Good afternoon, everyone. Thank you for attending this session this afternoon. Just so you are in the right room, the name of this session is Dirty Drugs, Electrophysiologic Complications of Cancer Treatments. My name is Jim Tisdale. I'm a professor in the College of Pharmacy at Purdue University, and I'm one of the co-moderators for the session. And my co-moderator is? Hello, everyone. I'm Estelle Torbay from Brown University from Rhode Island. I'm an electrophysiologist and will be co-moderating this session. Before we begin, I'm supposed to read a few items. So it's my pleasure to welcome you to San Diego and to Heart Rhythm 2025, the 46th annual meeting of the Heart Rhythm Society. If you've not already done so, please download the HRS 2025 mobile app from your preferred app store. This is how you can participate in live question and answer during the session. Please scan the QR code, which you'll see on the screen now, to access this session's Q&A. When using the mobile app, you can log in with your HRS credentials. Please note that visual reproduction of Heart Rhythm 2025, either by video or still photography, is strictly prohibited. And now I will introduce our first speaker. Our first speaker today is Dr. Michael Fradley, who is section chief consultative cardiology and medical director of the Thalheimer Center for Cardio-Oncology. He is also an associate professor of clinical medicine in the Perlman School of Medicine at the University of Pennsylvania in Philadelphia. And the title of his presentation is, With Every Beat of My Heart, Pearls and Pitfalls of Managing Atrial Fibrillation in Cancer Patients. Please join me in welcoming Dr. Fradley. Well, thanks for that kind introduction, and I want to thank the chairs and HRS for the invitation to speak today. I also happen to be an electrophysiologist, so I hope that over the course of these talks you're going to see that electrophysiology issues really are a common problem in cancer patients, and we really do have to work in a collaborative and nuanced way to manage these patients. So these are my disclosures. So a little roadmap for today's talk. I first want to review the current state of knowledge of cancer treatment-associated atrial arrhythmias. Then I want to discuss some novel data regarding arrhythmia management in cancer patients, and then finally highlight some opportunities to improve the care of cancer patients with atrial arrhythmias. Now arrhythmias are a commonly encountered toxicity of various cancer therapies. However, the mechanism of arrhythmogenesis varies. In some circumstances, such as with BTK inhibitors, it's likely due to direct effects on ion channels or intracellular signaling pathways, whereas in other cases it's secondary to another toxicity like myocarditis, ischemia, or systemic inflammation. So we're going to start off with a few pearls. So pearl number one is that atrial fibrillation is very common in cancer patients. You're going to see it over and over and over again. So multiple epidemiologic studies have demonstrated increased rates of atrial fibrillation in cancer patients, likely due to shared risk factors between the two diseases, systemic inflammation, as well as the cancer therapeutics themselves. In the study on the left from South Korea, the incidence of atrial fibrillation was 6.6 per 1,000 person years, and cancer was an independent risk factor for incident AFib. Amongst hematologic malignancies, it was most associated with multiple myeloma, and amongst the solid tumors, it was esophageal cancer. And then if you look at the study on the right, this was conducted by my colleague Avi Guha using the Seer Medicare database to evaluate breast cancer patients, and he demonstrated that the annual instance of atrial fibrillation was 3.3%, with the highest rate occurring in the first 60 days after diagnosis. And the higher the stage of the breast cancer diagnosis, the more likely you were to have atrial fibrillation. And a new diagnosis of atrial fibrillation in the setting of breast cancer was associated with increased one-year cardiovascular mortality. Now cancer therapeutics themselves can also lead to the development of atrial fibrillation, and rates vary based on the different therapy, but they occur most commonly with anthracyclines, the alkylating agent, melphalan, BTK inhibitors, as well as immunotherapies, and I'll spend a little bit of time talking about several of these. So melphalan is used primarily in the autologous stem cell transplant protocols, and it's especially arrhythmogenic with rates in the literature around 11%. And risk factors for the development of atrial fibrillation in the transplant period include older age, PACs, or AV conduction delay on a pre-transplant ECG, pre-existing cardiovascular disease, kidney dysfunction, left atrial enlargement, the use of melphalan, but then also prior exposure to anthracyclines and mediastinal radiation. If you had two or more of these risk factors, you were at a 12.7-fold increased risk of developing atrial fibrillation during transplant compared to those that had no risk factors. And all of this matters because patients who develop atrial fibrillation during transplant have worse outcomes. So these are data from the Memorial Sloan Kettering Group, and they showed that if you developed AFib during transplant, 52% of patients required ICU admission, 28% had in-hospital mortality, and 41% were dead within one year of their transplant. Now it's not to say that the atrial fibrillation is the cause of the mortality, but simply it is a marker of a sicker patient. Now moving to ibrutinib, this is a small molecule inhibitor of the Bruton's tyrosine kinase, and it's used in the treatment of various B-cell malignancies, particularly chronic lymphocytic leukemia. And ibrutinib is associated with the development of atrial fibrillation with rates in the literature up to about 15%. And in this systematic review and meta-analysis, the pooled rate of ibrutinib-associated atrial fibrillation was about 3.3 per 100 person years, compared to 0.86 per 100 person years for the non-ibrutinib regimens, with a relative risk of ibrutinib-associated atrial fibrillation of 3.86. Now while it's clear that there's an increased risk of AFib with ibrutinib, with the development of the second-generation covalent inhibitors, as well as the non-covalent inhibitors, there have been a lot of questions as to whether or not there's a class-related effect. And much of this comes from those early studies of the second-generation covalent inhibitors like acalabrutinib and zanubrutinib. For example, in Elevate, TN, and Ascend, which were two acalabrutinib studies, rates of atrial fibrillation were only between 3% and 5%. And then if you look at the Alpine study, which evaluated zanubrutinib, rates were again around 5%. So all of this made people think that maybe there are off-target effects that are causing the atrial arrhythmias. And a very intriguing study suggested that the mechanism of ibrutinib-associated atrial fibrillation was due to inhibition of the C-terminal-serc kinase, which isn't affected by those