat box. Um, in case you missed it here in the beginning. So for today's grand rounds, it is my pleasure. Thio, introduce Dr Rupel. O'Quinn. Rupel is one of the new faculty members to join us here at Penn Presbyterian Medical Center in Penn. Cardiology. Rupel received her medical degree from um d n j. Robert Wood Johnson School of Medicine and then completed her residency at the University of Michigan cardiology training at Beth Israel Medical Center in Boston. She has an amazing background, which includes global health and even aerospace medicine. Before settling into cardiology, she came depend in 2014 to receive additional training and cardio oncology, enjoying the faculty down the street at Hub, where she has helped lay the groundwork for the entire field of cardio oncology. She was very involved with the A C C Leadership Council that led to the recognition and the spreading of the importance of this field in cardio oncology. She has so many accomplishments that it's impossible for me to summarize all of these in such a short time, and I wanna leave most of the talk for her. So as we're learning more about the importance of cardio oncology, especially, his patients are receiving new types of therapies, including chemotherapies, hormone based therapies and immune based therapies. And I know personally, it's really tough to keep up with all of these new medications in these new classes of medications. Luckily, we now have Rupel to help guide us on these issues, so we're very delighted to have Rupel joined the faculty here, a Pen Presbyterian Medical Center, and we thought this grand rounds would be a nice way for folks to get to know her. A nice introduction for Rupel. All of you will quickly get to see how great of a person in physician she really is. So, as we have done in all of our webinars, three questions and chat boxes will be open. Feel free to leave any comments or questions there. The last 10 minutes or so, we'll leave for a question and answer session. And again, we'll run through the questions at the end. The CME code it once again eyes on the screen and will then be listed in the chat box. All right, RuPaul. I'll let you take it away from here. Sounds good. Can everyone hear me? Okay. Yep. Awesome. So, first of all, I'd like to thank everyone for coming to this. I'd also like to take Harvey Waxman as well a Samir Kendall for inviting me to give this talk. I'd also like to thank Linda Lafferty for organizing everything. And so, in the interest of time, I'm just going to get started. So I have no relevant financial disclosures. So by the end of this talk, I hope you understand that the importance of cardio oncology, and I hope you learn a little bit more about the definition of cancer therapy related cardiac dysfunction. I hope you feel more comfortable diagnosing this type of cardio toxicity as well as managing it. And finally, I want you to be better able to recognize some of the common cardiovascular side effects coming from some of the newer therapies and feel better equipped to manage these toxicities. So why has cardio on college to become its own niche? And especially since a lot of these cardio toxic in with Therapeutics have been around for a really long time, so many newer, more targeted their agents air coming out that have cardiovascular side effects that are both on as well as off target. And it's getting really hard to keep track of all of them. So people in general are living longer, and developments in cancer treatment as well as care have improved survival for cancer patients. A swell but often their hearts sustained some sort of damage that is meant for malignant cells. And so nowadays, many of these treatments also caused cancer to become a chronic disease. So the goals in this field include recognizing which therapies can cause or increase the risk of cardiac damage, preventing or mitigating cardiac damage, whether it be via medications or even earlier detection and then eliminating cardiac disease as a barrier to effective cancer treatment. We want to monitor these patients with based on cardiac issues as well as risk factors for either worsening or development of new cardiac problems. So research is extremely important because we need to find out why certain patients are much more susceptible to card a toxicity and also discover ways to mitigate the damage and find better ways to earlier detect this damage as well. And the goal ultimately, is to ensure a better outcomes for patients with both cancer as well as heart disease. So why should we all care about cardio oncology? So back in 2017 to 2018 18 heart disease and cancer with the top two causes of death? I imagine that 2020 will be a little bit different because of co vid. So multiple studies have also shown that there appears to be a link between cancer as well as heart disease. So hasn't it all show that heart failure patients are at increased risk of cancer and also have a worse prognosis? And then another study demonstrated that cancer increases the mortality in heart failure, so they have similar risk factors such as age, obesity, diabetes as well as tobacco use. Chronic inflammation and oxidative stress likely play a role in both the pathogenesis, as well as the progression of both heart disease as well as cancer. So patients are also going to be seeing articles in the news about cancer there. Pew Knicks and they're going to be asking us as their cardiologists about these questions. And they were also going to be asking their oncologists, their primary care physicians and the radiation oncologists about whether some of these treatments can damage their heart. So the most common type of cardio toxicity from Uncle Odjick agents is left ventricular dysfunction. So there have been many definitions of cancer therapy related cardiac dysfunction or C T. R C. D. So one of the more widely used definitions is a decline in L V E. F or left ventricular ejection fraction from a baseline of greater than 10% to a value of less than 53%. The baseline left ejection fraction is the E F. That's prior to any therapy, so other groups have also used it 10% drop from baseline to an E F off less than 50%. And then there are also multiple other definitions out there that have been used in the trial settings. So C T R C D can be symptomatic or asymptomatic, and it can be reversible or irreversible. Some believe that CTR C D can then further be broken down into a type one toxicity where, which is what anthro cycling's cause or type two, which consists of trust. Use a mob tiresome kind, kindness inhibitors as well as others. So Type one toxicity is thought to be irreversible damage and celebrate with cellular apoptosis as well as death. Would change is actually seen on pathology so often, patients will have a history of chemotherapy, and they won't be able to remember what kind of therapy they received. So what you should do is ask him if it's read it. If it is, there's a Dr. Robison is actually called the Red Devil, at least partially due to the fact that is bright writing color and almost looks like Cooley. And so one of the reasons also is probably the many side effects it has, and then Type two toxicity is thought to be secondary to chemotherapy that cannot cause cellular death, maybe seller dysfunction. There should be no changes in pathology slides. And the story, though, is becoming a lot more complicated with the advent of these newer therapies, because sometimes they don't fit the category of type one or type two, so it's likely many more types than we realize. So in regards to monitoring so historically multi gated acquisition or mug, A scans were used to monitor left ventricular ejection fraction during treatment. So some of the limitations, as many of us know, included accuracy, problems and reproduce ability as well as the radiation exposure. And then there was also limited information and other cardiac structures other than the E F. So nowadays, the most common imaging modality is two dimensional echocardiography, So advantages as we many of us Noah's well is that it is violent, widely available. There's no radiation exposure, which is extremely important. Some of our cancer patients, since many of their treatments as well as the images required, exposed them to additional radiation as well. Echo also offers the ability to see other aspects of the heart, like the great vessels as well as the ballots. But we all know that there are also disadvantages to