Heart and Vascular Health after Transplant – When a Cure is Not Enough

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Heart and Vascular Health after Transplant – When a Cure is Not Enough

Saturday, April 30, 2022

Presenter: Vlad Zaha MD, PhD, Medical Director of the Cardio-Oncology Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern

Presentation is 24 minutes long with 33 minutes of Q & A.

Summary: Stem cell transplant patients have an increased risk of heart and vascular problems after transplant. The risk of cardiovascular complications increases over time after transplant. This presentation reviews the major cardiovascular complications, their underlying causes, and the most effective preventative measures and treatment options for addressing them.

Highlights: 

• There are reversible risks for cardiac problems after transplant that can be reduced by behavioral and lifestyle changes.
• Baseline tests before transplant can help determine therapies and monitoring needed during and after transplant to reduce the risk of heart and vascular problems.
• Doing “prehabilitation” exercise before transplant and continuing physical activity after transplant is one of the most effective ways to minimize cardiac risk. The benefits of physical exercise can be as significant as an additional line of medication.

Key Points:

(03:41): Cardiac complications after transplant can be due to chemotherapy, radiation, other medications, lifestyle and genetic risk factors.

(04:13): Cardio-oncology is a specialty devoted to minimizing cardiac risk while maximizing cancer treatment.

(07:32): Certain chemotherapy drugs given before transplant as part of the conditioning regimen increase the risk heart complications after transplant.

(08:22): Previous heart disease is another risk factor for heart disease after transplant.

(09:20): Anthracycline medications along with hypertension is a particularly risky combination.

(10:39): There are many new techniques to evaluate each patient’s risk based on real time data about their condition.

(11:45): An initial clinical consultation can teach patients how to minimize modifiable risk factors.

(17:06): Pre-habilitation – getting the patient in good physical shape before transplant – can reduce the risk of heart disease after transplant.

(20:30): Cardiac rehab after transplant is a long-term process from hospital to home-based rehab and telehealth.

Transcript of Presentation:

(00:00): [Marsha Seligman] Introduction. Hello, everyone. My name is Marsha Seligman. Welcome to the workshop, Heart and Vascular Health after Transplant: When a Cure is Not Enough. It is my pleasure to introduce Dr. Zaha.

(00:12): Dr. Zaha is an Assistant Professor of Internal Medicine and Biomedical Engineering at UT Southwestern Medical Center in Dallas, Texas. He is the founding Medical Director of the Cardio-Oncology Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. Dr. Zaha leads the clinical program dedicated to the cardiovascular care of patients with the active cancer and cancer survivors, as well as an active research program. Please welcome Dr. Zaha.

(00:49): [Dr. Vlad Zaha] Overview of Talk. Thank you for the kind introduction. It is my absolute pleasure to be here today to be part of this forum and to present on Heart and Vascular Health after Transplant: When Cure is not Enough. What I would like to focus on today are five questions that will provide some information on why, what, who, when and how to reduce cardiovascular risks, and how cardio-oncology can be a bridge for the disciplines of cardiovascular medicine and oncology and help in this context.

(01:30): But let's first go back to the beginnings just to appreciate the significance of bone marrow transplantation pioneered in the 1950s by Dr. Donnall Thomas. He was the recipient of the Nobel Prize in Physiology or Medicine in 1990 for discoveries concerning organ and cell transplantation in the treatment of human disease.

(01:55): By 2030, there’s projected to be more than half a million stem cell transplant survivors in the U.S. Between the 1950s and 2012, more than one million patients were transplanted. Over the time, studies have been performed to evaluate what is the long-term survival after hematologic stem cell transplant both in adolescents, and young adults, and adult patients. Two of the larger studies have identified in both groups that at 15 years, for adolescents and young adults, and 20 years, the survival is more than 80%. This is fantastic news for the current times. So, looking forward at the number of survivors, which has reached more than 240,000 in 2020, the estimate is [there will be] more than half a million in 2030, only in the United States.