second-generation inhibitors. And we know from other data that C-terminal-serc kinase inhibition does play a role in the pathogenesis of atrial fibrillation. Other theories include decreased signaling in the PI3K-AKT pathway, as well as impairment in calcium handling. But with increased time and increased experience with these agents, we're seeing more atrial arrhythmias. And that really was demonstrated nicely in the Elevate RR study, which reported over a longer period of time that atrial fibrillation with acalabrutinib was approaching 10%. Now, that's still a lot lower than ibrutinib, but higher than those original studies. And I think that as we get more and more experience with these drugs, we're going to see more and more atrial fibrillation. Now moving on to the checkpoint inhibitors, we typically think of myocarditis as the primary cardiotoxicity with these agents. But if you really look at the data, for example, the study from Jack Cardio Oncology, the two most common cardiovascular issues are going to be arrhythmias and heart failure. And of those arrhythmias, atrial fibrillation is the dominant abnormal rhythm, although ventricular arrhythmias and conduction disorders can occur. And although we have typically thought that these arrhythmias are a result of the myocardial inflammation, data has shown time and time again that arrhythmias occur in excess of reported myocarditis. And now we're starting to realize that there's probably direct effects of the checkpoint inhibitors leading to atrial arrhythmias. And this was a really nice study that showed that PD-1 is downregulated in patients with atrial fibrillation compared to healthy controls, and it's even further downregulated in patients with persistent atrial fibrillation compared to patients with paroxysmal atrial fib. So somehow PD-1 downregulation is likely contributing to the pathogenesis of atrial fibrillation and why we're seeing those elevated rates in our checkpoint inhibitor patients. Now pearl number two, management recommendations for cancer patients are the same as for the general population, at least for now. So this applies not only to recommendations for rate versus rhythm control, but also when we're talking about things like the CHADS-VASc score and the HASBLED score, as you can see from these flowcharts that was published in our American Heart Association scientific statement. And if the decision is made to give anticoagulation, there's increasing evidence to support the use of DOACs in cancer patients. In this sub-study of the Aristophanes study, compared to warfarin, apixaban was associated with a lower risk of stroke and systemic embolism, as well as major bleeding, whereas rivaroxaban and dabigatran demonstrated similar rates. And if you use the CHADS-VASc and the HASBLED scores to guide therapy decision-making, then many cancer patients may not actually be getting guideline-directed therapy. This is a study that we published a few years ago in Jack Cardio-Oncology, showing that about 44% of eligible patients, meaning high CHADS-VASc and low HASBLED scores, didn't receive appropriate anticoagulation despite having atrial fibrillation. And of these, only 18% had low platelet values. So it really highlights the need to improve the application of standard AFib treatment algorithms to our cancer patients. But of course, there are some pitfalls when we're thinking about AFib in cancer patients. And the first is that common recommendations and risk scores, though we apply them, may not be accurate or appropriate for cancer patients. So are our typical rhythm control recommendations truly effective in cancer patients? That's a really important question. A few studies have looked at the efficacy of antiarrhythmic medications in the cancer population. And it's important to understand that one of the limitations is that drug-drug interactions can impact the use of antiarrhythmics, but also rate-controlling medications. And then if we think about catheter ablation, we do know that the periprocedural risk of clinically relevant bleeding is more frequent in cancer patients than in non-cancer patients. But there's truly a dearth of studies evaluating the efficacy of catheter ablation in cancer patients. The study that I put on here was a retrospective one looking at 251 cancer patients, or patients who had a history of cancer, I should say, who underwent catheter ablation. And what they showed was that at 12 months, there was no significant difference in the recurrence rate of atrial fibrillation or the need for repeat ablation in the cancer, the patients with a history of cancer, or those non-cancer patients. But when you start to dig this data a little bit deeper, you find out that only 18% of the patients included in the study had active cancer. So we're really dealing with heterogeneous populations, because cancer survivors and patients with active cancer are two very different cohorts and different phenotypes. Moreover, only 32% of the patients ever received any sort of systemic cancer treatment. So I would really caution drawing too many conclusions from these data. And I think it really leads to the question of whether the mechanism driving cancer treatment associated AFib is the same or different in cancer patients compared to non-cancer patients. And there's also studies to suggest that the CHA2DS2-VASc score may not be so accurate in cancer patients. In this population study from Denmark, the CHA2DS2-VASc score was relatively poor at predicting risk for thromboembolism, with higher risk seen with CHA2DS2-VASc scores of 1, and lower risk with CHA2DS2-VASc scores of greater than 2 when compared to non-cancer controls. And then a more recent study that was in Jack Cardio-Oncology demonstrated very similar findings. Looking at patients who had a CHA2DS2-VASc score of 0 to 2 who were not receiving anticoagulation, the 12-month cumulative incidence of arterial thromboembolism was about 2% in the cancer patients, and well under 1% in the non-cancer patients. So we may need to pay more attention to these lower CHA2DS2-VASc scores in our cancer patients. Now is there a better thromboembolism risk score for our cancer patients? So this was a SEER Medicare analysis which suggested that cancer was associated with a 9% increased risk of thromboembolism in the setting of atrial fibrillation. And as such, the authors determined that adding cancer to the CHA2DS2-VASc score improved model prediction. But again, it's important to note that in this study, they did not account for differences in anticoagulation status between the cancer patients and non-cancer patients. And data has clearly shown that cancer patients are not often getting anticoagulation. And so we published a study just a few weeks ago looking at epidemiologic data from Canada, and cancer was not associated with stroke risk if you match on stroke and bleeding and adjust for anticoagulation. So all of this being said, cancer at this point should not lower your threshold for anticoagulation amongst patients with atrial fibrillation, and we should still use those same recommendations. And pitfall number two is