Heart and Vascular Health after Transplant

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Heart and Vascular Health after Transplant

May 2, 2023

Presenter: Michael Fradley, MD, Hospital of the University of Pennsylvania

Presentation is 23 minutes long followed by 29 minutes of Q&A

Summary: This presentation reviews some of the short- and long-term cardiovascular toxicities that can develop after stem cell transplantation. It describes strategies that patients and their physicians can use to reduce the risk of developing cardiovascular problems after transplant.

Highlights:

• Cardiovascular disease and cancer are the two most common causes of mortality in the United States. About one-third of Americans have some form of cardiovascular disease.

• Approximately 10% of all complications after transplant involve cardiovascular problems that are often associated with a decreased quality of life and high mortality rate..

• A cardio-oncologist who specializes in managing heart disease in cancer patients is the best physician to consult about cardiovascular problems after a stem cell transplant.

Key Points:

(02:27): Short-and long-term cardiovascular toxicities can develop post-stem cell transplantation.

(03:18): About 30% of patients who receive cancer therapies will develop some type of cardiac complication, that may not be apparent until several years after treatment. These toxicities can affect a patient's survival as well as their quality of life.

(07:05): The early cardiovascular events are primarily heart failure, arrhythmias, which are abnormal heart rhythms, and pericarditis

(08:18): Atrial fibrillation is a common abnormal heart rhythm that occurs quite frequently during, or shortly after, stem cell transplantation. Patients may experience palpitations, shortness of breath, dizziness, or no symptoms at all.

(10:19):  Late cardiovascular complications that can occur years after transplant include heart failure, heart attacks, strokes, heart valve problems, and autonomic dysfunction, which is exhibited by symptoms such as fast resting heart rate, positional dizziness, and sometimes fainting.

(11:40): The risk of heart attacks and strokes increases with advanced age of the person at the time of transplant. This risk increases by more than four times in people with underlying cardiovascular risk factors.

(15:15):  We often use the ‘ABCDE approach’ to assess cardiovascular risk reduction.

(16:43): High blood pressure is common in stem cell transplant survivors, affecting some 18% of individuals. Hypertension significantly increases the risk for the development of coronary artery disease in cancer survivors, including heart failure, valvular disease, and abnormal heart rhythms. Because of this, blood pressure control is essential.

(20:31): Diet is extremely important and is often underappreciated. We know that stem cells transplant survivors have increased rates of diabetes and obesity compared to the general population.

(21:13): At least 20 prospective studies have shown that physically active cancer survivors have a lower risk of cancer recurrence and improved overall survival compared to those who are inactive.

Transcript of Presentation:

(00:01): [Lynne Spina]:  Hello and welcome to the workshop Heart and Vascular Health after Transplant. My name is Lynne Spina and I will be your moderator for this workshop.

(00:11): Introduction of Speaker. Today's speaker is Michael Fradley, MD. Dr. Fradley is an attending cardiologist, electrophysiologist, and an Associate Professor of Clinical Medicine in the Division of Cardiology at the Pearlman School of Medicine at the University of Pennsylvania. He serves as both the Section Chief of the Consultative Cardiology Section and the Medical Director of the Thalheimer Center for Cardio-Oncology at the University of Pennsylvania.

(00:47): As a trained electrophysiologist, Dr. Fradley has a particular interest in the diagnosis and management of arrhythmic complications associated with traditional and novel cancer therapies. He has published over 90 manuscripts and has served as the co-chair of the Global Cardio-Oncology Summit in both 2018 and 2021. Please join me in welcoming Dr. Fradley.

(01:20): [Dr. Michael Fradley]:  Thank you and good morning. I want to thank Marla, Sue, Lynne and all the organizers for inviting me to give this talk today about cardiovascular risk associated with stem cell transplantation.

(01:47): You might be wondering, What is a cardio-oncologist and what is an electrophysiologist? A cardio-oncologist is a cardiologist who specializes in the management of cardiovascular disease and risk in cancer patients and cancer survivors. An electrophysiologist happens to be another subspecialty of cardiology that focuses on abnormal heart rhythms. We are the doctors who will manage patients with atrial fibrillation as well as the ones who implant pacemakers. Stem cell transplant survivors must be very mindful of their cardiovascular health.

(02:27): I will be providing you with a road map for my presentation. I will review some of the short- and long-term cardiovascular toxicities that can develop post-stem cell transplantation. I will then highlight some cardiovascular risk mitigation strategies for survivors.