echo. And sometimes people with certain body habitants, no matter how many times we change their positioning, were unable to get a good image. There can also be significant differences and ejection fraction from one reader to the next. And given the fact that the definition of cardiac dysfunction where C. T R. C. D is a 10% change, this can sometimes be difficult to detect an echocardiogram, especially if the image quality is poor. So it's also important to keep in mind that loading conditions can be variable in these patients since many of them receive I V fluids as part of their chemotherapy. And then many also experienced volume contraction from nausea, diarrhea as well as low port or port pio intake. So the expect expert consensus of the American Society of Echocardiography and the European Association of Cardiovascular Imaging has recommended three dimensional echocardiogram, or cardiac emery, which is actually the gold standard to basically evaluate for cardiac cancer therapy related cardiac dysfunction. So studies have shown that three D echocardiogram has better reproduce ability as well as lower variability, and this is extremely important in patients who have a lower border, nine e f. However, it might not be as widely available. It can also be more costly, and expertise is often required when you're trying to obtain reproducible and accurate values. So the expert consensus notes that if three D is not available modified by plane, Simpson's techniques should be used to calculate the left ventricular ejection fraction, and that strange should also be used. So, as many of you know, strain measures myocardial deformation, it looks at the myocardial, thickening, shortening or lengthening in various dimensions that are commonly longitudinal. Radio or circumferential. Global longitudinal strain has been shown to be the most reliable and reproducible when you compare it versus sir compression on radio. And so this is the strain parameter that most commonly is used. And although echocardiography is helpful in detecting cancer related therapy, cardiac dysfunction by the time it's noted on echo, it's almost too late because we already done the damage. So ideally, we would like to detect the card, a Texas city before we see the actual decline and left ventricular ejection fraction. So based on this, there have been numerous studies that have looked into G l s in the world of cardio oncology, with most of them being done on patients undergoing treatment with either an three cycling's or trust use in that. So they have been shown that G L s can detect subclinical left ventricular dysfunction earlier and that these findings are more reproducible than just two dimensional echocardiography alone. It is also better than E f in detecting mortality from all causes, as well as providing better risk stratification and those who have heart failure. But there are caveats. As we all know, it's important to remember. That strain is also under the same issues that we have in terms of image quality. And then it could also be influenced by the same loading conditions. So often it can change based on the volume status of the patient. There is also both Inter, as was intra observer variability as well as test and retest variability. So it is recommended that echocardiogram labs do it. The inter and intra observer variability study, which consists of at least 50 echocardiograms before they begin reporting the jealous values and then is you know, to complicate matters even further, there is inter vendor and software variability. That makes accurate comparison of studies really difficult when you're using different kinds for serial patients or serial studies in the same patient, and here you can see that even the GLS varies between vendors and even software. So then biomarkers such a sir opponent, anti pro BNP have also been looked at and I will be discussing those on the next slide. The American Society of Echocardiography and European Society of Cardiology strongly recommend obtaining global longitudinal strain. In addition to LVF, Venezuela is a proponent. I did delete the same vendor, and software should be used in each patient during serial studies and the G S s value should be compared to baseline. So a relative reduction of GLS is considered to be a value of change of greater than 50% from baseline, and that is considered to be clinically significant and concerning for subclinical cardiomyopathy and those who have received cardio toxic therapy. A relative reduction of less than 8% is considered clinically and significant, and a change of 8 to 15% is indeterminant. So a good example is a patient with the G l s a baseline of 22% so she undergoes an echocardiogram after three cycles. If it has to, Zermatt, her GLS is now noted to be 17%. So the question that often comes up is whether this is clinically significant. So if you do the math, the change in G. L s is actually 23% which means that it is clinically relevant. So she was then referred to cardio oncology, and she had been on baseline anti hypertensive, consisting of hydrochlorothiazide side as well as a motive pain. So I switched her to carve out a wall in the center pearl for additional cardio protection. Her trust use a map was continued, since there's still no clear data to support stopping the trustees a map when the Onley abnormal parameter is just GLS. So then biomarkers have also been another tool that offer hope and potentially identifying subclinical cardio toxicity. So numerous studies with many of our own colleagues here at Penn, such as Bonnie Key, Joe Carver and Mariel share Crosby have shown that certain biomarkers, or elevated in certain therapies and then the most common by a marker right now so far is troponin. And many of you know that Proponent eyes goes sensitive as well, a specific from myocardial injury. And so although both Proponent I and T have been looked at, it is proponent I that has been studied the most in patients who have received anthro cycling's trust, use a mob and entire seeing Chinese inhibitors. Many studies have found a possible relationship between your opponent elevation as well as an in current or future cardiac dysfunction, although if you have not, one thing seems clear is that high sensitivity troponin is has ah high negative predictive value of Eve decline, and so it might help us identify those patients who are at low risk for cancer therapy related cardiac dysfunction. But still more research is needed in terms of finding out the best timing of the troponin draw, finding the optimal cut off values and then ways to increase the specificity off the high sensitive troponin. So then NT and pro anti pro BNP and BMP have also been looked at in multiple studies, but studies have been very small and the results have been conflicting. So there is a larger multi central predict study that's currently underway, and it's hopeful that they will be able to figure out whether there is a utility of biomarkers and identifying and recycling cardio toxicity. And so here a pen. What we many of us do is we checked your opponents an anti pro PNP in certain patients at both baseline as well as each cycle. And some of these higher risk patients include those who have received a significant amount of anthro cycling's as well as those who have preexisting LV dysfunction. And if the values increase from baseline, this often will prompt me to monitor them more closely and maybe have more frequent echocardiograms done. Thank. So now I'm going to be switching gears and talk about some of the newer agents that can cause cardiac toxicity. Since an through cyclones are the class that most patients or most people are familiar with, I won't be talking about some specifically, but you will see that I would be bringing them up. Even in this best of this talk, I'm not going to be talking about five. If you either. I will be concentrating on some of the newer, more commonly seen targeted agents that can cause cardiac toxicity, so the ones I will be concentrating on will be trust use a map. The badge F inhibitors some of the newer, tiresome kindnesses for chronic My life, just leukemia that target the BC are able and then Rutan's harassing highness inhibitors that are mostly used for chronic lymphocytic leukemia as well as other disorders as well. And then finally, I'll be ending with the case with checkpoint inhibitors. And so I know this already seems like a really long list. But this