remember that many cancer patients are at an increased risk for bleeding. This leads to challenges when considering anticoagulation in the setting of AFib. First, we have drug-drug interactions, which are a significant concern affecting both the metabolism of the drug and the anticoagulant. Moreover, various cancers are associated with an increased risk of bleeding, such as GI and GU luminal malignancies. Cancer patients often have hematologic abnormalities that can increase their risk of bleeding. And finally, some of the cancer treatments themselves, like the BTK inhibitors, can increase risk of bleeding through their effects on platelet aggregation. So for cancer patients who might not be a candidate for long-term anticoagulation, there's the possibility of left atrial appendage occlusion devices. This might be an attractive alternative. And there was one study from the Mayo Clinic that compared control patients who underwent left atrial appendage occlusion without cancer, and there was no significant difference in ischemic stroke, bleeding complications, or death in the cancer patients compared to the non-cancer patients. And so left atrial appendage occlusion may be a viable option for cancer patients with AFib who can't have anticoagulation. But remember, short-term anticoagulation is still necessary, or at least some degree of antiplatelet therapy. And there are definitely cancer patients who cannot tolerate even short-term antiplatelets or anticoagulants. And the risk of device-related thrombus could be potentially increased in a hypercoagulable cancer population. So in summary, atrial arrhythmias are a common occurrence with various cancer therapies, including BTK inhibitors and immunotherapies. Cancer patients should be receiving typical guideline AFib management and anticoagulation for thromboembolism prophylaxis, but are often not. We need more research to determine the best approach to the management of arrhythmias in patients with cancer. And beware of bleeding issues and drug-drug interactions when you manage AFib and other arrhythmias in cancer patients. And with that, I want to thank you all for your attention. I'm going to open up for questions, maybe one or two. I have a question. So what are your thoughts about half dose of blood thinners? For example, mainly Eliquis, and also for the Edoxaban, there has been some European trials showing benefit of using that at all. At this point, I'm not, primarily because we don't have any, I think, solid evidence to suggest that that is beneficial in these patients. I think the area that it comes up a lot are in the BTK inhibitors because of the increased bleeding and the potential anti-platelet effects of the BTK inhibitors. But ultimately, until we actually have some hard data to show that that is an effective strategy, I tend to just go with the standard recommendations. All right, we're going to move on to our second speaker. I'd like to present Dr. Zainal Abidin-Assad, who is a cardiologist at the University of Oklahoma Health Science Center, associate professor and fellowship director. And he's going to be talking to us about ventricular arrhythmia and QTC prolongation and malignancy. Good afternoon, and thank you so much to HRS and my esteemed monitors for this opportunity So I'll be talking about ventricular arrhythmias and QT prolongation in malignancy, so The focus of my talk here is gonna be To give you something in the next 10 minutes that you can take back to your clinic on Monday and actually start applying and understand this particularly complex patient population a bit better Okay, so we're gonna identify the common cancer therapies that can be associated with ventricular arrhythmias and QT prolongation and We're gonna try to outline a very simplified approach on how to navigate these issues So these are my disclosures this just includes some research funding from ACC and American Cancer Society and other organizations Let's start off with a case we have a 56 years old female with near syncope Her medical history is significant for acute promyelocytic Leukemia, and she is on this all trans retinol like acid and arsenic trioxide cancer therapy on basic workup the ECG shows a QTC of 530 and on telemetry she's having some Episodes of non-sustained VT with some mild electrolyte abnormalities So what are the key questions here relevant to our talk? I think pretty much everywhere Here agrees that yes QT is prolonged but one of the questions is how do you correct for the QTC in the context of Cancer, what do the guidelines recommend? How do we actually measure it? Very importantly Why the QT decided to be prolonged? Why is it prolonged and How do we move forward beyond this particular episode? So those are our key questions and by the end of this talk, we will have answers to all of them. Okay, so You know, this is straight from the guidelines in the context of cancer for males This is the number that is considered Criteria for prolonged QT. This is for females We use the for ratio formula Because it is less dependent on heart rate the exact formula overestimates at high heart rates and Underestimates at low heart rates. So as we approach these patients Try to make some medical decisions on them Our first question would be is it prolonged or not? And what formula are we using to? kind of Correct for the QT Let's move on. The next question was why was it prolonged? Okay So if you look at the spectrum of cancer therapies There are too many of them to remember on the top of your head Which can can prolong and which can cannot prolong and as the cancer therapy is involved I hope by the end of the session that will be one new cancer treatment that may or may not have QT prolonging effects So I think the idea is to make this very simple What are the most common ones that you as electrophysiologists or cardiologists should know about? Okay, so here's a very simplified approach to that. These are the top five Cancer therapies with QT prolonging potential top of that list is arsenic compounds that are used in acute leukemias Specific kind APA ML and the incidence of QT more than 500 is about 40% So it is no surprise that if you look at the package insert for this particular drug It says daily ECG monitoring Typically this type of medicine is given in the hospital with active ECG monitoring at least initially. Okay The second drug again 10 to 30 percent This is for cutaneous T cell Lymphoma, so as you know broadly we classify your cancers as liquid and solid So for the liquid cancers, I feel these are the top two that you should understand For the solid cancers, I think it's more important to remember this whole group of cancer therapies known as tyrosine kinase inhibitors Nomenclature wise even if you don't know the exact drug if you see something in the cancer That's adding that's ending in this 10 FTI and IB that usually specifies that this is from a tyrosine kinase inhibitor group the EGFR inhibitors happen to be a specific type of Tyrosine kinase inhibitors and the incidence of prolonged QT in them is pretty significant And of course then the common therapies for your breast