(02:58): Transplant can contribute to heart muscle disease, irregular heart rhythms and vascular disease, and the risk increases over time. So why worry about cardiovascular risks after hematologic stem cell transplant? One of the major concerns are the cardiovascular complications. So the cardiovascular death is increased following hematologic stem cell transplant, and it grows compared to the general population by the time that has passed since transplant. And the major problems that are arising are heart muscle disease, or cardiomyopathy, irregular heart rhythms or arrhythmias, and vascular disease.

(03:41): Factors that increase the risk of heart problems after transplant include chemotherapy, radiation and drugs to prevent or treat graft-versus-host disease. Why are they happening? The heart muscle disease is due to exposure to chemotherapy, to chest radiation, and also underlying risk factors. The arrhythmia is the second sort of a double-edged sword of sophisticated molecular treatments, such as ibrutinib, and vascular disease can be due to cyclophosphamide or the graft-versus-host disease.

(04:13): Cardio-oncology is a specialty devoted to minimizing cardiac risk while maximizing cancer treatment. So, what is cardio-oncology? Cardio-oncology has been developed as a bridging discipline due to the increased awareness of improved survival with revolutionary oncological therapies in the last 20 years. It is aiming to minimize cardiovascular toxicity while anti-cancer treatments are maximized.

(04:40): So, how does cardio-oncology help patients in this setting? The main intervention is to close the gap between the cardiovascular and oncological disciplines, where there is increased awareness on both sides of these intersecting complications, by preventing cardiac damage, by recognizing early cardiotoxicity, improving overall outcomes after treatment through various interventions that I'll review today.

(05:16):What is specifically cardio oncology doing for patients with hematological stem cell transplant? It allows the appreciation of the cardiovascular risk factors which include smoking, obesity, hypertension, diabetes, [and] hyperlipidemia. Of preceding cardiovascular diseases such as heart failure, or coronary artery disease, and valvular heart diseases, as well as a vulnerable territory due to age or female sex and other treatments that are happening before transplant, as well as the conditioning schemes, which all can lead, at the time of the transplant, to cardiovascular complications, which include arrhythmias, or irregular heart rhythms, development or progression of the cardiovascular disease towards heart failure, or the progression of atherosclerotic disease for development of coronary artery disease and new vascular events, as well as pericardial diseases that can happen in patients due to radiation treatment or to the immunologic changes.

(06:32): If we look specifically at the risk factors, they come at intersection between the type of cancer that is treated and the underlying heart disease. While the underlying heart disease is related to the risk factors mentioned before, there is also the potential for congenital heart disease to be contributing.

(06:54): Some risk factors for heart problems after transplant can be reduced by life-style changes. In the middle, there are several common risk factors, which I specified before, and several of them are modifiable. Other than the genetic risk, we can modify smoking, obesity, hyperlipidemia, sedentarism, diabetes, and hypertension. And all this is on a background of well recognized, nowadays, the social determinants of health. So if we take all the modifiable risk factors out, we are left with just a few that are sort of given and we'll have to address them medically.

(07:32): Several chemotherapy drugs given before transplant as part of the conditioning regimen can increase the risk of heart problems later on. So what are conditioning drugs doing for the cardiovascular risks? So there are several potential complications here. Myocardial ischemia, reduced blood flow to the heart, can be due to melphalan, etoposide, or carmustine. Irregular heartbeat or arrhythmias due to cyclophosphamide, carmustine, or fludarabine. Inflammation of the heart or the lining around the heart, the pericardium, can be due to cyclophosphamide, cytarabine, busulfan. And endocardial fibrosis, or stiffening of the inside of the heart, due to busulfan. So taken in all, unfortunately, eventually a lot of these medications can also lead to cardiac dysfunction, or heart failure as we call it.

(08:22): Identifying an individual’s risk for heart problems before transplant can help lower the risk of heart problems after transplant Now, next I will be addressing the question, who has high cardiovascular risks? And this is an important point of awareness heading into stem cell transplant treatment. It is recognized that previous heart disease is a major risk factor, but also the presence of elevated cardiac blood biomarkers before anti-cancer therapy, the exposure to high-dose anthracyclines or high-dose therapy in the pre-transplant time, or even a lower exposure to anthracyclines and radiation therapy, if there are combinations of other factors like age, more than 60 years of age, and the modifiable risk factors mentioned earlier. These are very important to consider because they can be addressed effectively and decrease the overall lower cardiovascular risk.

