By Katlyn Nemani, MD

In this edition of Clinical Innovators, we speak with Javid J. Moslehi, MD, co-director of the Cardio-Oncology Program at Brigham and Women's Hospital and faculty in the Department of Medicine at Harvard Medical School, about his passion for cardio-oncology. He is a leader in the management of cardiac complications associated with radiation and novel chemotherapies. His achievements include the development of new cardiac surveillance algorithms for oncology patients and care delivery models to improve the prevention and management of cardiovascular disease. Dr. Moslehi is also a basic scientist whose laboratory is interested in delineating the mechanisms of cardiotoxicities associated with novel targeted therapies, and what these toxicities can teach us about the human cardiovascular biology.

How did you become interested in cardio-oncology and the cardiovascular care of cancer patients?

Following the completion of my clinical cardiology fellowship at Brigham and Women's Hospital in 2007, I decided to start a basic science post-doctoral fellowship in the laboratory of William G. Kaelin, Jr., MD, at the neighboring Dana-Farber Cancer Institute. The major focus of the laboratory was kidney cancer and mechanisms by which mutations in tumor suppressor genes in kidney cancer (specifically mutations in the von Hippel-Lindau [VHL] gene) led to tumorigenesis. My immediate post-doctoral work was studying the role of VHL gene protein product and associated machinery in the cardiovascular system. I was able to get a career development grant for this work.

While at Dana-Farber, I realized the emergence of novel cancer therapies. For kidney cancer, for example, there were eight FDA-approved drugs in 2008; none of these had been approved just 4 years earlier. In fact, I remember as an internal medicine resident at Johns Hopkins in 2004, we had a famous urologist teach us about kidney cancer. He would go around the room and ask the residents what medical treatments had been approved for kidney cancer and no one had an answer. Then he'd say, "Aha! That is because kidney cancer is a surgical disease and you medicine people have nothing to give patients. We surgeons are the answer!"

By 2008, however, a number of drugs had been approved for kidney cancer. Because of the work done by Dr. Kaelin and others, most of these new drugs were angiogenesis inhibitors and specifically targeted vascular endothelial growth factor. What I found interesting as a cardiologist were the cardiovascular toxicities that we were beginning to see with these novel drugs. For example, we were referred patients who presented with hypertension, thrombosis, or cardiomyopathy, which were associated with the drug bevacizumab.

At the same time, I also realized that the cardiovascular issues that arose from these angiogenesis inhibitors represented just a fraction of toxicities from traditional and novel cancer drugs. Given the number of novel therapies tested in clinical trials and their potential cardiotoxicities, I saw an opportunity for a dedicated clinic to see these patients, as well as a clinical niche that would be a nice match to my basic science interests.

I spoke of this interest to one of my mentors at Brigham—Kenneth Baughman, MD—who quickly became my advocate and helped me in establishing a "cardio-oncology" clinic, initially at the Dana-Farber and then at Brigham. I was fortunate to get support from both our cardiology chief (Peter Libby, MD) and the leadership at Dana-Farber. Our clinic quickly grew in volume. Currently, we have four dedicated clinics at Brigham and Dana-Farber, which I co-direct along with my clinical partner, Anju Nohria, MD. I guess my biggest regret is that Dr. Baughman died suddenly and unexpectedly in 2009 (a few months after the clinic was started) and never had the chance to see how far our clinic and our program has grown in the last few years. Ken was a true gentleman, a man of integrity and a superb mentor for a generation of cardiologists both at Hopkins and at Brigham.

Can you tell us what you have learned about cardio-oncology since joining the faculty at Brigham and Women's 4 years ago?

Cardio-oncology is a new frontier in medicine and it exists as a new subspecialty in cardiology in part due to the advent of novel therapies in cancer. These "targeted" therapies are being tested and approved at a rapid pace and have completely reshaped the prognosis in certain types of cancer. As a result, cancer survivorship has been introduced as a new "theme" in oncology care. In 2012, for example, there were an estimated 13,700,000 cancer survivors in the US alone (3,000,000 were breast cancer survivors), numbers that were unimaginable a few years ago.

Cardiovascular toxicities are associated with some of the traditional therapies (such as anthracyclines or radiation) that form the cornerstone therapies for some types of cancer. In addition, some of the novel targeted therapies have adverse cardiovascular sequelae, in part because the same pathways that are important for the cancer cell, and which are being targeted by therapies, are important for cardiovascular homeostasis and their disruption leads to cardiac toxicities.

Given the growing arsenal of therapies and the increasing number of cancer survivors, cardio-oncology is a growing field. It is also an exciting field because there are no guidelines in terms of how to prevent and treat the new cardiotoxicities. In some cases, for example with new therapies only approved over the last few years, we don't even know if toxicities exist. And no one—not cardiology textbooks, not even the senior "master clinician"—can tell you if there are toxicities and what to do about them. As a result, this affords an incredible opportunity to really define a new field.

Speaking of a growing field, there are now multiple new cardio-oncology clinics and virtually in every academic institution. Yes, in New England alone there are now about a dozen cardiologists who have established clinics in cardio-oncology, and each cardiologist has unique interests. Just to name a few examples, Sanjeev Francis, MD, and Marielle Scherrer-Crosbie, MD, from Massachusetts General Hospital have interests in cardiac imaging and Susan Lakoski, MD, at the University of Vermont has an interest in exercise physiology and preventive cardiology. This is an exciting opportunity to collaborate in various projects.