cancer anthracyclines her to therapies Especially if they're used in a combination then your risk of QT prolongation is going to be higher now for some of these therapies where the incidence of QT prolongation is pretty significant Your FDA will kind of mandate a baseline ECG and an ECG to be done at certain intervals that interval would commonly reflect how the initial trials were done and when you would expect to see the peak plasma levels for that specific cancer therapy for some of the breast cancer therapies That's baseline two weeks four weeks for arsenic. We just learned that it's daily ECG, especially if it's abnormal That's gonna guide when the next ECG is gonna happen. Okay? So I think this is a very simplistic framework as far as the common drugs are concerned This list is by no means exhaustive This is just a starting point but I think the idea was to give you Some concepts about the class effects of these drugs and what to do if you see some QT prolongation Now this becomes a very important question Like I think almost all of us in cardio oncology world get this phone call at some point Like should I stop the cancer therapy? So There are some answers to that. It's rarely a yes or no. The answer is almost always it depends There are some Cut-offs like the case we described where the QT was 530 like yes, you should for time being stop the cancer therapy you always go back and look if the change in QTC is more than 60 milliseconds from baseline and How severe is your presentation? because we know an asymptomatic prolonged QT is very different from somebody who came in with TORSAD or VT and of course if you're suspecting that the presenting symptoms could be related to Prolonged QT or VT. Okay, and in some instances you would stop the medicine in some instances You will look at is the cancer therapy really responsible for the prolonged QT or there are non cancer therapies for example a lot of these patients for Infection prophylaxis would be on quinolones for nausea and vomiting They will be on other medicines that can prolong the QT So all of that is part of your decision-making as when you are deciding when you should stop Okay, so we just talked about Criteria to stop these therapies and how we are monitoring the standard clinical practice is If you need QT monitoring these patients have to come back to your center get a 12-lead ECG Which happens to be the gold standard, but one may wonder we are living in 2025 it's the era of wearables Is there a role for QT monitoring with those agents? And that's exactly what was the question for our studies here the onco QTC our essential question was is Smartphone capable ECG reliable meaning when you compare it with the gold standard. Can I trust this data? Especially when it comes to their automated QTC interpretation algorithms Because then I can just send the patient home with this device They can do their ECGs as much as they want it gets to a portal and then it can alert me if it's getting prolonged that Next question. Is this a cost-effective approach one may think? Yes, you're saving and interface with health care transportation costs other things and the last and most important question is this concept Acceptable to the patients and the oncologist So these were our questions the study was funded by American Cancer Society. It's a prospective cohort study Our patient demographics are here Our sample size for this pilot study was just 34 patients and all of them have to have Been on cancer therapies with QT prolonging potential. Okay, that was the inclusion criteria These are our preliminary unpublished results we compared to available smartphone capable ECGs the single lead and the six lead And compared it with the gold standard of 12 lead and reliability we found them reliable within six milliseconds for the single lead and three milliseconds for the Six lead the benchmark according to published standards for this reliability is anything within 15 milliseconds of the gold standard ECG that is considered acceptable now cost savings in a cost-effective analysis on average for each of these were pretty significant and this includes the cost of doing the ECG Physician interpretation of ECG and of course you add the patient transportation cost to it and Because this is quicker This does not involve the patient undressing getting the leads getting into a patient room rooming unrooming We found that at least in this patient population and this Physician and provider population which was all oncologists and oncology staff. This seems to be an acceptable method Now here is a summary of all we discussed if for approach to QTC and ventricular arrhythmias So just a quick recap for patients on QT prolonging therapies You will do a baseline ECG for QTC interpretation. You will use a Fred ratio formula 450 460 are the numbers to remember if it's acceptable You can start the cancer therapy if it's prolonged even at baseline you look at concomitant drugs and other things that can prolong the QT and if it's more than 500 Milliseconds at baseline or after the treatment or more than 60 seconds from baseline with the treatment You either stop the cancer therapy or in some instances you can do some dose adjustments and still continue the treatment Thank you very much Are There questions for dr. Assad remember you can come to the microphone or you can scan your QR code and submit your question Dr. Assad You mentioned potentially lowering the dose. Are there ever situations where? The cancer is so severe and needs to be treated so much that you might keep a patient on cancer therapy despite a prolonged QT interval I Think that depends on the QT interval itself above 500. That's really challenging really not possible There have been instances if it's in this 480 to 500 range where you will bring them in have them on active monitoring Try your best to minimize the non cancer therapies that can prolong it and still do it in my practice I just had to do it once for an lung cancer with EGFR and embitters and it worked. Okay Just In your study for the day, you know the day, you know QTC changes How do you factor this in? You know, they'll be called, you know, like it could be giving you falsely low or Well, what if it's a you know, right? so since this was a pilot study for reliability the 12 lead ECG and The single lead ECG and the six lead ECG were done at the same time Like they were done within five minutes of each other But I think once this gets start to be used, we're gonna get a lot of phone calls. Yes Now from Hong Kong There's in the presence of trying to maintain sinus rhythm in the older or not is commonly used particularly in cancer patient How does that impact with this QTC assessment, which is quite a difficult issue? That's an excellent question So am your drone not only for QT, but because of its drug drug interactions, I think that's where Pharmacists have to be integral part of your cardiac oncology teams where up front we can actually run these Interactions and there have been instances where we had to either stop am your drone or switch to something different For the duration of