is actually nothing compared to the entire list and especially because this list keeps growing. So if case number one is, we have a 60 year old woman with the history of hypertension, hyper lipid, EMEA and left side of breast cancer who underwent four cycles of chemotherapy, consisting of Dr Robison as well, a cyclophosphamide that then resulted in remission. She unfortunately is then diagnosed with metastatic right sided estrogen receptor negative progesterone receptor negative her two positive breast cancer and is then started on trust. Use a map so her baseline left a particular ejection fraction was noted to be 60% but then she undergoes an echocardiogram after five cycles, at which time she's also experiencing winking as well as dis Mia and her new ejection fraction is lower at 35%. The Trust Jews UM A, which is also known as her septum and may have been the more common name for which you know, was approved in September of 1980 1990 80 as the first FDA approved targeted cancer agent in women or people who have heard two positive breast cancer so over. Expression of this epidermal growth factor sub unit was previously associating with poorly differentiated tumors, higher rates of metastases and poor patient survival. So her two positive breast cancer was the type of cancer you did not want to get. However, addition of trust, use a map to standard chemotherapy when Dr Robison and Cyclophosphamide resulted in a 20% increase in real observed 20% decrease in risk of death at one year. The first pivotal study was actually notable for symptomatic heart failure as well as asymptomatic cardiac dysfunction in over 25% of patients who had also previously received an anthro cycling based regiment. Along with the trust is a mad, and this may be because her to is actually very important for service cell survival. Subsequent trials and clinical experience have showed that trust use a mob actually has a lower incidence of part of my heart to myopathy, and this may just be due to the fact that people are looking for and that closer monitoring is done. But I also think that many of these trials excluded patients that had preexisting cardiac disease and heart failure. So certain factors that have been associated with higher risk of trustees. McCarty toxicity. And these include older age obesity, hypertension, those who are being treated with an three cyclists who have had a previous exposure. Those were the low ejection fraction of Baseline and those who have received a prior history of cardiac radiation exposure. The cancer therapy related cardiac dysfunction usually manifest during active treatment and can improve with interruption of trust. Use a map or the initiation of cardio protective therapy such as A C inhibitors or Arabs and be blockers. The toxicity due to trust issues. Map is not thought to be a cumulative dose related, which is different from anthro cycling's where cumulative doses actually very important. But it has been found that duration can be a factor for toxicity. They have found that LV discussion that dysfunction can be twice the rate and those treated for 24 months versus those who have been treated for 12 months. Also, some of the newer her two agents can cause cardiac dysfunction. But the incident and so far, has been lower. One recent study did show that cardiac toxicity was seen in patients receiving trust, use, event and tensing, but that the overall event rate was low and that most patients remained asymptomatic with an improvement in their E. F after the therapy was discontinued. So this algorithm I'm showing is suggested by the American Society of Echocardiography. They recommend obtaining the baseline LVF three days preferred, as I mentioned earlier, or two day if it's not available. And they also want you to consider obtaining either global longitudinal strain and or a troponin tie. If the base fine F is less than 50 per 53%. 3 recommend that a car Dick Emery should be done for verification. If an indeed notes that F is not normal or and if the G L s is decreased or two opponents are elevated, all of the's should prompt a cardiology council. If all of them are fine, then you could look on the right side, where an echo as well as GLS android proponents should be checked every three months with therapy and then if patients have previously received an three cycling's. They also recommended an echocardiogram be done six months after completion of trust using them. And the reason for this is because smaller studies have suggested that mortar cardio toxicity is, or most cardio toxicities scene after an three cycling based community therapy within the first year. And so recovery has also been shown to be more likely if you initiate treatment earlier. So the reason these patients on trust is a mad get echocardiograms every three months is that the package insert by the FDA actually states that you should, and then the Canadian consensus guidelines actually recommended as well. And then, if there is evidence of toxicity, we should hold or you should hold trust. Using math should initiate guideline directed medical therapy with either Baylor blockers, ace inhibitors or arms, or all three or all, too, with the classes of beta blockers and eastern ARB, and then you can re image after 3 to 4 weeks. One thing to note is that the breast cancer clinical practice guidelines actually recommend withholding or discontinuing if the ejection fraction drops by more than 10 to 15% or below the lower limit of normal, which in women is 54%. There have been studies but very small about 20 patients. So this one showed that patients who were treated and followed for one year and during that study period, about 90% of patients continue to increase. Trust Susan Matt, despite the fact that they had a mild decline in their F to an ejection fraction, about 40 to 54% or if they're called F had dropped by 15% or more. But none of these patients had symptoms, so the graph on the right shows that the baseline ive had been 60%. And then there was that decline. The graph on the left shows a closer look at that e f change over the subsequent one year trial period in which patients underwent serial echocardiograms while also receiving treatment with either a sin him bitters and or beta blockers. You can see that although the E F dropped by less than 40% in about 10% of patients, symptoms of cardiomyopathy improved after trustees the man was stopped, and over the study trial period, there was actually an increase in E F from about 49 to 55% in patients. Where can trustees Matt was still continued? So these findings suggest that maybe even we may be able to continue trustees to map and even if especially if the by cardio toxicities mild as long as these patients are closely monitored and they receive treatment with ACE inhibitors and or ARBs and then later blockers as well. So there was another really small study, also of consisting, of 31 patients called Safe part, in which patients with mock cardiac dysfunction who are receiving her to target therapy were closely followed by cardio oncologist. And it was found that 90% were able to complete their whole entire treatment course without any significant decline in E. F at the end of treatment. So these studies help highlight that many of these patients should maybe continued therapy sends often that is actually the best thing for their cancer. But then there's still more research needed that needs to be done overall in this in the area in particular. So we need to be able to identify patients with the highest risk of irreversible disease, as well as determine the best way to monitor these patients. We we need to make sure which aspects or types of standard heart failure therapy are the best ways to treat these patients. And then the populated question that often comes up is whether there is melted away. Thio actually prevent cardio toxicity by profile acting starting certain medications. And there have been a few smaller prospective randomized control trials that look at this, the studies have included. So the ones I've actually listing here are the ones that have included trust. Use, a map. And then most of these studies have been small, consisting at about 100 to 200 patients. The take away from them have been that metal parole did not actually prevent cancer therapy related cardiac dysfunction. One trial did show benefit with Candace certain, but another one didn't. And then Manticore found that parent