(09:20): The use of anthracycline medications in people with high blood pressure increases the risk of heart problems after transplant. And I would like to emphasize here the significance of hypertension and this graph shows a combination of the effect of exposure to anthracyclines and the presence of hypertension, and the combined effect of both that is more than just an addition. So it is a major problem, which we are focused on addressing both in patients on active treatment and in long-term survivors.

(09:52): This brings the question to when and what tests and procedures are recommended? And we have looked at a combination of the risk factors, and now we are going to acknowledge the effects of the different classes of therapies that can be involved in this process, including chemotherapy, radiation therapy that involves the heart field and the blood vessels, the targeted therapy with novel molecular interventions, as well as the revolutionary immunotherapies. So they can all lead to cardiovascular toxicity, and this awareness is key.

(10:39): There are many new techniques to evaluate each patient’s risk based on historical and real time data about their condition. The good news is that we have many modalities to follow and diagnose. So we have a combination of blood-derived biomarkers, multi-modality imaging, electrocardiography, electronic medical records that can integrate all these data nowadays, the utilization of wearable sensors that can give us real time and collect data regarding health and physiology, as well as the advent of artificial intelligence and machine learning that can take all these data together and allow us to create predictive models and support us in the decision process.

(11:28): So when do we want to apply all these approaches? We can apply them at any stage and preferably during pre-treatment, but also as needed during the treatment and/or surveillance after treatment.

(11:45): Teaching patients about their risk for heart problems after transplant, and how to reduce the risk is important. A pragmatic approach to prevent cardiotoxicity involves the initial clinical consultation that, in our program, is in conjunction with the other visits that the patient has in the cancer center, where we also consider ambulatory blood pressure monitoring or detailed instructions for self-measured home blood pressure monitoring, as well as blood tests including tests for glucose, lipid profile, cardiovascular tests, kidney function, electrocardiogram, cardiovascular imaging studies mentioned here. And following all this, conclusion about recommendations for actively managing modifiable cardiovascular risk factors and diseases, as well as encouraging exercise on a regular basis, which we do trying to involve the patients in specific programs, as well as healthy dietary habits, including support from a nutritionist.

(12:58): This timeline of the involvement of cardio-oncology as an approach to support patients with hematologic stem cell transplant is key to realize that there is a baseline evaluation with the tests specified here, emphasizing blood pressure tests, baseline blood tests, electrocardiogram, echocardiogram, and the cardiac CT in certain patients with higher risk, as well as a follow-up set of evaluations at 100 days at the end of the first year, and then one to five years following transplant.

(13:42): Several blood tests can help assess changes in heart health. This is an example of commonly used blood tests in cardio-oncology that patients are routinely tested with, and it is important for recognition of what they do. For example, troponin is a test for heart damage, and it can tell us whether there are effects of narrowing of the blood vessels or inflammation. Brain natriuretic peptides, such as BNP or NT pro-BNP, are tests that tell us about heart failure, which can be a result of the underlying treatments. As well as the D-dimers, the test for blood clots.

(14:24): Cardiovascular imaging is another valuable tool to assess cardiovascular changes. Another example slide is for cardiovascular imaging used specifically in cardio-oncology where novel technology allows us to have detailed evaluation of the cardiac structure and function in pre-transplant stage using 3D echocardiography, speckle-tracking echocardiography and cardiac MRI, as well as screening for low or inadequate blood flow to the heart, also called cardiac ischemia, with coronary CT. And then evaluating the narrowing of the blood vessels and the presence of plaque with coronary artery calcium scoring.

(15:12): Once we have all this information, what can we do to further reduce the cardiovascular risks?