cancer treatment and of course We intensify our acuity Monitoring if they are already on anti-arrhythmic drugs because the fact that they are on am your drone also means they have some underlying Other heart structural issues that also predispose them to QT prolongation Thank you very much, dr. Sun Our Next speaker is dr. Iona Cosmo Dow she is director of the cardio oncology arrhythmia program at the Memorial Sloan Kettering Cancer Center an Associate professor in the Weill Cornell College of Medicine in New York City The title of her presentation is slow it down bradycardia and conduction system disease and cancer Good evening. Thank you to the HRS committee for inviting me to give this probably not very sexy talk for a Heart Rhythm Society meeting. But what I will do in the next ten minutes is, first of all, I will try to convince you that there is some importance to this particular topic, especially for the cancer patient population. And it is certainly a topic of significant interest for the electrophysiology community. None of my financial disclosures I think are pertinent to that particular topic. So over the next ten minutes I will try to do a couple of things. Number one, explain why I think it's important that we discuss cancer-related cardiotoxicity even at a Heart Rhythm Society meeting. Number two, what specifically is the impact of cancer and cancer therapies on the cardiac conduction system. We will discuss some mechanistic insights from epidemiologic and clinical research data. We will go over very briefly our current approach to bradyarrhythmias in the setting of cancer. And a couple of slides specifically dealing with amyloid, which we're all bound to see more and more frequently over the next several years. Starting with the why, I think it's important for all of us, irrespective of us not being oncologists or hematologists, to recognize the fact that increasing cancer prevalence, as well as increasing cancer-related survival, inadvertently has led to an increasing need for management of cancer-related or associated comorbidities. And if you look on the left side panel, data from the National Cancer Institute very effectively show that over the past five decades, the cancer prevalence has increased dramatically in the United States population. It is projected to increase even more within all age groups, including even patients less than 50, to about 25 million patients or so. And this is largely patients with either active cancer or recent cancer diagnosis. Whereas on the right side of the panel, you can see what the projected cancer survivorship is over the next decade or so. We're kind of halfway through that decade, as it was originally described. And as you can see, because of the very, in my opinion, amazing progress that has been made in the hematology and oncology fields, the cancer survivorship, which is determined as an over five-year cancer-free survival in patients with cancer, has dramatically increased, and it is expected to increase by over 24%, up to over 20 million individuals that will be deemed cancer survivors in the next five years or so. Alongside with that, we now see the ever-rising tide of cancer therapies-related cardiac toxicity. And this is a slide that I took from one of the gurus of cardio-oncology, Dr. Herman, who very nicely described how we have come to determine cardiac toxicity in patients with cancer. And as you can see here, in the early years of chemical compound utilization for the treatment of cancer, we did see a significant number of patients having cardiotoxic side effects. Largely, cardiotoxicity was determined as cardiomyopathy at that time. But as we entered the era of molecularly targeted agents in the early 2000s, these are now much more specific medications that we use against several different types of cancer, we began to recognize vascular toxicity. And even more, we started recognizing rhythm toxicity related to these otherwise wonderful medications. As we are entering the era of immunotherapy, and now we are seeing an explosion in survivorship in patients with cancer, more and more we're seeing more cardiomyopathy, more vascular toxicity, and alongside, much more rhythm toxicity. So, tachy and bradyarrhythmias in cancer are a very complex topic. And that is because cancer is not just the cancer itself, it's the surgical approach to cancer, it's the cancer therapeutics that are more and more sensitive and specific. They're very, very effective for treatment of cancer, but they come with a host of side effects. And I would like to point out that, especially on the left side of this very bizarre looking slide, there is a number of things that we need to remember. And number one, cancer and cancer surgery, especially in the thoracic and head and neck region, can cause bradyarrhythmias as well as tachyarrhythmias, which Dr. Fradley very nicely described earlier. Inflammation and radiation therapy, again, mainly radiation therapy in the thoracic cavity, can cause significant bradyarrhythmias and conduction system defects. Immunomodulation, immune checkpoint inhibitors, CAR T cell therapy, thalidomide, targeted therapies. Probably none of these ring a bell to any of us here. It certainly took me a number of years to start recognizing what each of these mean. But suffice to say, you will see more and more patients that have received some form of immunomodulation therapy. So it's important to recognize that all of these can cause tachy and bradyarrhythmias. And the arrhythmias, our conduction system defects, will, in fact, actually impact cancer therapies. It will be your decision whether patients can continue on their cancer therapy journey or not. With that, I want to bring up there a slide that is a little bit busy, but there are a couple of points I want to make. There are a lot of different cancer therapies that can cause specifically conduction system defects and bradycardia. That being said, they're not all the same. For example, thalidomide can cause severe sinus typically bradycardia in up to 40% of patients. So the frequency of bradycardia is substantial. And at the same time, this bradycardia, more often than not, will require pacing, especially in patients that have received either radiation therapy or have been previously exposed to anthracycline use. In contrast, five of you in paclitaxel, again, you may not recognize this, but you will see more and more patients that are undergoing active cancer treatment. These are very commonly used medications. Both of them are associated with a significant risk for typically their sinus or junctional bradycardia. However, in contrast to thalidomide, very rarely this is severe. Very rarely do we do anything for it. Now, last but not least, the immune checkpoint inhibitors. I'm fairly certain that all of you, irrespective of whether you work in a big cancer center or not, will have seen immune checkpoint inhibitors-related cardiotoxicity. It is quite rare that we see conduction system defects in the overall patient population exposed to ICIs. On the other hand, when it occurs, it should be a very, very red flag for