does April as well as the super law attenuated the E F decline but did not prevent modeling. And then we have the overcome trial from 2019. So this is so far the largest trial we have with almost 470 patients. It was double brought blinded and it randomized patients with her two positive breast cancer to receive carvedilol, 10 mg extended release listener Pearl, 10 mg or placebo. And this basically was a 33 groups. So Karnataka City was the primary outcome, and they found that cardio talk says he was actually so learn all three groups despite treatment, and that it was actually higher at about 30% compared to prior trials. The one thing that they did find out was that in the pre specified analysis of women who had previously received anthro cycling's in addition to the trust you Samantha, they actually saw a protective effect of both with center parole as well as carvedilol. The one thing to remember also, though, is that there were a number of issues that were noted with this trial, including the fact that they used a very broad definition of cardio toxicity, which may be one of the reasons why they saw such a high rate and that also mug a an echo were used to measure the cardio toxicities. So there may have been some variability there as well, since a lot of the other trials used cardiac Marai. So basically, the jury is still out. What I end up doing that if patients are on anti hypertensive baseline, I usually will switch their therapy toe a combination of either carvedilol and this Oprah law or ACE inhibitors. So sorry, Corrigan Orbis Oprah Law in addition to a sin ARBs, especially if they've raised anthro cyclones in the past. So next I'm going to be a to doing a few cases with terracing kindness, I inhibitors. So if this slide makes you feel even the slightest bit overwhelmed, that's actually good, because it was my intent. The whole purpose is just to show you that there are so many tires seeing kindnesses expect there's over 60 receptor ones and then also 30 cytoplasmic, and they all do many of different things. And so when we talk about tires and Chinese inhibitors, it's actually a very broad term. Targeting one aspect may manage one type of cancer while targeting another country. It's something else. But many of these have downstream effects, and so targeting a pathway can also have married effects on many other organ systems, cause you're off target effects. So this is one of the reasons that this group of medications can have such a diverse side effect profile. And so I'm actually going to be specifically talking about three classes of ties in Chinese inhibitors. So this case number two is a 63 year old man with a history of metastatic renal cell cancer, as well as hypertension on hydrochloric thighs I he presents to oncology. And it started on a veg F inhibitor called Saravanan, So his baseline blood pressures have been very well controlled at about 1 22 seventies after starting Saraf in it, he actually blood pressure stark of going up, and over the next 10 days they increased toe 1 90/1 02 So the veg a singling pathway which is also called the VSP, leads to activation of FGF receptors among many others, and then that leads sit down stream activation of multiple pathways, including Vasco tiled ill in hospital. Three Chinese, which results in the release of nitric oxide sympathies, which increases nitric oxide production as well as increasing processing of violent production. So nitric oxide then migrates the adjacent soon muscle cells, and that eventually leads to cycling GMP generation and that causes subsequent days debilitation. All of this leads to angiogenesis, endothelial cell survival, visibility, ation and normal contract. I'll function, which is all necessary for cardiovascular homeless Stasis. But the same pathways can also contribute to tumor growth, since they're used by the cells there as well. So the veg of signaling pathway inhibitors target this pathway to suppress the tumor growth, and as a result, the nitric oxide pathway suppress and the end of the oil one pathway stimulated process, the cycling production decreases, and this leads to increase oxidative stress, cell injury and audio dysfunction, basil constriction and then hypertension. In addition, many of these veg of targeted therapies air also associated with an increased risk of our arterial from bolic events that include stroke, Tia's myocardial infarction, angina as well as other arterial events. So plate like activation is also accompanied by the risk lease of the Jeff. And so this seems to normally regulate endothelial cell survival and repair of the vascular chart. So if you inhibit by Jeff, this likely also can cause microvascular injury and potentially a thrombosis as well. So as you've probably gathered hypertension is the most common side effect with these by Jeff INHIBITORS, so risk factors include pre existing hypertension age greater than six years old and a B M I of over 25. Three Effect is likely dose related, since it is more frequently seen in people who have been treated with higher doses of that Jeff inhibitors. The interesting thing is that Polly Morsi want polymorphisms and veggies are thought to be associated with the risk of hypertension, and that also is important for efficacy against tumor. This is very important because in hypertension is actually thought to be a marker of treatment response. There was a study done in 2015 that's found that overall survival was higher at 25 a half months in patients who had experienced a hypertensive response with these veggies inhibitors compared to 11 months, and those who had not, and so hypertension can actually be a good effect to see in these patients. But many of us know that it is also important to control the hypertension, since this can lead to heart failure and myocardial ischemia down the road. If we don't do a good job, it is thought that there is also an eye atra genic imbalance between the rain and engine Tencent and at the Austrian system, as well as the bed jet that contributes to the hypertension. So starting these patients who have elevated blood pressures of baseline with either a sin hitters or arms or switching them to this class can maybe attenuate the increases as well as protect against protein area. This class was also associated with improved overall survival as well as progression free survival in patients who had renal cell cancer. So calcium channel blockers are also very effective with the nine die hydro purity and should be avoided since they inhibit the cytochrome P four p p for 50 system, which can then cause higher levels of the of the bed Jeff inhibitors. And then finally there is severe resistant hypertension. You can interrupt therapy, improved treatment of this and then hopefully restart. So Case number three is a 73 year old man with a history of hypertension, Hyperloop, anemia, diabetes, obstructive sleep apnea, who then presents with new chronic myelogenous leukemia. He started on therapy with a magnet. He unfortunately progresses unimaginative as then switched to to Staten. He begins to experience nudist SPEEA and so in echocardiogram is ordered and this is notable for a newly elevated pulmonary. Are the systolic pressure of many millimeters of mercury when previously his pulmonary pressures were normal at baseline, So chronic myelogenous leukemia is commonly due to dis regulated terracing. Chinese called BC are able so prior to 2001 on Lee. 33% of patients diagnosed with CML We're live at five years. Nowadays, with the advent of multi targeted TK inhibitors as well as men that nib the predicted survive, your survival is over 90%. In a matter of itself. Usually it can cause fluid retention as well as rare cardio with congestive heart failure. So, out of all the new retires and kindness inhibitors for CML the satin, it has been assisted pulmonary hypertension and up to 11% of patients, and it may not be reversible upon discontinuation. One possible mechanism is that the satin it causes pulmonary vascular endothelial damage and management includes stopping the deceptive and treating with standard pulmonary arterial hypertension therapy. The satin. It can also increase the risk of vascular events such as myocardial infarction or stroke QT prolongation that needs to be monitored and then pleural and pericardial effusions. My latinum is another newer generation T K I. For CML, it can also cause vascular events such as myocardial infarction, stroke as well as powerful vascular events. It can also cause hyperglycemia as well as Q T prolongation. And rarely it has been found to cause that in cardiac death and then put anonymous the last type of going to talk about in this class. And it's special because it is multi targeted and has potent activity against the evil one. Chinese mutations and why that's important is that hyper pretension is also very common, along with coronary, cerebral and peripheral vascular events. There was a study done by M. D. Anderson that review the charts of approximately 530 patients and the assessed how many of them had cardiovascular or arterial from bolic events during the course of therapy with thes and medications. So people other received a magnet 400 mg daily or imagining 800 mg daily. Other medications included a sad nip on a lot in it and then punitive, so they found that 45% almost half develop cardiovascular events with hypertension being the most common. 