Heart Failure Podcast

Approach to Cardiotoxicity: Art That Needs More Science

Michelle M. Kittleson, MD, PhD; Bonnie Ky, MD, MSCE


September 07, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Michelle M. Kittleson, MD, PhD: Welcome to Medscape InDiscussion: Heart Failure. I'm your host, Dr Michelle Kittleson. This is the 10th episode in our 12-part series, and today we're talking about approaches to cancer-associated cardiomyopathy. Why is the emerging field of cardio-oncology becoming more important today than ever before? And with over 18 million cancer survivors in the US, how can cancer treatment-related cardiotoxicity be prevented, detected, and treated to improve the quality of cancer survivorship for these patients? For expert guidance on these questions, we've invited Dr Bonnie Ky, director for the Thalheimer Center for Cardio-Oncology, director of the Penn Center for Quantitative Echocardiography, Founder's Professor of Cardio-Oncology and professor of epidemiology and biostatistics at the Perelman School of Medicine, University of Pennsylvania in Philadelphia. She's also the inaugural editor-in-chief of the journal JACC: CardioOncology, if you had any doubt about her expertise. Welcome, Bonnie. It's a delight to have you.

Bonnie Ky, MD, MSCE: Michelle, thank you so much for having me. It's such a great honor and pleasure to be with you today. It's a lot of fun to talk with you.

Kittleson: You are very welcome. I'm going to start by picking your brain. You wear so many hats, cardio-oncology being one of the biggest. How did you become an expert in the field of cardio-oncology? What sparked your interest, and what keeps you engaged today?

Ky: Yes, Michelle, let's pick away. I first became interested in cardio-oncology as a cardiology fellow back in 2008-2009, and it was really through science. That's what drew me into cardio-oncology. I always knew that I loved asking questions, looking for answers, and I became introduced to and really intrigued by the neuregulin/erbB signaling pathway, and it's actually through an original research manuscript that I read in JACC. From that article, I started asking questions in human heart failure related to this pathway, and I signed up for a master's of science in clinical epidemiology. I pursued that and then it was really under close and careful mentorship of many. There are many to thank but certainly Tom Cappola, Steve Kimmel, Martin St. John Sutton, and Doug Sawyer.

These physician scientists really helped guide me, and this pathway is also perturbed by trastuzumab. It's a monoclonal antibody that targets the erbB signaling system. I became interested in how this pathway applies to cancer therapy and cardiotoxicity, and I pursued that. So, really, I trained as a physician and as a scientist, and I started a research program in cardio-oncology back in 2009. And it was that transition from fellow to faculty and the close mentorship of many that caused me to start asking questions in cardio-oncology, and I really got hooked. Cardio-oncology combines my love of science and my desire to have an impact on patients. My patients inspire me every day, and I want to advance science so that we can take the best possible care of them.

Kittleson: I love that answer. I love that the JACC story comes full circle.

JACC inspired you, and now you are the editor-in-chief of JACC: CardioOncology. I love the power of having a research question that is fueled by your desire to take care of patients and the wisdom of the apprenticeship of medicine. Everything about your story is very inspiring. And because cardio-oncology is an emerging field, it may be important to define it first. What does cardio-oncology mean? Why is it important that we know about it?

Ky: You're right: It's a field in growth, and it is just an exciting time to be a part of this field. Why is it important to know about it to be a part of it? Because all of us as physicians and as care providers will take care of cancer patients and survivors. And, to me, cardio-oncology means several different things and exists on multiple levels.

First, we know that there's epidemiologic overlap between cancer and cardiovascular disease — shared risk factors, including obesity, smoking, and so forth. We also know that there's an increased burden of cancer in our cardiovascular disease patients and vice versa: Our cancer patients suffer from increased risk of cardiovascular disease.

Second, there's mechanistic overlap. We know common pathways, inflammation, the immune system, clonal hematopoiesis — they're common both to cardiovascular disease and cancer. And it's important to understand that cardio-oncology also exists on that level. Third, we all know that highly effective cancer therapies that are lifesaving have adverse cardiotoxic effects, and perhaps this is most common and most evident to us as cardiologists and to the oncologists. The pillars of cancer treatment and standard chemotherapy, such as anthracyclines, which have been in use for decades, have toxicity. Targeted therapies, such as vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs), radiation therapy, and immune therapy can all result in cardiovascular toxicities. Cardio-oncology is also growing in importance as there is a growing population of patients living with cancer and beyond cancer.