(15:23): Doing exercise and physical activity before and after reduces the risk of developing cardiac problems after transplant. In addition to the specifics of each intervention and specific treatments that can be started in preparation for the bone marrow transplant, a key aspect is the potential benefit of exercise. The risk factors don't come alone. They come in combination, and we call that multiple-hit situation where there are the baseline risk factors such as obesity, hypertension, more advanced age, as well as the direct injury of the anti-cancer therapy. These are two already. And then number three would be the indirect injury which is happening during the treatment due to deconditioning. So more sedentary lifestyle and weight gain. One of the main points for the patients is to realize that maintaining physical activity around the time of the treatment and following successful treatment is reducing a major risk factor. At the same time, including exercise in this therapeutic process is important for increasing the cardiorespiratory fitness, increasing the quality of life, decreasing the fatigue and decreasing the cardiovascular risk factors that are part of that multiple hit. So there are multiple benefits for exercise.

(17:06): Pre-habilitation means getting as fit as possible before transplant to minimize cardiac complications. So, how can we apply exercise in the context of cardiovascular and rehab in patients with hematologic stem cell transplant? At the time of the evaluation before transplant, functional assessment and the cardiovascular risk stratification, I would say, go hand in hand. So the cardiopulmonary assessment involves, in addition to the visit mentioned earlier, potentially a cardiopulmonary exercise test, which can be monitored with the electrocardiogram, with echocardiogram, or a nuclear profusion stress test, or a six-minute walk test. This is in conjunction with a psychosocial assessment and physical functioning assessment, or physical therapy evaluation, and an assessment of associated conditions that may further exacerbate the cardiovascular risks, such as low blood counts and the presence of bone lesions, metastasis that limit the functional status, as well as muscle disease or myopathy.

In this context, what has been designated and we have embraced is the concept of pre-hab. So, instead of rehabilitation, we want to be proactive and to engage patients in increasing their physical activity and capacity before they go through the transplant program. This is where the referral to cardiac rehabilitation or to a designated program within the cancer center is important.

(19:05): Physical activity counseling can promote a holistic approach combining exercise, nutrition, and other healthy behaviors. So, how can we use physical activity to improve our function during the transplant timeline? There is a physical activity counseling that can happen at the beginning, and it can include multiple components going from physical, occupational, speech therapy, depending on what the patients need. And it is combined with nutritional counseling with the management of the modifiable risk factors, which remain central in this process. as well as recognizing and intervening for psychological management and counseling. And not the least, a designated exercise program that can combine aerobic activity, a mainstay for cardiovascular health, as well as resistance exercises to maintain the muscle mass. This can be delivered in a supervised or unsupervised fashion, including both hospital and health center-based approach, as well as home, taking advantage of the new telehealth resources.

(20:30): Cardiac rehab after transplant is a long term process from hospital to home-based rehab and telehealth. If we head towards the actual cardiac rehab, so post-transplant, this is a long-term process that is extremely helpful for patients to recover their functional status. And it involves transition to home-based rehab sessions and the involvement of telehealth as a feedback mechanism. And what we're using is an athletic coach that can be involved in the support for the patients, as well as combining these exercises with previously presented serial cardiac assessments that would balance the risk of having cardiovascular complications that are going unrecognized. And I would say, not the least here, having a quantifiable way to recognize the fitness level. So measuring what is called the V̇O₂ max, or the oxygen utilization during exercise, is another component.

(21:55): Post-transplant cardiac risks are significant challenges but they can be addressed and reduced through various strategies.  I would summarize here and I would like to come close to open the discussion that cardiovascular disease is a significant risk after hematologic stem cell transplant, where the risk prediction is challenging, but important and addressable with several modifiable risk factors being involved. With the recognition of cardiovascular problems that are underlying and may become manifest during the time of the transplant but can be addressed ahead of time for successful transplant without complications. That survivors are particularly sensitive to hypertension, and that is something that continues to be underappreciated. And again, in the current era of technology, it is addressable even using telehealth modalities.

(23:08): The benefits of physical exercise are as significant as an additional line of medication. That physical exercise is beneficial, and sometimes I tell my patients that physical exercise is as good as having one more line of medication added onto their therapy. And that we have new diagnostic modalities, and there are new treatment options that are being developed that allow patients to stay healthy in the process of transplant and to remain healthy following successful transplant completion.