9% developed Arturo throw ma'lik events on then. These events were highest in the early years of TK I therapy and varied among the tiresome Chinese inhibitors. So in this graph, the top row highlights that Pernetti therapy is associated with higher risk or the highest risk of cardiovascular as well as our tears. Dramatic attacks. The middle well shows that overall hypertension as well as new uh, said hypertension was also greatest in protecting it. And then the bottom row shows that patients with the greatest number of risk factors also had the greatest risk of this type of toxicity and that it was especially seen in Panetta. So management includes treatment of complication according to the guidelines and consideration of dose reduction. After weighing the risks versus benefits, Banana was actually briefly pulled from the U. S. Market in 2014. But given the fact that it is able to treat after patients develop resistance to the others, it is was now being used again. But there is that caveat that it should, you know, one should exercise caution if patients have based on cardiovascular risk, and then this picture I'm not sure of. Many of us remember learning about so much cells in medical school, but here you go. And the next case is a 65 year old man with hypertension diabetes who presents with progressive chronic lymphocytic leukemia. So he started on a medication called I Brewed in It. He's actually initially attire, writing it very well, but then developed palpitations and presents to the emergency department, where his E C G shows atrial fib relation with the rapid ventricular rate. So to back up chronic lymphocytic leukemia is actually one of the more common B'Tselem malignancies in the Western world and primarily affects the elderly, which we all know have multiple corm abilities and calm abilities, especially cardiac. So the course of CLL can be indolent, with the manager being observation, or it can be rapidly progressive. Eso inhibitors. The B cell receptor pathway represented an attractive option for CFL tart for a target. For CLL, Rutan's harassing Chinese or B T. K, is a cytoplasmic tyrosine. Kindness that is essential to BC are signaling. So I brought in. It was the first Bhutan's terracing Chinese that was studied in the clinical trials. It has been shown to improve both progression free as well as overall survival in relapse and refractory CLL. And these were from the studies that were done in the New England Journal of Medicine initially back in 2014. I wouldn't be talking about it if there weren't cardiovascular side effects, though. And so there are a number. So most common is a tribulation, which was found to be four times more likely in patients receiving I brewed in it and thought to be due to reduce Vasco I nossa taste three activity and then almost 1/4. The patients can also be noted to have hypertension and a three year follow up, and this, as we know, can then lead to a tribulation as well. So increase bleeding was also seen downstream due to effects on local protein as well as bond gillibrand factor receptor. So this is important for many reasons, so this drug needs to be held prior any invasive procedure, including cardiac catheterization. So for Katherine minor procedures, I usually recommend holding it for approximately three days, but it could be up to seven days for any major procedure or surgery, and then the newer B T K inhibitors that have been approved for CLL and small M Pacific lymphoma were back in 2019 and is called al a cat. Nobody knew. Studies so far have suggested a lower rate of a tree population and bleeding. But only time will tell whether this is the case when patients in the real world you're using it more. So. We've also been starting to see other cardiovascular effects with I Bruni. So one studied actually queried the International Farmer Co Vigilance Database, the vigil base, and they found that seven cardiovascular events consisting of super ventricular tachycardia, hypertension, ventricular arrhythmias, CNN's hemorrhagic as well as the scheme, IQ events, heart failure and then conduction disorders were more likely to occur in patients receiving I brewed in it compared to all the other drugs in the database, and so that these are also additional potential side effects to be aware of so treatment of atrial revelation. When patients are on Uprooting, it is a bit more complicated due to many drug drug interactions. So I Bruton it is metabolized primarily by the side of chrome p 4 50 as a result, any concomitant use of multiple drugs such as amiodarone or rapper Millard. Autism can cause increased I brunette levels in routine. It, I mentioned earlier, can inhibit peak like a protein, and as a result, it increases plasma to Jackson levels. So you have to be careful when using the Jackson as well. Thea Other question that comes up is whether we should anti qualities patients, since I mentioned earlier that they have a higher risk of bleeding, has already a based on with this drug. The things to consider is that militancy also increases the robotics Rick. And so the chance to vast can often underestimate the risk in this population. And then some have tried using the had split for a scoring system to figure out the risk of bleeding. But again, it doesn't take into account of Bruton it, and so it may underestimate the risk of bleeding to bay things more complicated. I'm Bruton. It also increases factor 10 inhibitor levels such as River rock, Saban A picks, a band as well as the docks Urban, and it could also increase levels of direct thrombin inhibitor like the big entrance, and then also increases warfarin levels as well. So what? I've been usually doing is actually using Factor Tennessee. Most of these people, sometimes at a lower dose. But it is actually a very personal decision. And what I've been doing is leaving it up to the patient in regards to the risk versus benefits. And I've actually been really surprised to see that many patients have a very strong opinion about whether they want to be on additional anti coagulation or not. So this is the last case. So we have a 53 a woman with a past medical history of metastatic ovarian cancer who undergo surgery, and then it started on Pemberley is a mob she presents to the emergency department within exertion. All chest pain and her EKGs showed this. So it's an accelerated in your ventricular rhythm or slow B T, and you can see that it's quite different from her baseline BCG. So her labs air, also remarkable for an elevated troponin as well as the sea can be. Her trans drastic echocardiogram shows a reduced of BF of 35% as well as RV dysfunction, and she had had an echocardiogram a few months prior that showed normal E f. So she started on appropriate cardiac medications. She undergoes cardiac catheterization that shows no obstructive coronary artery disease. And then she undergoes cardiac and rye, which confirms myocarditis would delay Catalonian enhancement predominantly in the ethical septum as well as global t two elevation. So she is treated with steroids 1 mg per kilogram. But unfortunately, she continues tohave ventricular tachycardia. So what is this class of medications? So checkpoint inhibitors. So our immune system is really important preventing as well as controlling cancer. And the T cells are a major component and that the process is actually regulated by a Siris of CO stimulatory, as well as inhibitory signals that conserve as checkpoints. So CTL a four as well as P D one are two of the