(02:53): Cardiovascular disease and cancer are the two most common causes of mortality in the United States. About one in three Americans have some form of cardiovascular disease. There are also approximately 12 million patients with active cancer. What you may not realize is that there are over 14 million cancer survivors, with that number expected to increase dramatically over the next decade.

(03:18): About 30% of patients who receive cancer therapies will develop some type of cardiac complication. This may be a new problem or the exacerbation of underlying, preexisting disease. These cardio toxicities can affect a patient's survival as well as their quality of life, independent of their oncologic prognosis.

(03:39): Some of these complications may not become apparent for many years after the completion of cancer treatments. It is becoming increasingly important to monitor for and treat these cardiovascular complications since patients with cancer are living longer and are, in many cases, surviving their disease.

(03:56): You can see from this chart, the five-year survival rates for many cancers has increased significantly over the last three decades, with some approaching 100%, and some cancers are now even being managed as chronic diseases. The last thing we want is for cardiovascular disease to become a barrier to receiving effective cancer therapy, or to survive cancer, only to be left with lifelong debilitating cardiovascular disease.

(04:23): We know that cardiovascular disease is common after cancer treatment. These are data from the childhood cancer survivor study out of St. Jude's Research Hospital, where they looked at over 10,000 adult survivors of a pediatric cancer and compared them to 3,100 [healthy]:  siblings. This was an attempt to control, as best as possible, such things as genetics or other environmental factors and exposures.

(04:50): What they found was, by the age of 45, coronary artery disease, valvular disease, abnormal heart rhythms and heart failure, were significantly increased in the survivors compared to their siblings. When you look at serious life-threatening events, the incidence was at around 5.3%.

(05:15): When you consider complications post stem cell transplant, it's important to recognize that cardiovascular issues account for only about 10% or less of all transplant related complications. When you all are thinking about the various issues that can occur post-transplant, cardiovascular complications are not the predominant issue.

(05:39): But if a cardiovascular complication occurs, it can be associated with a high mortality rate and decreased quality of life for long-term survivors. At 25 years post-transplant, approximately 22% of these survivors will experience some sort of a cardiovascular event. Therefore, it's essential to try to reduce cardiovascular risk in transplant survivors.

(06:04): Cardiovascular events post-transplant are related to multiple factors including the exposure to anthracyclines, which are a common chemotherapy given prior to transplant for various different malignancies; the exposure to radiation, especially if it's directed to the chest; exposure to various targeted therapies or immunotherapies, which are becoming increasingly utilized for the management of these diseases; exposure to high-dose cyclophosphamide, which is often a part of the preconditioning regimens for transplant; the development of graft-versus-host disease; the presence of baseline cardiovascular disease and risk factors when a patient is going into transplant, such as hypertension or diabetes.

(06:48): We can divide cardio toxicities into early events, which are those that occur within the first hundred days post-transplant, and later events that occur after the 100-day mark, and may not even become apparent for many years post-transplantation.

(07:05): The early cardiovascular events are primarily heart failure, arrhythmias, which are abnormal heart rhythms, and pericarditis. The incidence of an asymptomatic decrease in heart function, which is also known as the ejection fraction, is more common than appreciated clinically and may occur in up to 33% of patients. That means that patients may not have symptoms, but if you're following their heart function via echocardiography, which is an ultrasound of the heart, we'll see that quite a few patients are having declines in their heart function.

(07:39): Fortunately, the incidence of symptomatic heart failure is less than 5%, which means that most patients don't develop such symptoms as shortness of breath or fluid retention as a result in this change in heart function. The risk is increased in patients who've received prior anthracycline treatment; there was no difference in this early cardiotoxicity whether a patient had an autologous transplant or an allogeneic transplant. It's also important to note that these early decreases are generally reversible, and they're thought to be related to the overwhelming stress that the transplant takes on the body.

(08:18): Atrial fibrillation is a common abnormal heart rhythm that occurs quite frequently during, or shortly after, stem cell transplantation. Patients may experience palpitations, shortness of breath, dizziness, or no symptoms at all. For some people, atrial fibrillation can become a persistent issue and can lead to an increased risk of stroke. For others, this is just a transient phenomenon; we're still learning about who are the ones that are going to develop a more persistent long-term problem.

(08:48): We know that risk factors for developing atrial fibrillation in this early period include older age; premature atrial complexes or delays in their conduction on an EKG taken pre-transplant; if they have preexisting cardiovascular disease; if they have abnormal kidney function; elevated creatinine; or if their left atrial is enlarged, which is a measurement we get on the ultrasound of the heart…most everyone gets this test before they undergo transplantation.