(23:44): I would like to thank our program at the Simmons Cancer Center, and specifically to thank my colleagues in our program, Dr. Chandra, Dr. Vallabhaneni, and Dr. Zhang for helping to provide care for the population in North Texas. And also, would like to acknowledge the very active research programs at our center, going from molecular research to population research, to enhance the resources for our patients.

(24:24): I thank you all for your attention, and I'm ready to take any questions.

Question and Answer Session

(24:32): [Marsha Seligman] Thank you, Dr. Zaha, for your excellent presentation. We will now take questions. As a reminder, if you have a question, please type it into the chat box on the lower left hand corner of your screen. The first question, Dr. Zaha, is, what is the risk of getting left ventricular problems at the 10-year mark or the 5-year mark?

(24:55): [Dr. Vlad Zaha] That is a very good question. And I would say that the overall risk for the population will depend on what is the personal risk. So looking at the different classes of treatments, the risk can be for one in 10 patients, or one in 20 patients. But if there is an underlying cardiovascular problem such as atherosclerosis, or if there are some of the risk factors mentioned here present, that risk can go up sometimes to one in three patients, sometimes one in two patients. So I think it all depends in what category of risk the patients are.

(25:47): [Marsha Seligman] The next question is, "When is low blood pressure a problem? I am pre-SCT and can have a very low blood pressure such as 90 over 45. More typical is 100 over 55."

(26:03): [Dr. Vlad Zaha] Okay. That is an excellent question. And we see many times the challenge of low blood pressure. In itself, lower blood pressure is good. And as long as the blood pressure is not leading to lightheadedness, the risk of falling, in itself. Systolic blood pressure in the 90 to 100 range would be okay. The challenge is when there may be some other complications related to the medications during transplant where the blood pressure can potentially go lower than that. In that case, having, again, a cardiovascular specialist on the team to manage the blood pressure to bring it up to a range where the body functions normally are important. It is sometimes a little bit of a roller coaster, I would say, for some patients where the blood pressure can be low at times and high at other times. There are sometimes adjustments that have to be done in the cardiac management to address the fluctuations in blood pressure during the hematologic stem cell transplant.

(27:48): [Marsha Seligman] The next question is, "I have had many chest CTs over the past six years from pneumonia, fungal infection and lung GVHD. Can CTs affect heart health?"

(28:03): [Dr. Vlad Zaha] This is an excellent question regarding the exposure to radiation and what is the effect on the heart health. So thinking about the radiation it is important to be aware that the radiation dose is accumulating. So, once the body's exposed to a dose of radiation, that cannot be taken away. At the same time, there is a very big difference between the amount of radiation that is necessary for radiotherapy, so radiation as treatment, compared to the dose of radiation that is used for diagnosis. So the radiation used for diagnosis is very relatively low. And there is a balance of decision of the risk of exposure to that amount of radiation and the benefit of having a diagnosis.

(29:10): So sometimes, I would say it is necessary to be able to move forward with the diagnosis. So that being acknowledged, it does accumulate, but at a very small fraction compared to the amount of radiation that is used for therapeutic radiation in the radio-oncology protocols. And the second type of use of radiation, as a therapy, is reaching such a high level that it can cause complications in the heart. So the usual CTs that are done for diagnosis do not cause that type of effect.

(30:02): [Marsha Seligman] The next question is, "I am 32 years out of radiation and an auto BMT. I live in a small city that does not have a cardio-oncologist. I have seen several cardiologists here and all say, 'Come back when you are having symptoms', is this a suitable approach?"

(30:22): [Dr. Vlad Zaha] That is a good question. And I would say it is more of the traditional way of looking at the risk profile. More recently, we have recognized that sometimes the risk due to these exposures is not following the typical risk calculators that are being used in general cardiology. So one potential approach would be to discuss the amount of radiation that was used. And considering the three decades, there is increased appreciation of the fact that therapeutic radiation causes accelerated aging of the vessels, for example, that were exposed. So it is reasonable to use some of these guidelines that are recommended, I would say, a more thorough checkup at some time intervals.