many checkpoint receptors. So a simplistic way of thinking about this is that our T cell activation is actually turned off by the tumor cells because they're really smart and when they especially what they do it by attaching to these receptors. What immune checkpoint inhibitors do is that they actually latch onto these receptors that prevent the tumor cells from latching on. And this causes RT stills to stay activated, which in turn can attack the tumor cells. So these medications essentially enhance her immune system and then has shown progression free as well as overall survival in a growing number of adult cancers, and that had been refractory to traditional chemotherapy. But as you can imagine, from what I've told you, many of these side effects or autoimmune so this was back in 2015, and these were some of the cancers where immune checkpoint inhibitors were showing promise. But in the last five years, there have been almost 57 approvals by the FDA and which shows that how many times these medications are being used in health common, they're becoming so. More recently, thes inhibitors have been associated with a forceful increase risk of major adverse cardiac events. But initially, cardiac testes city was actually thought to be rare. It was more likely to occur with combination therapy, and even in the initial trials, though, they found out that myocarditis, which was the most common card a toxicity, was seen to be highly fatal, with the mortality of up to 50%. And then early case reports also showed this and that LV dysfunction, a scene with both positive proponents as well as negative proponents. And so there's some thought. There may be different 10th of theologies that are causing these variable presentations. So talks to talk with you bill pericarditis vasculitis basis fastened in a CF have all been seen as well. We don't even know the long term effects of implement that all the information yet, and it's very possible that this class of medications may increase the risk of an throw sclerosis and patients down the road. And these toxicities can occur at any time. But most studies have found that they often occur early, usually within the first two cycles. The toxicity is especially hard to diagnose, since F could be normal and the troponin could be negative in the non inflammatory I'll be dysfunction, so there's still quite a bit that we need to learn. So for management includes stopping or holding the agent, it is important to rule out other causes, such as coronary artery disease, and then, since my oh card itis is the most common, the next step after doing SCG TRA opponents and even echocardiogram would be to do either a cardiac Marie or a biopsy toe look for bio card itis And then if if it is positive for my card itis, you should initiate steroids. And there's currently no consensus in regards to stare reducing. But studies have shown that there is a lower risk of Mace if you use higher doses and if you initiate earlier. But not everybody is going to be responsive to steroids. And so other immune suppressive agents should be considered so you can see the list over here. But one of the ones that we often use that the pen has been afflicts the MAB. So the reason for the black box warming with the fix the map has been that it has shown development of heart failure in patients who have had rheumatoid arthritis from earlier trials. We've actually had pretty good luck using that hub, and we have used in patients have actually had cardiogenic shock. We recently submitted a paper that highlights a multi disciplinary approach involving oncology pharmacy I. D. C T. Surgery and heart failure in terms of managing these patients, and then there are also a number of other medications you can consider, such as Michael Fennelly, I V. I. G. A, T, G or plasmapheresis, among others. and then restarting immune checkpoint inhibitor is actually a very controversial. Some people have done it for patients when the risk versus benefits have outweighed trying to it again. And then also the most of the time, these patients have had a much more benign presentation. I think that it is important to talk to the patient and decide whether there are other options for therapy. But one thing I will say is that at this time, given the lack of information, I wouldn't feel comfortable starting it again in somebody who had experienced Pullman in myocarditis. And so there are so many more medications that I'm not gonna have time to get through. What I showed you is really just a glimpse of the world of cardio oncology. And then this image over here on the right shows that what we know about cardio oncology right now is really just the tip of the iceberg. And then, since 2013, there have been even more medications that I've listed on the left compared to the ones they had talked about into on that image. And so we really need to talk about these one day. But today isn't it. So take home points. So monitor cancer therapy related cardiac dysfunction with echocardiogram, preferably three dimensional or cardiac Marai along with strain or troponin tie. So far, there's been no overwhelming benefit for profile active medications prior to initiation of some of these cardio toxic agents. But I do recommend that if patients are in baseline, I pretend and baseline antihypertensive that they get switched to either beta blockers, preferably car beta law. So for law and ACE inhibitors, or ARBs so that Jeff inhibitors can cause hypertension. But which can actually be a really good thing because it can be a marker for efficacy. But this blood pressure response needs to be well controlled. Some of the newer Take I inhibitors for CML can cause pulmonary hypertension, which we hadn't seen with the magnet. And then it can also cause increased cardiovascular as well as vascular events as well as hypertension, especially in Panetta. Nip So I Bruton. It increases the risk of a tribulation, but there are many drug interactions, which makes treating it difficult. It can also increase your bleeding risk, and so treatment should be first line beta blockers, since that has the least amount of interactions. And then you should also stop it before procedures and have a careful discussion regarding the risk versus benefits of anti coagulation. So recognizing immune checkpoint inhibitor toxicity, it's the key. So initiating higher doses of steroids early, especially if they have vomited myocarditis is important as well. And then you should consider other agents, such as Inflicts Map or some of the other ones I mentioned in patients who are refractory to steroids. And then, ultimately, the goal of cardio oncology is to optimize cardiovascular help, impede into patients, using all the diagnosis and management whose have hopefully taught you now. And hopefully we can optimize your cardiovascular care. And so, um, last slide is, I just really want to thank you all for being here today and for your time and attention this morning because I recognize that everyone here is very busy and then, additionally like to thank our B and Brian and the entire Waxman group for such a warm welcome. It's been an amazing six weeks so far, and I'm actually looking forward to more now. I'd also like to think of the Pen Cardio Oncology Group, specifically Joe Carter and Bonnie Key, who have provided me with a great foundation from which to build. And then I wouldn't be here as a cardio oncologist if I wasn't a cardio Cardiologists at heart with passion and images first. And so I'd like to thank my constituted cardiology colleagues back and help for their friendship and mentorship as well as all these individuals who have given me guidance and support throughout the years. And there are many more to thing. But as you can see, I'm running out of room as well as time. So I'm going to stop now and just thank you again. Alright, Rupel, that was fantastic. Thank you for that overview. And I have to say I'm super impressed with your ability toe announce all of those drugs because I know people that that struggle with Met Oprah, LOL, let alone some of these other cancer medications. So that was super helpful. And, uh, and a fantastic overview. Um, I know there are several questions that came through, but I'm going to start with a couple of practical questions. Do referrals to you typically come from oncologists? Andi, how do we who's the right patient to get to someone like you. And at what point is when? Uh, the cancer has