(09:20): [Other risks include]:  If melphalan was part of their pre-conditioning chemotherapy, which is quite common in the autologous transplant group; and then, of course, prior exposure to anthracyclines or mediastinal radiation.

Pericarditis is an inflammation of the lining around the heart. While pericarditis itself is not dangerous, it can be quite painful and impact quality of life and the speed of recovery in that early post-transplant period.

(09:48): We recently published data from our experience at The University of Pennsylvania. We found that the incidence of pericarditis was around 3.2%. Patients with pericarditis were more likely than patients without pericarditis to have received total body irradiation. Importantly, a medication called Colchicine, which is a safe anti-inflammatory medication, was an effective intervention. Patients who received at least 90 days of Colchicine had reduced recurrence of their pericarditis.

(10:19): Moving into the late cardiotoxicity, there are common symptoms that occur following the 100-day mark, including many years after a person has gone through transplantation. These include heart failure, heart attacks, strokes, heart valve problems, and autonomic dysfunction, which is exhibited by such symptoms as fast resting heart rate, positional dizziness, and sometimes fainting.

(10:48): We have talked about decreased heart function in the early transplant period, but it can also occur at a more delayed time. Heart muscle dysfunction was found in around 42% of survivors of whom 28% were symptomatic. Again, this is something that can occur many years after transplant.

(11:06): Dysfunction was associated with age; the total dose of anthracycline; the presence of graft-versus-host disease; and the number of cardiovascular comorbidities at the time of transplant; such as hypertension or diabetes. Dyspnea, which is shortness of breath, is the most common presenting symptom, one that can continue for decades. The median time to the development of problems is around 17-years-post transplantation.

(11:40): The risk of heart attacks and strokes increases with the increasing age of the person at the time of transplant. This risk increases by more than four times in people with underlying cardiovascular risk factors. In those undergoing allogeneic transplant. Interestingly, neither chronic graft-versus-host disease nor total body irradiation are considered significant risk factors for the development of one of these arterial events.

(12:12): Another late cardiovascular issue that can be seen in transplant survivors is heart valve disease. This most commonly occurs in people who've received prior mantle or mediastinal radiation. However, there may also be an association with anthracycline exposure. We know that the aortic and the mitral valves are the most commonly affected because they are the ones that sit closest to the chest wall. Problems generally occur more than 10 years after treatments and include shortness of breath, dizziness, fainting, swelling of the legs, chest pain, or fatigue.

(12:51): Something that is a significant problem for many people, is autonomic dysfunction, which is a condition where the nerves that control such vital functions as heart rate, blood pressure, and digestion, may be damaged. In cancer patients and survivors, this is most commonly due to radiation, but can also be related to chemotherapy.

(13:12): The symptoms of autonomic dysfunction include dizziness, palpitations, elevated heart rates, fatigue, weakness, and even cognitive impairment. In addition to its impact of quality of life, there may also be an association with long-term mortality. However, this has not been well established.

(13:34): We know that certain baseline risk factors in stem cell transplant patients increase the likelihood of developing frank cardiovascular disease in the post-transplant period. These include age at the time of transplant, anthracycline dose; hypertension; diabetes; smoking and chest radiation. And if you take each of these as a potential risk factor, and then create a risk score, you can see what the incidence is over 10 years.

(14:08): The low-risk group had fewer than three of the risk factors that I demonstrated previously. Within that age group, the youngest were considered to have one risk factor. The in between age showed two risk factors, and the elderly presented three risk factors. In a patient with fewer than three risk factors, the 10-year cumulative incidence of developing a cardiovascular event was around 3.7%. With four to five risk factors, the incidence was almost 10%. With six of those risk factors, the incidence of developing heart disease was over 26%.

(14:49): This information can be concerning; I suspect that many of you are wondering what you can do to reduce your risk of developing heart disease after transplantation.

(15:01): There are, of course, some risk factors that can't be changed, such as radiation or the specific chemotherapy exposure. We want to focus on those risk factors that we know are modifiable.

(15:15): When I see patients in clinic, I use something called the ABCDE approach to cardiovascular risk reduction, which is simplistic, but provides a validated framework for discussion with patients. These are the issues that every person should consider for good cardiovascular health, but they are even more important for cancer survivors.

(15:36): A stands for the awareness of symptoms, as well as aspirin, in select cases. B is for blood pressure control. C is for cholesterol control, coronary artery disease screening and cigarette avoidance. D is for healthy dietary choices in diabetes control, and E is for echocardiogram and exercise. I'm going to go over a few of these in a bit more detail.