As they grow older, they're at risk of cardiovascular disease. And, of course, you know that cancer and cardiovascular disease are two leading causes of morbidity and mortality worldwide.

Kittleson: That really frames it in such an important way. As cardiologists, we need to know about it because it can touch our patients in different ways. You talked about how it can touch our patients. Let's approach a few cardio-oncology scenarios that a general cardiologist should feel comfortable managing.

Let's start with the cardiac care of the cancer survivor. Tell us some tips, pearls, and guidelines that we can turn to for resources for that scenario.

Ky: Absolutely. As you said, cancer survivors are crossing our clinics every single day. There is a growing population of patients living beyond cancer, and I think one critically important take home message is that we need to treat modifiable cardiovascular risk factors.

There is a wealth of epidemiologic data that suggests in our cancer patients and survivors that there is a high burden of cardiovascular risk factors. Commonly, these are undertreated and undermanaged. A mentee of mine, Lova Sun here at Penn, performed a large retrospective analysis of veterans with prostate cancer treated with androgen deprivation therapy.

She found that there was a very high prevalence of common cardiovascular risk factors like hypertension in 78% of the population. But despite this high burden, a large proportion were being undermanaged and undertreated in terms of cardiovascular risk. And we know that this is important because cardiovascular risk factors — hypertension, dyslipidemia, obesity — they're associated with an increased risk of cardiovascular disease, even more so in our survivors of cancer compared to the general population. In addition to common cardiovascular risk factors that are imperative to treat, I think other common risk factors relate to cancer treatment. Patients who receive anthracyclines, of course, are at increased risk of developing subsequent cardiovascular disease.

We commonly think of a 250 mg/m2 doxorubicin equivalent as a high dose, but we also know there's no safe dose of anthracycline chemotherapy, and we can see toxicity at lower doses. Radiation also causes increased risk of cardiovascular toxicities. Heart failure with preserved ejection fraction (HFpEF), a study performed by Maggie Redfield many years ago suggested that there's a dose relationship with the development of HFpEF. Valve disease, pericardial disease, coronary disease, and arrhythmia may arise.

We commonly think of a dose of total of 30 Gy as high dose. But again, data suggests there is no safe dose of radiation therapy, so a general cardiology consultation would be appropriate. Other cancer therapies, such as the TKIs, I mentioned those briefly before HER2-targeted therapies. We also talked about patient-specific risk factors.

I always say beware of the patient with the borderline normal ejection fraction (EF) who is about to get cardiotoxic cancer therapy. I think those patients need increased attention. Then there are, of course, biologic factors as well — that is an area of emerging science. And, of course, the social determinants of health are another area of emerging science that's critically important to cardio-oncology.

Kittleson: Oh my gosh, I have so much to unpack there. I'm very excited. So, the general cardiologist must realize that when you meet a patient who has ostensibly won the game — they have survived their cancer — there's no rule in life that you're only going to get one problem. You must not forget their risks for cardiovascular disease, and you must help them win the second game, which is the battle against cardiovascular disease.

So, pay attention to those risk factors. Practice primary prevention. Use aggressive, optimal primary prevention for atherosclerotic disease in your cancer survivors. Don't just pat them on the head and say, "You've already won the lottery. Good luck." I love that advice. Now, you also gave us a very nice framework to think about those cancer therapies and your risk of cardiotoxicity.

You put buckets of the anthracyclines, the HER2, the TKIs, the radiation. Let's now transition to that more advanced scenario that the general cardiologist may face. There is a patient who's receiving cancer therapies. They're referred by the oncologist to the cardiologist for co-management.

Tell us, which of these do we need to be most aware of? What's a good resource to know? What surveillance should the cardiologist implement when patients are receiving cancer therapies?

Ky: That's a great question. I think cardio-oncology is a lot about an evolving field and really there's a lot of learning every single day in clinic and outside of clinic in the labs. And, of course, as editor-in chief of JACC: CardioOncology, I'm going to say where to go and get the best knowledge is JACC: CardioOncology.