been diagnosed and they're still planning the treatment or is it after symptoms start to develop? So I think what's been happening right now is because there's so many things that need to be done with these patients that often they get referred after toxicity develops because that's when it becomes much more urgent. If possible. I would prefer for patients to be for earlier just because, as I mentioned, we can probably do certain things that maybe beneficial prior to them actually receiving chemotherapy. And so I think, the best way to actually, you know, I guess what you can do is just call me honestly can call me, text me, email me, excuse me and decide asking questions. And then I can decide what the best thing to do, whether it means managing it by just me telling them what to do versus actually seeing the patient. But I do think that earlier is better, since there are things we can potentially help, you know, in terms of risk stratification as well as optimization of their heart. That's great, um, for patients, blood pressure medications, you know, folks get older. Obviously, the two co morbidity is they're gonna The prevalence is gonna be high. Are you routinely altering their blood pressure medications pressuring, you know, preferring something like carvedilol or bus Oprah law if they're on a diuretic or a calcium channel blocker, I do, because all the reasons I actually mentioned so most of the time I think patients sometimes may actually be on those classes, which is great. But if they are specifically on calcium channel blockers or ACE inhibitors, I'm sorry. Custom china blockers or diuretics. I try to switch them to, as I mentioned, either carvedilol, usually first, especially in the case of hypertension tension, since it has a better hypertensive response compared to some of the other beta blockers and then also either ACE inhibitors or a R Bs. And normally what I will also do is I usually try to start. If it's a new patient, right, who has maybe undiagnosed hypertension. It'd be nice to get these patients in as well, because we can start therapy and then hopefully managed them also, as they're getting their treatments for, um, let's say, for the general cardiologists that gets a call from from their local oncologist and and says, I'm planning on starting in medicine or somebody has symptoms. Is there a other than reaching out to you? Is there a good resource where you can enter the name of the chemotherapy medicine into and kind of get a clear breakdown of cardiac risks associated with it? That's a great question. So not right now. There's actually a few of us who are working on a paper right now to try to do at least within your oral agents. Ah, list of all of them. A swell as the toxicity in the monitoring involved one of the farm. These is actually helping us with this and had already put together a list, and now it's turning into a paper. But as of right now, I think the A c c dot organ, the cardio oncology website Cardio Smart is actually a really great resource for cardiologists to help them figure out whether there is something more that they should be doing in terms of either changing therapy or maybe even in terms of management or diagnosis with certain tests. No, that would be that would be great and sounds like there's still a lot of work being done for a lot of folks that don't have high sensitivity troponin as part of their ability to screen patients, um is regular troponin adequate? Or do you prefer So we you know, that's a great question, because that's what we've been using, an element that almost most of my patients have not had a proponent elevation. There has been one where, after she received an three cycling's, her troponin started going up. But it did make us realized that something was wrong and Onley after we saw that we call her. And then she admitted that she had been experiencing waking and also been having more shortness of breath recently. And so that prompt is that do an echocardiogram, which showed a new declining EFTA from 50 to 35%. So it was helpful there. But often troponin, I have seen at least here we haven't seen as much of an increase. I think that as of right now, since high sensitivity isn't always available, it's worth just trying because more than anything, it may just trigger us tow. Watch these patients a lot more closely. It's negative, it's there's no hard right But if it's positive, it'll prompt you to think about them and then potentially have them come in more frequently for closer follow up, get more echocardiograms, and then also touch bases with them about their symptoms in between cycles. All right, And the interest. If I got a couple more questions, I'm going to kind of give out your rapid fire here, thio them in in the next few minutes. Um, in terms of eco imaging now, I'm not in echocardiography for I know we have the ability to do three D imaging. Um, I think most folks are familiar with three D imaging, primarily for mitral valve disease. Um, we do have the ability to do three D imaging for ejection fraction. How much better is that? I know. Ah, lot of the new machines and Softwares have more and more capabilities. And so how important is three D, Uh, L b ejection fraction imaging. And then the second part is strain imaging. How important is that? And I think that's probably become fairly readily available. And what? What cutoffs do you use for both of those? Yes, that's a great question. So for three D, one of The reasons it's found to be more helpful is that especially with the new Softwares, it's often automated, so it kind of takes the person out and the variability out. So if you're using some of those newer machines and software, I think it's helpful because as long as you don't have to adjust the border, it can actually provide a better study in terms off, I guess. What's the right word? Less variability and in measuring that L d. At from patient to patient and also within the same patient. So I think it's helpful in that. And, as I mentioned earlier, is also less geometric assumptions with three D. So I think if we had to pick it would be the ideal way of doing things. And I still think that there's still a lot of work to be done with improvement in the image quality as well as a software. And as we know, if someone has poor image, Windows three D is not gonna help fix that. Unfortunately, so that is still where I think card A camera is really helpful where if you can't see what's going on, I think a cardiac and I will give you the best, UM, estimate of what their ejection fraction or they're left ventricular systolic function, as well as its a better test for right ventricular size and dysfunction as well. And then in regards to strain. It's interesting. I actually initially wasn't a believer because to me it was just, I wondered if it was under had the same issues where regular e. F. Had. But there have been quite a few studies now that show that it has the ability to pick up cardiac dysfunction prior to the actual F decline. And I still think that there's a lot of work to be done because there seems to be a lot of variability between the Softwares as well as the vendors, and I think that's true. That's getting better. But I think what is the most important is the decline, the relative changes I had mentioned where if you can try to at least use the same machine and software which I realize that in a clinical lab is very difficult to do, but at least maybe the same type of, say Bender, you can at least compare the pre M post and what you're looking for is that 15% relative change. So the absolute number. I think we've seen all kinds where you know negative 20 seems to be normal. But even sometimes, like negative 19, negative 18 will consider normal as well. But the more important thing is to get that done at baseline and then also repeated with after chemo and to see if there's been a decrease using the same hopefully technology that we use the first time. I think that's been shown to be the most helpful because otherwise, yeah, as you're pointing out, there's a lot of variability, and it's very hard to, you know, it's not apples to apples anymore. It's apples to oranges comparison. So great ruble can you comment on, I guess, how big of a problem is cardiac complications within chemotherapy and within cancer treatment. Um, you know how big is the how big of a scope of a problem is it? So what percent of patients that are receiving treatment for, you