everybody. We never dismiss conduction system defects, even though they're rare in patients who are undergoing active ICI therapy. Why that is? Because it may be an early signal of ICI-related cardiotoxicity. In approximately 10% of patients with proven ICI myocarditis, you will see very significant conduction system defects that may end up being even lethal. In this even more busy slide, again, I would like to bring your attention to two things. There are certain cancer therapies that cause both bradycardia, either sinus or junctional bradycardia, or AV block, and concomitantly they can actually impact upon the QTC, as my colleague discussed earlier. So I will not touch upon QTC, but it is important to recognize the risk of TORSAD in those patients is effectively double. So whenever you have a patient on, for example, arsenic, which, as you now know, has a very, very high risk for QTC prolongation, arsenic can also cause AV block. So when you have a patient who is bradycardic, on arsenic, and also has a QT prolongation, we know that the risk of TORSAD is high. We know that there is an associated risk of sudden cardiac death. The same thing with capsaicin. Again, if somebody does not really do cardio-oncology on a daily basis, all these medications do not mean much, but capsaicin is a very common medication used in solid tumors, so it's important that you recognize patients who are actively on it when you see them in your EP clinic. It's important to recognize that capsaicin also can cause bradycardia and has been associated with sudden cardiac death, and we just don't know why. So there is a very good possibility that this is TORSAD-mediated death. At the very bottom, again, immune checkpoint inhibitors. As we discussed earlier, bradycardia is relatively rare, but then they all come with a risk of sudden cardiac death. Now, largely for ICIs, this risk is related to acute myocardial injury. That being said, some of this risk is also related, obviously, to ventricular arrhythmias. Some of these ventricular arrhythmias may be TORSAD. In the middle of this very busy slide, there is a number of medications that are very new, so I want to point out the fact that obviously none of us, not being oncologists, can ever begin to learn each individual of these medications. But keep in mind what we call multi-target kinase inhibitors. These are new medications. Monoclonal antibodies. Again, new kids on the block. So we don't have much data, but the more data we have, the more we recognize that they're all associated with a risk of conduction system defect. So you will all come across them at one point or another. And again, I think already we discussed a little bit about QTC, but this is again driving a point that a lot of these anti-cancer therapies, be it new or old, are associated with a risk of QTC prolongation. And all of these agents are also associated with a higher risk for bradycardia. So keep in mind you have kind of a two-hit situation. And in fact, in a lot of patients, and I will go over a case that we had very recently of an 18-year-old female with metastatic Ewing on multiple cancer therapies, highly needed cancer therapies, 18-year-old with metastatic cancer. So this is not the type of situation where we actually say stop the cancer treatment because we're concerned about the heart. This is a patient that was admitted with bacteremia, ended up getting on multiple broad-spectrum antibiotics on top of everything else. Normal baseline QTC, and this is Bazette's QTC, she ended up being severely bradycardic on telemetry on day 17. Nobody paid attention until about a day later when we realized that on EKG, her QTC now was prolonged. She also had uniform PVCs, and of course that led to what we all recognize to be TORSAD. This became a sustained phenomenon. This patient required pacing and, of course, the usual medications for TORSAD. But this is to show that we should always be concerned when a patient with cancer, especially active cancer, is exposed to both cancer therapies as well as any other hits that can come along the way. So a few special considerations in cardiac amyloid. Again, in the past we used to say that cardiac conduction disease is, yes, it is important. We see it in cardiac amyloid. We recognize it as a disease more and more, but we didn't consider it of substantial clinical interest. We did not consider that it impacts patients on a clinical level. However, there are some interesting studies out there actually using ICMs in cardiac amyloid patients. Now, these are advanced stage cardiac amyloid patients, so it may not apply to earlier stage amyloid patients. Nonetheless, it appears that cardiac defects, cardiac conduction system defects, and severe bradycardia more often than not are what lead to death in those patients. So keep in mind, again, any bradycardia, any evidence of conduction system disease in a patient with documented amyloid, some of these have multiple myeloma, they're exposed to other medications that can cause the same thing, you should take this under advisement and make sure that these patients are very actively treated. So we still don't know what causes sudden cardiac death in amyloid patients, but bradycardia and conduction system disease is one of the considerations nowadays. I will end with a brief note on management and prevention of bradyarrhythmias in cancer. Again, I would like to reiterate that we do not know who are the patients at risk for bradyarrhythmias while they're undergoing cancer therapy or have previously been exposed to it. We always need to consider common risk factors. A lot of these patients have concomitant cardiac conduction abnormalities or AV block from before their cancer diagnosis, so all of that needs to be taken into context. However, keep in mind the poor tolerance of bradycardia in patients with cancer therapies, especially prior to initiation. There are certain chemotherapeutics. We went over a few of those that should be very carefully monitored throughout therapy, mainly thalidomide. Any life-threatening bradycardia typically requires immediate discontinuation. Keep in mind if you work in close collaboration with oncologists or hematologists, the last thing anyone will want is to stop treatment. So we're very quick to actually address conduction system disease with obviously pacing in that patient population. More and more these days, before of other comorbidities in that patient population, we tend to utilize a lot of leadless pacemakers. Patients with cancer obviously that require permanent pacing should be managed per general population guidelines. Again, we tend to go to pacing very quickly if necessary, especially if it would allow us to continue cancer therapies. Also keep in mind ICI therapies, and I'm showing this again in this slide, with immune checkpoint inhibitors, any atrial ventricular conduction disturbance, including even PR interval, should immediately lead to serial EKGs. Assessment for SCI myocarditis, pacing as needed. For other medications, when you see especially sinus bradycardia, again, if the patient is symptomatic, we tend nowadays to use