Of course, I'm biased there, but that is really my goal and my mission as editor-in-chief — to bring together the best possible knowledge so that we can impact care in a positive way and equip the clinician with the best evidence-based science that's actionable. Really, that is my mission. And we try to do that through the journal and through how-to series. I think sessions like this that Medscape is producing also help to serve and educate. And the work of other societies, such as the American College of Cardiology (ACC), we had a live course advancing the care of the oncology patient, the American Heart Association (AHA) with their symposium, and the International Cardio-Oncology Society (ICOS).

I think a lot of this is about current, evidence-based education. That's critically important and necessary to advance knowledge. Also, the European Society of Cardiology (ESC) published extremely comprehensive guidelines. That was in the summer of last year in JACC: CardioOncology. Really, this was a tremendous and amazing effort. I encourage everyone to read this important document. The authors undoubtedly need to be congratulated for this phenomenal work that serves as a guidance, a guideline, and a roadmap for our field. But I think an important point to also acknowledge about the guidelines is it also highlights the need for greater evidence.

There were over 270 recommendations in the ESC guidelines, and 76% of these were Level of Evidence C. There were 156 or so Class I recommendations and only 3% were supported by Level of Evidence A. So, as a field, our work is cut out for us. We need to generate the necessary science to inform clinical medicine. I'd say a lot of learning also comes from just collaboration — from talking to our colleagues, from talking to oncologists, from collaborating with our PharmDs — to take the best possible care of our patients.

Kittleson: I think that's so important, and I know my mentors taught me that when you go into medicine, you don't need to always know the right answer. You need to know the right questions and where to look for the right answer. I love that the JACC: CardioOncology series is so practical for clinicians.

So, knowing when you have a patient and you're thinking, warning, warning, potential risk of cardiotoxicity because they've got the risk factors and they've received one of the big therapies that's a high risk for developing cardiotoxicity, go to these resources for the best guidance. This will be art that uses a little bit of science for now, but they will continue to improve through your efforts and those of many of your colleagues.

I'm going up the ante a little bit. What about a patient who's got cardiomyopathy attributed to their chemotherapy? We know that shared decision making and multidisciplinary collaboration will form a huge part of future therapy decisions, but are there certain absolute contraindications and prohibitive scenarios that every cardiologist should know about when working with the oncologist to make decisions about future cancer therapeutics?

Ky: Michelle, that's such a great question. I think a lot of medicine is about the art and the science. You're right: A lot of this is shared decision making. And, indeed, these are really challenging situations. I currently have a patient with severe anthracycline cardiomyopathy with class IV heart failure, and they're not able to tolerate much in terms of guideline-directed medical therapy.

I could give you, let's say, a top-10 list of what I think are important take home messages or pearls in cardio-oncology, maybe not absolutes per se because a lot of times in medicine things aren't always black and white. I feel like there's a lot of gray. But I think as it pertains to cancer therapy, cardiomyopathy, or anthracycline-associated cardiomyopathy, there's commonly been a notion that it's irreversible, and that it occurs very late. I think there are increasing data to support that that idea is no longer true. This is at least by EF standards. And we could have another Medscape podcast about EF and heart failure, but at least by EF standards, the irreversibility idea is no longer true. We do see recovery of EF with neurohormonal therapy, and cardiomyopathy declines in EF can occur earlier. In fact, 1 to 2 years after exposure to cancer therapy. I also think there's an increasing notion in cardio-oncology of permissive cardiotoxicity, so this balance between administering and ensuring our patients can receive that lifesaving oncologic therapy and balancing cardiovascular risk. So, meaning I'm going to allow for a little mild left ventricle (LV) dysfunction in my patient with HER2-positive breast cancer so she can continue and complete her trastuzumab and have the best possible oncologic survival with very careful management with neurohormonal therapy and close collaboration with the patient and the oncologist. I also think an additional pearl, and maybe this is an absolute, but never stop HER2-targeted therapy for asymptomatic decline and strain alone — global longitudinal strain, that is. I think there's still a lot of emerging science in this area. There's not strong enough evidence that strain alone should be guiding care decisions. And I'm saying strain alone, for example, in a normal EF.