know, for breast cancer or for one of the human geologic malignancies will actually developed cardiac complications? So another great question. I think that people are still grappling with so some of the trials had shown right earlier that if you had received anthro, cycling's plus trust is a mob. That risk was almost 20 to 25% so actually very high and so and I think that risk is very variable depending on the treatment you're using. I think the other pieces that is going to become much more important is that we don't know why some people at risk. So I think genes as we start getting better with figuring out what people's genes look like and figuring out which genes increased susceptibility, we're gonna find out which patients are more susceptible to others. And I think right now we have certain risk factors and scoring that we can use toe helpfully determine if someone's high risk versus not. But I think that percentage still changes from person to person. I think on average, I can say that I think people with who are receiving trust use a map, are probably monitored one of the most closely right because they are required by the FDA package insert to get echocardiograms every three months and most oncologist follow that, and so as a result that's probably the most data we have and I think overall that risk of toxicity is actually very low. But it does go up with patients, you know, if they have pre existing hypertension, prior history of radiation and anthro, cycling, exposure, age, obesity like all the ones I mentioned earlier. And so I think then we have seen a decline and we've seen either the strangest decline or we've actually seen the decline. But I think the tick tick away point for that will be is that I still think more important, more importantly than not, is that we need to figure out ways to continue therapy because these patients with at least a trust use, um, have anthro. Cycling or transmissible toxicity often get better, and they're more likely to die from their cancer than they are from their heart dysfunction. If we're what monitoring closely when we start medications and we're taking the time to actually talk to them and saying things are going okay, so I think that is the take away. But unfortunately I don't think the percentage for actual risk electricity is so variable and wide, and I think it's also we have no idea yet because even now like that last night I showed were beginning to just recognize that some of these agents that in the trials and have any issues are having multiple big issues in the real world. How do you approach men, um, that are on androgen deprivation therapy for prostate cancer? It's a great question. So I think the biggest things is a lot of those, um, can cause not even just during therapy. But even after the fact, it can cause metabolic issues, right? So hyperglycemia hypertension and that affect, since these patients are on it for quite some time can also continue years later and during therapy, maybe even after therapy. So for most of these patients, the most important thing ends up. Being is my optimization of risk factors, which is what all cardiologists are very good at doing. So I think that that is another group of people. We've been starting to see referrals for just baseline optimization because they're going to be receiving therapy for quite some time and the other. I also like to commend a lot of the radiation. Oncologist has been referring patients prior to therapy or at the time of therapy, when they recognize that these patients are going to have cardiac exposure. They've been preferring them just to make sure that their risk factors are optimized. All right, we'll try to get two more questions in here quickly. Um, one has to do an African American patients. Um, is there any data to suggest similar to the A F trial? That something like I straddle hydrology seen maybe better than east inhibitor? Not that I'm aware of. And I think part of that problem is is like even the data for as you can see, it's inhibitors and arms, right? Our trials are very small. E think we treat patients who have actual dysfunction, very similarly to how we treat all patients who have heart failure. So if I do have blood pressure and heart rate room, I will add all of them. So I usually start with carvedilol and then add in Eastern ARB. And then, if there is blood pressure room right, and depending on what the F is, you can try switching 10 presto or then adding spironolactone and then patients were extremely hypertensive. I would still do the hydra and ice ordeal as well, but I think a lot of these patients and, you know, have don't have elevated blood pressures. And often therapy makes their blood pressure's lower, too, so that, I think, also changes what we end up doing. All right, last question for you is, let's say somebody does develop a cardiomyopathy with the drop in their ejection fraction, and then they recover. Um, how long do they have to be on cardiac medications? If things depend on there, how long they have to be on their cancer medications? And if they complete their cancer medications, do they still need to be on their cardiac medications? It's a great question, I guess. Well, eso I think what many of us have been doing Is that the way I personally think about it? If you drop the ejection fraction right when so many others don't that think means something. Even initially, I think that you have some sort of genetic predisposition or risk factors that predispose you to doing that. So what I normally tell people and this is differs from different therapies. And so right now, particularly thinking about anthro cycling's I usually say that you know they need to be on these medications if they're f doesn't recover. But if it does, my recommendation is that they continue them because what answer cycles and often do is also decrease that cardiac reserve. So that means in times of stress, even if they're e f has now normalized later on with stress, it may decrease again. And what these medications can do is prevent them. So my recommendation is always to continue it, especially there were tolerating them very well. Like for life long to be honest, because I don't know what's gonna happen down the road. And even though those trials have shown that anthrocytes okay and cardio toxicities, usually it's going to show up in the first year, right after therapy. I think we've all seen patients who do this where patients had a normal E f. And then they got septic where they got sick or they ended up getting an infection or something happened, and they're the ones who end up dropping their F later. And so I do think that there is some additional benefit to continuing these medications. That being said, though, I also think it's a very personal decision and I have patients that either don't tolerate it well, right and have side effects or they just hate taking medications and that to them it's really important to take, you know, as fewer pills as possible. And then I think, you know, you have to do right by them as well. And so I kind of give them all my thoughts and my recommendations and why I think this. But I would never make anyone do anything. And so I think that if they feel very strongly will stop it and then we'll just continue to monitor and it obviously look for new symptoms. And I'll probably also chipped in with serial imaging as well. No perfect group. Well, thank you very much for the talk. That was fantastic and clearly an area that's very important and that we're learning more about. And so thank you for leading that effort. I think it's gonna help a lot of patients in the future. Thank you for honestly for even giving me the opportunity so great. And hopefully folks will get to know Rupel more and more and this will be the beginning of it. A za reminder. We will have grand rounds again next week. It's gonna be Brian Jackman speaking about cardiac amyloid. And then, after Labor Day, we'll start back in the fall, Um, actually moving toe Wednesdays. But next week we'll still be on the Thursday. Um, sorry I didn't get to quite all the questions, but this was great in the interest of time, I think Let's wrap things up for today. And folks are questions. Feel free to reach out to Rupel by email. Alright? Or through Linda with myself. And we'll, uh, we'll make sure we get those answered. All right, take care, Everybody. Thank you again.
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