(16:03): The role of aspirin in primary prevention, meaning the prevention of a problem that has not yet occurred, is controversial, especially in women. I'm sure that many of you have heard about recent recommendations against the use of aspirin in many individuals. But we may still consider aspirin in certain high-risk cancer populations such as those patients who had received prior radiation to the chest, or perhaps to the neck, or to patients who have evidence of calcium buildup in their arteries. This is an area that requires additional data and research.

(16:43): High blood pressure is common in stem cell transplant survivors and affects around 18% of individuals. Hypertension significantly increases the risk in cancer survivors for the development of coronary artery disease, heart failure, valvular disease, and abnormal heart rhythms. Because of this, blood pressure control is essential. The goal blood pressure should be less than 130 over 80. If your blood pressure is generally running above those numbers, regardless of your age, the goal is to get it below 130 over 80, since that's been shown to reduce the risk substantially of developing things as heart attacks, strokes, and heart failure.

(17:33): If you've had radiation exposure, especially to the chest, it's reasonable to have a stress test every five to 10 years after exposure. For those of you that haven't had a stress test before, it involves walking on a treadmill and then, every three minutes, the treadmill gets a little bit faster and a little bit steeper.

(17:52): People often ask, "Am I having to run from the very beginning?" And the answer is ‘no’. In general, you aren't running until the eighth minute. It's really that incline in the treadmill that causes your heart rate to increase. Your blood pressure's going to be measured periodically and you'll be hooked up to an EKG machine throughout and we want you to exercise until you reach at least 85% of your maximum predicted heart rate for your age. If you cannot exercise for whatever reason, there are other types of stress tests that use medications to provide equivalent data.

(18:29): We know cholesterol abnormalities can occur even before transplantation, because of the shared risk factors that often exist between the development of heart disease and cancer. But stem cell transplant survivors often experience significant metabolic abnormalities after transplantation, including hyperlipidemia, even if their pre-transplant cholesterol levels were completely normal. As you can see from this graph, the incidence increases with the duration of time post-transplant and is more common in patients who underwent allogeneic transplant compared to autologous transplant.

(19:09): Transplant survivors need aggressive monitoring and treatment of abnormal lipids. We generally recommend initiating a moderate intensity statin medication to lower cholesterol levels in stem cell transplant patients if they have established clinical atherosclerotic cardiovascular disease, if their LDL cholesterol is above 190, if they fall between the ages of 40 and 75 and have diabetes with an LDL between 70 and 189, or if they fall between the ages of 40 and 75, have an LDL between 70 and 189 and an estimated 10-year risk of having an atherosclerotic cardiovascular event of 7.5% or higher.

(19:56): We calculate that risk using the Pooled Cohort Equation, which incorporates your age, gender, race, cholesterol levels, blood pressure, diabetes, and smoking history.  We are then able to ascertain the likelihood of you experiencing a cardiac event in the ensuing 10 years. That calculator doesn't specifically consider cancer treatments; therefore, we feel that for cancer survivors, it might even be higher; currently, this is the best information that we currently have.

(20:31): Diet is incredibly important and is often underappreciated. We know that stem cells transplant survivors have increased rates of diabetes and obesity compared to the general population. The red line on the graph demonstrates that stem cell transplant survivors have increased rates of diabetes compared to the non-transplant patients in blue. We know that obesity increases the risk and reduces the likelihood of disease-free and overall survival amongst those diagnosed with cancer in general. And we also know that a diet higher in vegetables, fruits and whole grains has been associated with reduced mortality and less cancer recurrence.

(21:13): At least 20 prospective studies have shown that physically active cancer survivors have a lower risk of cancer recurrence and improved overall survival compared to those who are inactive. Exercise has been shown to improve cardiovascular fitness, muscle strength, body composition, fatigue, anxiety, depression, and overall quality of life. The current recommendation from the American Heart Association is 150 minutes per week of moderate intensity exercise, which should be something like a brisk walk or 75 minutes per week of vigorous exercise combined with strength training.

(21:53): Echocardiograms are ultrasounds of the heart and tell us the strength of the heart muscle. They give us that ejection fraction measurement. A screening echocardiogram should be considered in all patients at six- and 12-months post-transplantation. The medium and high-risk patients, which include those patients exposed to anthracycline or chest radiation or those who have multiple cardiovascular risk factors, should be considered to have additional echocardiograms every two to five years thereafter.