I think a really important clinical pearl that I want to make sure everyone goes home with is to treat the modifiable risk factors and treat cardiovascular disease in our patients living beyond cancer. Just because a patient has a cancer diagnosis does not mean that you don't treat the modifiable risk factors.

Also, an important notion in the field is there is no safe dose of anthracycline. It's important to manage these modifiable risk factors. When we think about more current therapy — for example, immune therapy — myocarditis has gotten a lot of attention, although it's still relatively uncommon, less than 1%. And we do believe now, secondary to perhaps increased recognition and better management, that the mortality rates are really decreasing, but there may be other cardiovascular toxicities.

So, stay tuned. There's a lot of emerging science here as relates to atherosclerosis, for example, accelerated coronary disease. I also want listeners to know that [when it comes to] cardiotoxicity, we think a lot about heart failure. Of course, this is a heart failure session, but cardiotoxicity is really a broad term.

Don't just think of HFrEF. There's also heart failure with preserved ejection fraction (HFpEF). I do believe that anthracyclines are associated with increased risk of HFpEF in the long term. Also, arrhythmia, venous thromboembolism (VTE), coronary disease, and so forth. The last pearl as it pertains to cardiac masses as in life is tissue is the issue. A lot of times you need a sample. Don't be fooled by the imaging.

Kittleson: I cannot tell you when you started out this amazing pocket lecture just now saying you are going to give us your top tips and tricks and pearls, I wept with happiness a little bit inside. I was on the edge of my seat like all our listeners I'm sure are right now, because that was hugely important guidance.

We'd all love in medicine to have a test that's 100% accurate, a treatment that's 100% effective, and to just deal with absolutes. But we can't, and it's so important to know the subtleties, and I'm going to play that little clip over and over. That was so valuable along the spectrum of cardio-oncology.

With all that wisdom, what's the one thing you want listeners to do differently after hearing this discussion?

Ky: I'd love for listeners to come and join us in cardio-oncology, train in cardio-oncology, and be in involved and active in the science. Cardio-oncology is a growing field, and it's an exciting time to be involved. We need greater evidence. We need more clinicians and care providers.

The patients in cardio-oncology are remarkable, and they will inspire you. So, come join us.

Kittleson: I love it. The brief takeaways from this conversation should be number one, don't just think you won the game if you survived cancer. Treat your patients for their cardiac risk factors aggressively. Number two, remember there's no safe dose of anthracyclines or radiation. Have a high index of suspicion for the patients you see with that history. Number three, this is a team sport. If you are a general cardiologist practicing in the community and have a question, the answer is no farther away than resources like JACC:CardioOncology and podcasts like this.

Dr Ky, I'm so delighted. It's always a pleasure to have an excuse to pick your brain. Thank you so much for being here.

Ky: Thank you so much, Michelle. This was a lot of fun.

Kittleson: Thanks for joining our discussion with Dr Bonnie Ky. There's so much more ahead in the coming episodes, so be sure to check out the Medscape app and share, save, and subscribe if you enjoyed this episode. I'm Dr Michelle Kittleson for Medscape InDiscussion.


Heart Failure

Cardio-oncology: A New and Developing Sector of Research and Therapy in the Field of Cardiology

NIH Office of Cancer Survivorship

Cardiovascular Effects of Neuregulin-1/ErbB Signaling: Role in Vascular Signaling and Angiogenesis

Heart Failure in Patients With Cancer Treated With Anthracyclines-Revisiting the Foundation of Cardio-oncology

Major Adverse Cardiovascular Events Associated With VEGF-targeted Anticancer Tyrosine Kinase Inhibitors: A Real-life Study and Proposed Algorithm for Proactive Management

Assessment and Management of Cardiovascular Risk Factors Among US Veterans With Prostate Cancer

Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-onset Cardiotoxicity

Heart Failure With Preserved Ejection Fraction

2022 ESC Guidelines on Cardio-oncology Developed in Collaboration With the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)

Neurohormonal Activation in Heart Failure With Reduced Ejection Fraction

Breast Cancer and HER2

Association of Global Longitudinal Strain With Clinical Status and Mortality in Patients With Chronic Heart Failure

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