(31:35): And the recommendation for high dose radiation treatments is at every five years intervals, including an evaluation by a cardiovascular specialist and as needed, stress tests that would evaluate further, if there are manifestations of cardiovascular disease that are not present at rest.

(32:04): Maybe one more point to add here is the importance of exercise as a potential red flag. So if someone is exercising, they would need to have a good level of fitness. They would have to have a cardiovascular system that is in good shape, and they would be able to notice earlier a limitation. And a progressive limitation can then lead to a more focused discussion with a cardiologist in a smaller community where maybe there is no direct access to a cardio-oncology specialist.

(32:49): [Marsha Seligman] Dr. Zaha, the next question is, what can a post-transplant patient do to help or minimize ongoing congestive heart failure?

(33:02): [Dr. Vlad Zaha] This is a very good question, and I would think that probably who asked this question is concerned in such a situation. So, I would say that it is unfortunate, and it is something that will require close collaboration with a specialist, because there are multiple lines of treatment nowadays that can be applied to maintain the heart function and the quality of life, even if the heart function is not perfect. So I think the diagnostic will be very important, and then the choice of the right medications, and close follow up with the specialized center.

(33:49): [Marsha Seligman] The next question is, with cardiac damage and arrhythmias occurring, what are the most common areas for damage, the right side versus left side or everywhere, and the most common arrhythmia to watch for?

(34:09): [Dr. Vlad Zaha] That is a very good question, that is giving some technical insight there. The challenge with the radiation therapy is the exposure of the vascular system of the heart called the coronary system. And depending on what area of the heart is exposed, the vasculature in that area will be more prone to inflammation, the formation of plaque, and then the risk of obstruction and of a heart attack down the road. While the risk due to radiation therapy is increased in the first year after treatment, it does not go down completely after that. And then following an interval of several years to do five years after exposure, it can gradually go up such that it can reach five-, sixfold higher risk in long-term survivors that have reached more than a decade. That is one aspect that is important to be kept in check. And the same risk factors that are present in the general population for atherosclerosis are applying here, but they need to be scrutinized very closely and intervened upon early.

(35:39): Regarding arrhythmias, there is a risk of arrhythmias that are affecting both the upper chambers in the heart, such as atrial fibrillation and ectopy, or abnormal early heartbeats from the lower chambers in the heart. Some of the risks of arrhythmia are exacerbated during the treatment, not as much in the long-term survivors. But any changes in the heart that would make potentially the heart differ, such as some of the treatments, the chemotherapies and radiation, can make the heart chamber stretch. And atrial fibrillation can be a problem down the road.

(36:30): [Marsha Seligman] The next question is, "I recently developed PAD. Besides exercise, what about medication?"

(36:38): [Dr. Vlad Zaha] PAD stands for peripheral artery disease, and it signifies the narrowing of the blood vessels in the peripheral vessels, such as in the legs for example, or in the carotid arteries. That is a significant problem that can have long-term consequences. Again, what is important to do there is to recognize all the modifiable risk factors and to have a specialist that is going to monitor blood tests, such as lipid profiles, and to manage any inquiries in blood sugar, or hyperglycemia, diabetes to address weight management. And examples for successful weight management programs are available now around the country, such as a weight wellness clinic or program. And all those sorts of taken together would be helpful interventions to decrease, I would say, the burden that is associated with peripheral artery disease. Specific treatments would be then prescribed to address blood clotting or blood thinning, and interventions may be necessary to open the blood vessels and then to keep them open with stents. Again, this is, I would say a very specialized area of peripheral interventional cardiovascular medicine, and it would be reasonable to consult a specialist.

 (38:43): [Marsha Seligman] Someone has a question asking, "How does chemotherapy affect the cardiovascular system?"

(38:50): [Dr. Vlad Zaha] That is an excellent question. Chemotherapy can act directly on the heart muscle and weaken the heart muscle causing something that's called a cardiomyopathy, or, if that is left untreated, an evolution towards heart failure. Chemotherapy can also affect the blood vessels directly and cause a more general inflammation in the blood vessels with progressive changes over time that can exacerbate blood vessel disease related to cholesterol or to diabetes.