(22:27): Most patients with cardiovascular disease can safely undergo stem cell transplantation. Unique cardiovascular toxicities like arrhythmias, pericarditis, heart failure, strokes, heart attacks, and valvular disease can incur both early and late after transplant and can be related both to the transplant itself as well as to the treatments leading up to it. It's essential to focus on cardiovascular risk factor modification and I highly recommend that you seek out cardio-oncology evaluation to ensure optimal cardiovascular health if you're a transplant survivor who has risk factors. Thank you for your time and attention today. I'm happy to answer any questions.

Question & Answer Period

 (23:10): [Lynne Spina]:  Thank you, Dr. Fradley, for this excellent presentation. First question: This is about blood clots. I am five years post-transplant and recently started to develop arterial blood clots in my legs. My doctors don't know why I'm getting them. Are patients who have had a transplant more prone to blood clots and is it related to the heart?

 (23:39): [Dr. Michael Fradley]:  There are two parts to that. First, the more common blood clots occur in the veins, such as the ones people may experience on a long airplane ride. Then there are the ones that could move to the lungs and cause what's called a pulmonary embolus.

(24:02): Then there are the more unusual blood clots that form in the arteries; we do think that there is some effect to the arterial tissue from transplant. That's one of the reasons why we see, over time, increased rates of heart attacks and strokes because those are also blood clots in arteries, the coronary artery or one of the arteries that go to the brain. Similarly, people can develop blood clots in the arteries to their legs and there's likely a complication or long-term cardiovascular complication related to transplant.

 (24:40): [Lynne Spina]:   I am a 10-year allogenic [allo] stem cell survivor with a family history of cardiac disease. Is it wise for me to get baseline tests and establish a relationship with a cardiologist even though I'm not having any cardiac symptoms, my blood pressure and heart rate are low to normal?

(25:05): [Dr. Michael Fradley]:  That's something that would be very reasonable for you to do, especially even more so depending on what treatments you may have received prior to your transplant. I talked a little bit about things like anthracyclines and radiation, but there really are quite a lot of medications that people have received that may have some long-term risk. When you combine the fact that you have a strong family history, getting a baseline evaluation is appropriate and reasonable.

(25:42): I see many patients like yourself who come in for that type of risk factor assessment. What would be beneficial for you is to find a specialized cardiologist close to where you live, who has some expertise in the field of cardio-oncology since that person will understand nuances and risk-factors better. Sometimes if you see a regular cardiologist, s/he may not be as familiar with your risk factors and may not be aware of the things that must be monitored in a person like yourself. If you have access to a physician with a greater cardio-oncology expertise, that would be the most beneficial for you in terms of evaluation.

 (26:35): [Lynne Spina]:  We've been talking about stem cell transplants, and someone asks, Are the risks the same if you've had a bone marrow transplant?

 (26:47): [Dr. Michael Fradley]:  Yes, potentially, even higher if you had a bone marrow transplant. Some of the treatments that go into bone marrow transplant may even have a slightly higher toxicity but treat the two as essentially the same in terms of what we need to look out for.

 (27:12): [Lynne Spina]:  Is there data available on CAR T-cell therapy and cardiovascular issues?

 (27:21): [Dr. Michael Fradley]:  There are data, and we're learning more about CAR T. The information that we have is predominantly in the early period of CAR T therapy and it's usually in the setting of the cytokine release syndrome. In patients that are experiencing significant CRS or cytokine release syndrome, we do see various cardiovascular issues like abnormal heart rhythms, we can see heart failure. We've even had patients who've had sudden cardiac death as a result of this severe inflammatory response. What we don't know is if there are long term effects, which is something that we are interested in. There are longer term survivors who've received CAR T, to measure long-term effects. What we're seeing, at least in the short term, is that if a problem happens, it usually happens in the setting of that CRS; in the majority of cases, they resolve as the CRS resolves.

 (28:35): [Lynne Spina]:  The next question:  What is LVEF?

 (28:41):[ Dr. Michael Fradley]:   LVEF stands for left ventricular ejection fraction or sometimes you'll see just EF written which is ejection fraction, how well the heart is squeezing. A normal ejection fraction or EF is between 50 and 70%. No person is ever at a hundred percent, but that's essentially when we're talking about the strength of the heart; we talk about it as the ejection fraction or EF.

(29:20): [Lynne Spina]:   When is low blood pressure a problem?

 (29:26): [Dr. Michael Fradley]:   In general, low blood pressure is a problem if it's causing somebody's symptoms. When it comes to high blood pressure, we know that there is sort of an absolute cutoff, above which your risk increases for cardiovascular disease. However, for lower blood pressure in general, it has predominantly to do with symptoms. Some people have looked at what's called a U-shaped curve of blood pressure, that as you start getting lower and lower, you have increased overall risk. Some of that has to do with the fact that as people's blood pressure gets lower, it may be in the setting of someone who is very sick. Perhaps they're infected, maybe they get dizzy and fall and injure themselves. But really, it's a lot about the individual and how they feel.