more event monitoring or even implantable cardiac monitors. If therapy is continued, we may need to do pacing. For asymptomatic patients, especially when exposed to immune modulation or ALK inhibitors, more often than not, we continue therapy but with very strict monitoring. In conclusion, tachy and bradyarrhythmias, syncope of anonymityology, are very common in the cancer patient population. Keep in mind that multiple cancer therapies, both pharmacologic but also radiation transplant therapies, can cause both brady and tachyarrhythmias. These can also affect our therapeutic options, patient care and outcomes. So whenever you have a patient with cancer and syncope or presyncope, always consider occultarrhythmias, tachy or brady. Always consider at the same time concomitant QTC prolongation, and more importantly, recognize that we will see more and more cancer survivors or patients under active cancer therapy, so it's important that we manage them well. Thank you. Any questions? I have a question. So it's kind of easy to understand how a chemotherapy drug could prolong the QT interval. You could just say it inhibits potassium channels, but it's a little harder to understand how a drug could cause bradycardia, even like profound bradycardia, like complete AV block. Is there any data on how these drugs cause bradycardia, the mechanism? Right. So it depends on the type of bradycardia. Most of these medications that we discussed cause sinus bradycardia or even sinoatrial exit block. Do we know the exact mechanism? Actually, no. There has been some research showing that there is an oxidative stress-related effect on the sinoatrial node, and that may be the case. But in terms of whether this is the mechanism for all individual drugs, we don't actually know. We know much more about arrhythmias. We know how they can cause atrial fibrillation, for example. It is through specific kinase pathways. Whether the same pathways also result in conduction system defects is not very clear. Again, these are more rare phenomenon than atrial ventricular arrhythmias. Hi. Thank you for this talk. It was great. It was so interesting and I think so necessary in EP. There's lots of literature out there on tamoxifen in women post-breast cancer therapy. Has anyone dug into the data to see if there's any conduction defects in that post-therapy group? Yes. To my knowledge, and please, Michael, actually, you may have more experience with that too. To my knowledge, tamoxifen has not been readily associated with bradycardia. All of these medications, especially hormone medications, can, of course, one way or another, impact either the atrial arrhythmias or cause some bradycardia. Again, there is no clear-cut association with it, certainly not to the extent of other cancer therapeutics. In the interest of time, I think we'll move on to our next speaker. Thank you very much. Our next speaker is Dr. Kaveh Karimzad. He's an electrophysiologist at MD Anderson and an associate professor at the University of Texas. He's going to be talking to us about autonomic dysfunction in cancer. Right. Good afternoon. Thank you chairs. Thank you to HRS for inviting me to talk about autonomic dysfunction in cancer patients. And over the next 10 minutes or so I will try to touch upon different chemotherapy drugs associated with autonomic dysfunction and talk about prognostic relevance and causes of autonomic dysfunction in cancer patients and share with you some important articles in literature in regard to autonomic dysfunction in childhood cancer survivors, breast cancer and Hodgkin lymphoma. And finally talk about bare reflex failure due to head and neck radiation which is an important etiology of autonomic dysfunction in cancer patients with head and neck cancer. Different certain chemotherapeutic agents can cause autonomic dysfunctions. Platinum compounds like cisplatin and oxaloplatin has been shown to cause autonomic dysfunction in small studies. In another study more than a third of patients who were treated with vincristine manifested signs of autonomic dysfunction primarily orthostatic hypotension. The onset was early after exposure and recovery was expected after cessation of vincristine. In another small study 19% of patients with ovarian cancer who were treated with paclitoxel or docetoxel showed developed orthostatic hypotension. And finally the most important drug in field of cardio-oncology, anthracycline has been shown to cause autonomic injury and possibly this response is dose dependent the same similar way that it causes myocardial injury. The key manifestation and the primary clinical presentation of autonomic dysfunction is orthostatic hypotension. To a lesser extent we can see inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome. But primarily the manifestation of autonomic dysfunction is orthostatic hypotension which is typically seen when cardiovascular adaptive mechanism fail to compensate for reduction in the venous blood return which normally occurs in assuming an upright position. It reflects the structural and functional sympathetic denervation or a deranged reflex regulation of sympathetic outflow. Causes of autonomic dysfunction in cancer patients is multifactorial. Cancer itself can cause autonomic dysfunction. It can directly invade autonomic nerves or through perineoplastic syndrome. Cancer therapies we talked about certain chemotherapy drugs that can cause autonomic dysfunction like platinum based chemotherapy. Radiation is very important especially cranial and neck radiation and also mediastinal radiation and also other factors like medications, opioids, antihypertensives, chronic pain, malnutrition, cachectia. All of these can contribute to autonomic dysfunctions in cancer patients and a lot of times they overlap and that makes management of autonomic dysfunction in cancer patients challenging. The prognostic relevance of autonomic dysfunction in cancer was very well demonstrated in this large close to 5,000 patients with breast cancer and it showed that patients who had resting heart rate at the highest quantile of more than 85 beats per minute had significantly higher risk of all cause mortality compared to those who belong to lowest quantile of less than 67 beats per minute after adjusting for other prognostic factors. Another study on autonomic dysfunction in patients with very advanced cancer showed that autonomic dysfunction is very prevalent in this patient population. About 80% of these patients had either definitive or severe autonomic dysfunction based on Ewing's classification of autonomic dysfunction and these patients had increased severity of fatigue and also reduced survival. In another study on breast cancer patients, the authors demonstrated that anthracycline, trastuzumab, and left-sided radiation were associated with a higher heart rate at rest and also impairment of heart rate recovery, but exercise training at least twice a week appeared to mitigate these changes over time. In this very nice review article on autonomic dysfunction in breast cancer, the authors emphasized on lifestyle perturbations like psychosocial stress, sleep