Some view cardio-oncology simply as a subspecialty within heart failure. Do you agree?

That could be one model. However, heart failure represents just a fraction of the cardiotoxicities associated with cancer therapies. In fact, many of the newer therapies have diverse cardiovascular effects that extend beyond heart failure. For example: angiogenesis inhibitors cause hypertension and thrombosis; novel bcr-abl inhibitors are associated with vascular disease; HDAC inhibitors cause ECG changes and arrhythmias; and mTOR inhibitors cause cardiometabolic changes. Indeed, a successful cardio-oncology program must incorporate various groups within cardiology to succeed, including cardiac imaging, vascular medicine, genetics, preventive cardiology, and metabolism.

On the flip side, I think cardio-oncology can teach us about cardiomyopathies. One thing we have already learned in cardio-oncology, for example, is that not all systolic heart failures are the same. This observation may provide insight into the biology of heart failure and even as it pertains to the general heart failure population. Our own research suggests that the pathophysiology of cardiomyopathy due to angiogenesis inhibitors is similar to ischemic cardiomyopathy, suggesting that the "one-size-fits-all" approach dominating heart failure care for the last 2 decades may not apply to our cardio-oncology population.

In a manuscript that you published recently in the European Heart Journal, you stressed the role of novel noninvasive imaging for the detection of cardiovascular disease in the cardio-oncology population. Can you expand on this?

The manuscript—co-written with John Groarke, MB, BCH, MSc—suggests that cardiovascular imaging is an important and critical part of a successful cardio-oncology program. This is partly due to the fact that noninvasive imaging is a routine means of monitoring for cardiovascular toxicities, and this is true in preclinical studies, early clinical trials, and even drugs that have been approved for treatment.

Let me give you an example: In the United States, 20% of new cases of breast cancer over-express a receptor called HER2. Treatment of these tumors with anti-HER2 therapies (such as trastuzumab) is effective, but, because of the early cardiotoxicities associated with trastuzumab, every patient being treated with it must undergo a baseline assessment of EF, and further assessment every 3 months during the year-long trastuzumab therapy. This is something that every oncologist knows and agrees on.

Unfortunately, we have very little idea of what the right assessment should include. Should it be a MUGA scan or an echo? Is EF really even a good parameter to base clinical decisions on? These are just some of questions that we can only begin to answer in close collaboration with our cardiac imaging colleagues. At Brigham, we have the luxury of having some of the biggest experts in imaging and are beginning to form partnerships to tackle these questions.

In an intriguing editorial for the New England Journal of Medicine, and a second manuscript for Science Translational Medicine, you build a vision for cardio-oncology in the future. You suggest an interesting link between cardio-oncology and basic science in cardiovascular medicine. Can you expand on this?

The manuscripts, and in particular the Science Translational Medicine editorial [written in collaboration with Susan Cheng, MD], highlight the theme that cardiovascular toxicities arising from novel targeted therapies can teach us much about cardiovascular biology. The cardiotoxicities that were observed from trastuzumab, for example, has led to an entire biology focused on HER2 signaling in the heart with the potential for therapeutic intervention for heart failure with neuregulin (a HER2 ligand). But I believe this represents just the tip of the iceberg given the explosion of novel targeted therapies. For example, many of the novel treatments being developed in oncology target cancer metabolism and some of these will undoubtedly have adverse cardio-metabolic consequences. This creates a unique opportunity to study and understand cardiac metabolism in humans. My colleague, Ben Olenchock, MD, PhD, who is joining the Brigham faculty as a critical care cardiologist, is leading this effort with a goal of understanding these cardiotoxicities at a molecular level.

In this regard, cardio-oncology has the potential to serve as a novel platform for basic and translational research—and may arguably provide a nice track for the basic scientist cardiologist. I strongly feel that institutions that recognize this and provide resources for these research initiatives will ultimately help define the field of cardio-oncology.

What do you see as key obstacles to national efforts in improving cardiac care for cancer patients?

One area that needs to be improved is greater communication and collaboration between oncologists and cardiologists. It is important for the oncologist to realize the potential cardiovascular sequelae of traditional and novel chemotherapies. In cardiology, we must appreciate the big picture and what the oncology community has been able to accomplish over the last 2 decades.

The advent of novel therapies in oncology has drastically changed the prognosis of certain types of cancer and has completely rewritten cancer textbooks in terms of potential therapies. We need to learn about these therapies just to be able to carry on a conversation with the oncologists. There also needs to be greater input from cardiologists in oncology clinical trials where the definitions of cardiovascular toxicity used in clinical trials appear, at times, arbitrary. This input is important in both helping identify cardiotoxicities but also in cases where the oncologist clinical trial may overcall "toxicity."

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Katlyn Nemani is from Tufts University School of Medicine in Boston.

Keywords: Antibodies, Monoclonal, Humanized, Genes, Tumor Suppressor, Cardiovascular System, Translational Medical Research, Anthracyclines, Kidney Neoplasms, Thrombosis, Survival Rate, Cardiomyopathies, Heart Failure, Cardiovascular Diseases, Hypertension

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