(30:24): There are people who have blood pressures where the top number being in the nineties and feel perfectly fine and that's just normal for them, in which case there's no risk or concern. Conversely, another person may have blood pressure in the nineties, leaving them feeling tired and/or dizzy; in that case we intervene to try to get them to feel better.

 (30:49): [Lynne Spina]:    Another question. The day I left the hospital for my second BMT, I had atrial tachycardia and had to have electro cardioversion. Was this due to the melphalan? Does it need further follow-up? I'm now six months post BMT and it has not been a problem.

(31:17): [Dr. Michael Fradley]:   It most likely is related if you receive the melphalan as part of the preconditioning. We know that anywhere between about 10 and 15% of patients who get exposed to melphalan will have an atrial arrhythmia at some point in the peri-transplant period. Generally, the median time to developing it after transplant is around 15 days.

(31:55): The second question that you asked is a more challenging one since we aren't sure if a person develops atrial fibrillation or atrial arrhythmia in the setting of transplant, and if that translates into long-term risk of recurrence. If a person were to come into my clinic and said, "I was at my regular doctor's office and they noted my heartbeat was irregular and told me I was experiencing atrial fibrillation," we would consider that person to have Afib. Even if they go in and out of it, this is a problem for life. What we're not sure about is whether that same problem for life it exists if the person develops it in the transplant period and had this provocation as it relates to the melphalan.

(32:46): That is something that we're actively looking at in our transplant population at The University of Pennsylvania where we're following patients post-transplant who've developed atrial fibrillation. We're monitoring them with small subcutaneous monitors, that are implanted beneath the skin, which allow us to check their rhythm 24/7 to see if they're experiencing recurrences. That gives us good information about whether or not we need to institute additional medications in the long term for their overall health. That's important since, if someone is having recurrent atrial fibrillation, it could increase their risk of having a stroke in the future. To sum up your question, if you're not having follow up with a cardiologist, or cardio-oncologist, you should be doing so to be alert to the possibility of recurrences.

 (33:50): [ Lynne Spina]: Will CAR T affect Atrial Fibrillation (AFib)?

 (33:55): [Dr. Michael Fradley]:  It absolutely can, in large part due to the possibility that CRS and the inflammatory state can occur can definitely flare up someone's atrial fibrillation.

 (34:09): [Lynne Spina]: What is high Adriamycin? I'm a 30-year survivor of an autologous BMT for breast cancer and received that type of chemotherapy.

 (34:24): [Dr. Michael Fradley]:  The American Society of Clinical Oncology [ASCO]:  suggests that a high-risk individual is someone who has received over 250 milligrams per meter squared of doxorubicin or its equivalent. Breast cancer regimens currently are generally 240. Hodgkin's lymphoma regimens are usually around the 300 mark. [Older breast cancer regimen, so perhaps the time that you were treated, you may have received higher doses at that point in time.]:

 (35:07): [Lynne Spina]:  Could a person's low blood pressure be caused by GVHD? Their blood pressure is in the range of 120 over 48 to 52 and the person is seven years post-transplant, relapsed at seven years post-transplant for AML and the AML is currently in remission. They are not on any immunosuppressants.

 (35:32): [Dr. Michael Fradley]:  I would say that it's possible but certainly not definitively associated.

 (35:44): [Lynne Spina]:   Does the allogeneic transplant process, i.e. the pre-conditioning, the full body radiation, cause damage to arteries, decreasing the flexibility and increasing blood pressure?

 (36:05): [Dr. Michael Fradley]:    It absolutely can. We know radiation has a lot of adverse effects to the vasculature, so it can affect the extensibility of them and can lead to some blood pressure effects. It can also affect the integrity of those vessels, which is why we think there's an increased likelihood of thrombotic events, heart attacks, and strokes.

 (36:35): [Lynne Spina]:   My previous LDL, before transplant, was a hundred. I am 14 months passed and LDL is now 176. When should I be treated with medicine to bring it down? Perhaps you can make a few comments about this.

 (36:55): [Dr. Michael Fradley]:   Your experience is not unusual at all, this kind of dramatic change from a pre-transplant LDL to a post-transplant LDL. I think we're still trying to understand exactly what and why transplants have these effects on the metabolism so much in general.