disturbances, weight gain, or metabolic dysregulation which ultimately lead to increased activation of sympathetic nervous system and decreased activation of parasympathetic nervous system and eventually through different systems and accesses like RAS, it can lead to oxidative stress, reduce vasodilation, atherosclerosis, and all of these ultimately promote cardiovascular disease. This article was recently published in Jack Cardiology. Investigators prospectively look at more than 1,000 patient survivals of childhood cancer who were treated with anthracycline chest radiation, both or neither of those, and they compared it with 286 community-controlled subjects. They looked at four different measures of autonomic dysfunctions and they categorized patient in four different groups based on the number of these abnormal measures and they concluded that they saw that the 24% of cancer survivals had two or more measures of autonomic dysfunction compared to only 6% in community control group and also patients who were treated with carboplatin, chest radiation, or cranial radiation, head and neck radiation. These patients were associated with increased likelihood of having two or more measures of autonomic dysfunction. Autonomic dysfunction measures that they looked at were elevated resting heart rate, decreased heart rate reserve, decreased blood pressure response to exercise, and delayed heart rate recovery. And as you see in this graph, in all of these four measures, patients' cancer survivals did worse than community control. And also, cancer survivals with two or more measures of autonomic dysfunction had increased risk of impaired cardiorespiratory fitness, which was defined by peak oxygen consumption of less than 80% predicted compared to survivors without autonomic dysfunction. The same group, the same authors, investigators also looked at Hodgkin lymphoma, 263% survivors of Hodgkin lymphoma who were referred for exercise treadmill testing 19 years after radiation to the chest, thorax, and they compared it with 526 MASH control subjects. Their defined autonomic dysfunction has elevated resting heart rate and also abnormal heart rate recovery. And they correlated these measures with exercise capacity and all-cause mortality over a median follow-up of three years. And the investigators very nicely showed that patients who got radiation treatment has increased prevalence of elevated resting heart rate and abnormal heart rate recovery. And these abnormalities contributed to decreased exercise tolerance. And also, patients with abnormal heart rate recovery had increased mortality. In this graph, you can see that patients who received radiation had higher heart rate and blunted systolic blood pressure response during all stages of exercise and recovery compared to control subjects. And in this graph, you see abnormal heart rate recovery was associated with increase of all-cause mortality. Another important etiology of autonomic dysfunction in cancer patients is baroreflex failure. Baroreflex is basically a reflex that regulates blood pressure. And what happens is that an increase in blood pressure activates baroreceptors located in the carotid sinus. And then afferent signals through glosopharyngeal nerve activates a nucleus in the brainstem. And this in turn activates neurons in medulla, which basically provide inhibitory input where the sympathetic activity originates. This result in decreasing sympathetic tone that goes through the preganglionic efferent fibers in the spinal cord and then postganglionic efferent fibers that innervate the heart and blood vessels to restore the blood pressure to normal levels. Afferent baroreceptor baroreflex failure is often due to damage to carotid sinus nerve because of neck radiation and neck surgery. And the clinical picture is characterized by extremely low blood pressure, very severe hypertensive crisis associated with hypotensive episodes and orthostatic hypotension, making this condition very challenging to manage. We see a lot of these patients at MD Anderson, the patients who have received neck radiation. And the mainstay of treatment in this patient is long-acting sympatholytic drugs like methildopa or clonidine patch. We should avoid short-acting agents in these patients because of rebound hypertension. And sometimes in these patients we have to use pressure agents even though they have hypertensive at baseline. Sometimes they have significant drop in blood pressure and orthostatic hypotension. Afferent baroreflex failure is basically loss of inhibitory input from carotid sinus, leaving the cortical input of mental stress to a medulla on a post. And this leads to surges in sympathetic nerve output and parallel increase in blood pressure and heart rate as you see demonstrated during tilt table testing. As opposed to that, primary autonomic failure is where autonomic regulation is impaired because of neurodegeneration of efferent autonomic fibers. And the clinical picture characterized by supine hypertension and orthostatic hypotension. And during tilt table testing, this is not associated with compensatory heart rate increase as opposed to the afferent baroreflex failure. This is the largest group of patients with afferent baroreflex failure, 104 patients studied from Mayo Clinic. The most common etiology was head and neck radiation followed by surgery. Most common finding was hypertension, fluctuating blood pressure, and orthostatic hypotension. And interestingly, about 20% of these patients had to receive both antihypertensive drugs and pressure agents. And median latency from completion of radiation to baroreflex failure was much longer, months and years after radiation as compared to surgery, which is usually after a few weeks or months after surgery. So in summary, autonomic dysfunction is common in cancer patients and cancer survivals. It is multifactorial and can possibly increase mortality in cancer patients. Early detection of autonomic dysfunction where it still might be reversible and identification of all mechanisms involved are important to develop a successful treatment strategy. We should have high suspicion and low threshold for testing for autonomic dysfunction in cancer patients and survivors. And finally, we should be aware and familiar with challenges in management of cancer patients with afferent baroreflex failure, which will present with extremely labile blood pressure, hypertensive crisis, and orthostatic hypotension. With that, thank you for your attention. There's an online question. Would you consider a tilt table testing, like just a guide for these syncope evaluations? Not routinely because sometimes it doesn't change the management. We don't routinely do tilt table testing, but in some situations we consider, yeah. Well, I want to thank all of our speakers for what was really an excellent session. Thank you all for coming, and this session is closed.

electrophysiologic complications

cancer treatments

atrial fibrillation

arrhythmias

QT prolongation

ventricular arrhythmias

bradycardia

autonomic dysfunction

cardiotoxic therapies

management strategies