(37:20): There are various aspects that help guide our decision-making as to when to begin statin therapy. With cholesterol levels above 160, we start to get more concerned about the need to initiate a statin. If someone's level is above 190, the answer is ‘absolutely’. When someone falls into that intermediate range, say less than 190 but still high. That's where the ASCVD calculator can be very helpful; that's where we start looking at such aspects as age, gender, your actual numbers, your actual blood pressure numbers, and what medications you are or should be taking. This allows us to ‘plug it into a calculator’ and determine your risk for a problem over the ensuing 10 years. If you attain a certain percentage, 7.5%, that's when we determine that a statin is necessary.

(38:26): In addition, there are other factors that we look for. Sometimes if that number's lower, I'll look on a CT scan to determine if there is any calcium deposition in your arteries. If you do have calcium deposition, that suggests a higher risk individual who we would start on a statin in order to try to prevent future events. In your case, it's highly likely that you will need to start on a statin medication. It is important to have an appointment with a health-care professional who understands this risk and ascertains your specific health-care history and determine the best strategy for you.

 (39:15): [Lynne Spina]:   Does an asparaginase-induced stroke predict future issues?

 (39:23): [Dr. Michael Fradley]:    Not necessarily. That’s its own sort of unique type of stroke, so it doesn't necessarily suggest increase in the types of strokes that we typically think about either in the post-transplant period or just sort of in the general population that you'd think of as sort of a typical stroke.

 (39:47): Lynne Spina]:    My aortic valve is leaking steadily at 10 to 20%. My cardiologist is waiting and watching. Is my only option open-heart valve repair down the road?

 (40:01): [Dr. Michael Fradley]:    Unfortunately, at this time the answer to that is ‘yes’. For leaky aortic valves, we currently do not have less invasive options than open heart surgery. For valves that become stenotic, those cases have some of these non-invasive management strategies, but for leaky valves at the moment, at least leaky aortic valves at the moment, that's our only real option.

 (40:38): [Lynne Spina]:   Is it normal after a BMT to have random episodes of racing heartbeat? I had scans done and nothing shows up.

 (40:52): [Dr. Michael Fradley]:   Yes, I would say that it actually is probably a lot more common than people recognize and acknowledge. This goes back to that topic of autonomic dysfunction that I spoke briefly about. We don't fully understand what and why autonomic dysfunction occurs, but essentially, the way I explain it to patients is just like you're told that you can develop a peripheral neuropathy related to some chemotherapy where they'll tell you might develop pain and numbness and tingling in your hands or your feet. Well, the same thing can happen to the nerves that control these more classic homeostatic functions like heart rate control or blood pressure control. People will often tell you, after they've had these various treatments and exposures, that they have palpitations, heart rate elevations for no particular reason, as well as wide swings in their blood pressure. It's not that the heart is dysfunctional, but it's that the heart is responding to the signals that's being told. It's just those signals are wrong and it can be really problematic and really impact people's quality of life.

(42:08): Our job is to manage the symptoms as best as we possibly can. There are many things that can cause autonomic dysfunction in individuals even outside of the transplant world. Many of you've probably heard of long-haulers syndrome as it relates to COVID-19 infection. A lot of the symptoms that people have in the long-haul are such things as racing heart sensations and blood pressure variations, which we think are the same thing. In that case, it's the virus that is damaging those nerves. Your symptoms are something that a lot of people experience and are probably under-recognized.

 (42:55):[ Lynne Spina]:   Can immunosuppressant drugs increase blood pressure?

 (42:59): [Dr. Michael Fradley]:   Some can; for example, cyclosporine can definitely increase blood pressure.

 (43:09): [Lynne Spina]:  Would you recommend a cardio-oncologist versus a regular cardiologist for prostate cancer survivor experiencing atrial fibrillation?

 (43:23): [Dr. Michael Fradley]:   I think that a cardio-oncologist, if you have one available is always going to be an ideal physician for you to connect with because they understand some of the complexities of the treatments, the potential interactions of the treatments with other drugs that we may offer from the cardiology standpoint, that there may not be as many options available due to drug interactions and just sort of understand the overall interplay of cancer and cardiovascular disease. Now, I say that recognizing that there are a lot of people out there that are not necessarily in an environment where they have someone who specializes in this field, and so certainly general cardiologists are capable of managing these issues, but I think that the cardio-oncologist kind of just gives you a different approach and perspective about the conditions that you're experiencing and has that more subtle understanding of the overlap between the two conditions.

 (44:45): [Lynne Spina]: Does long-term tacrolimus use provide any risk to having future cardiac complications in a young previously heart-healthy patient?

 (45:00): [Dr. Michael Fradley]:    Not generally. Certainly, tacrolimus could create some kidney issues which may lead to blood pressure issues down the road.  However, we use that drug quite a bit in people who've had heart transplants as well to prevent rejection and that doesn't necessarily lead to additional or new cardiac problems for their transplanted heart.

 (45:30): [Lynne Spina]:  How does pericardial effusion affect or predict cardiovascular issues?

 (45:41): D[r. Michael Fradley]: : In general, pericardial effusions themselves do not necessarily predict any sort of long-term cardiovascular risk or toxicity. They tend to be their own unique isolated problem that's often indicative of some other issue. In a malignant effusion, a person develops the fluid around the heart because of the cancer itself or because of a viral infection. Or they may have developed this sort of systemic inflammatory response where they developed swelling and fluid buildup in various areas of their body. Probably the biggest association between a pericardial effusion and another cardiovascular event is the development of pericarditis, which is inflammation of the lining that can be very painful for patients. It often results in intense chest pain, but doesn't necessarily increase risk of future heart attacks, strokes, heart failure or other related issues.

 (46:43): [Lynne Spina]:  For a few days after conditioning, I had a very high heart rate …150 resting. Would this have caused lasting damage or have just been a temporary reaction to this chemo?

 (46:58): [Dr. Michael Fradley]:   In general, if it's temporary, it does not create lasting damage. If it's the normal rhythm, that doesn't seem to cause lasting damage even for people that are in a fast heart rate for a long period of time. If a patient is in an abnormal rhythm with prolonged periods of increased heart rate, that could potentially create long term problems. If it was transient as you suggest, then it shouldn't lead to any long-term issue.

 (47:33): [Lynne Spina]:  Have you seen any patients that have experienced numbness along the path where their PICC line was? Would you consider this neurological issue or a cardiology issue?

 (47:50): [Dr. Michael Fradley]:    This is not something that I have personally encountered. However, I would say that based on the description with the numbness, it sounds more likely that it is potentially neurological based, just from where they make the incisions of the port. There might be damage from the nerves and as they regrow, it could create some of those problems. I would say that it sounds more neurologic, but it's not something that I've personally encountered.

 (48:19): [Lynne Spina]:   Are there genetic tests for cardiovascular risks?

(48:24): [Dr. Michael Fradley]:   There are. It usually depends upon the individual and what we're looking for. We certainly don't do genetic screens in most cases. We need to have a focused approach, so if a person has a strong family history of certain conditions, we might think about running specific genetic tests. Similarly, if somebody's cholesterol is quite elevated, we may want to run specific genetic tests to ascertain if there is a familial hypercholesterolemia syndrome, so we can base the decision on other symptoms, family history, et cetera.

 (49:30): [Lynne Spina]:  This one is pretty specific, but I think if you could shed some light on it, it would be helpful. This person had an auto transplant February 10th of this year, and they've had strange symptoms since her myeloma treatment. It happened more on Revlimed® but she's been off it since January. She hadn't had the symptoms in about a year but had it several days ago. It happens at rest. It starts in my nose and mouth with strong burning in my tongue and mouth and in her jaws, then starts in my chest ribs and through my back. It is always at rest and lasts 20, 25 minutes. I had an echo and an EKG prior to stem cell and no issues were found. I do walk a lot and use an exercise bike and no symptoms with exercise. It just happens occasionally.

 (50:44): [Dr. Michael Fradley]:   I don't have a great explanation for what you're experiencing. I think certainly the echo and the EKG are a good first step, but I think it probably warrants some additional evaluation from a cardiologist.

 (51:01): [Lynne Spina]:   What can a post-transplant patient do to help minimize continuing congestive heart failure?

 (51:12): [Dr. Michael Fradley]:   Number one is make sure that you are regularly seeing a cardiologist, ideally a cardio-oncologist. There are various medications that can be given to try to improve symptoms and potentially even improve heart function, so making sure that your doctor has kind of thought through whether those are medications that are needed and really kind of following those ABCDEs that I had suggested. If a patient is at risk for dysfunction, for example, they've received the treatments but don't actually have any symptoms or don't have any cardiovascular dysfunction, those ABCDEs become even more important since we can then manage and alter those risk factors and, hopefully, prevent the development of a problem in the future.

 (52:10): [Lynne Spina]:   I'd like to thank Dr. Fradley for this excellent presentation. On behalf of BMTinfoNet and our partners, I'd like to thank the audience for your excellent questions. Please contact BMTinfoNet if we can help you in any way.