(39:34): [Marsha Seligman] And then someone would like to know, "Are there genetic tests for cardiovascular risks?"

(39:41): [Dr. Vlad Zaha] That is an excellent question. And then in this day and age, there are genetic tests. For example, specific tests to evaluate for familial diseases, such as familial hypercholesterolemia, so high cholesterol that runs in families. We don't have, at this point, a lot of genetic tests that would predict the risk in the case of hematologic stem cell transplant. But we can identify, if we find, for example, very abnormal lipid profile, then we can test for those genes. There are other tests that would allow us to look for abnormal proteins. For example, there are proteins that can be infiltrating the heart condition called cardiac amyloidosis that can be determined genetically in some patients. And the importance of those tests is for the entire family, where if the patient has an abnormal genetic test that can lead to cascade of tests for the descendants, and that way potentially help them to prevent any other risk factors that would exacerbate their disease.

(41:15): There are other tests now that are being developed and are associated with new treatments for a condition called hypertrophic cardiomyopathy. While these conditions are not directly related to hematologic stem cell transplant, it's important to know that if there are any events in the family, for example, unexplained or sudden death of family members, it is important to bring those to the attention of the medical providers to discuss the potential or the concern of the presence of a genetic disease in the family. And as any other cardiovascular disorder present before the time of the transplant, the recognition, the awareness is number one as being able to create a plan that would decrease the risk of transplant.

(42:19): [Marsha Seligman] The next question comes from someone who is three and a half years post-allogeneic transplant. They'd like to know if they should be followed by a cardiologist or primary care physician. "I have a new onset hypertension post-transplant, and also have new onset of SVT."

(42:41): [Dr. Vlad Zaha] That is an excellent question. And I would say the answer to both problems is yes. And probably it may be a combination of a visit with a cardiovascular specialist and then a follow-up with the primary care program, considering the other aspects of survivorship, where there are more general points that would need to be followed. But regarding those two points and emphasizing in the didactic talk, the presence of hypertension is increasing significantly the risks down the road. So addressing that risk early is beneficial. And there are specific ways to intervene and to monitor. So I would encourage contact with the cardiovascular specialist definitely.

(43:40): [Marsha Seligman] And there's a question asking about studies looking at alcohol use and those who have had BMT related to cardiac concerns.

(44:05): [Dr. Vlad Zaha] I see. Yes. So, there are studies looking at the toxicity of alcohol. So alcohol metabolites can be toxic in themselves. And we have, unfortunately, encountered in our program, patients that have developed cardiotoxicity where one of those multiple hits that I was mentioning was recognized to be alcohol. And so both research studies have demonstrated that, and in patients who are consuming more alcohol, we have observed that there is cardiotoxicity. And removing alcohol from their diet has helped in the recovery. So, I would say that is quite well established and is quite remarkable. So, it is an important preventive measure to hold alcohol consumption in this context.

(45:10): [Marsha Seligman] The next question has two parts. First, they ask, "Does TBI being included in the pre-transplant regime increase cardiovascular risk? And does long term use of CellCept after transplant to control GVHD after afterwards cause hypertension and increased cardiovascular risk?

(45:33): [Dr. Vlad Zaha] Yes. And again, I think I would say the nuance to the answer is that, again, these are successful and well-established modalities for treatment. I think the part of the risk versus benefit balance there is established from hematologic and oncological perspective. And what is important to realize that what we do in medicine, unfortunately, many times it's double-edged sword. And this is something that we recognize in cardio-oncology that sometimes the treatments that are the best will have a high risk. So what we have to emphasize on the other side is, how can we intervene and decrease the cardiovascular risk and optimize everything that can be optimized to allow those treatments to be completed successfully? So I would say this was, this was a very good question of awareness that there are certain interventions that will be potentially causing a risk. Again, having a cardiovascular specialist in the team there will be key to be able to maintain the balance between risk and benefit.

(47:05): [Marsha Seligman] The next question is, GVHD affected my heart after treatment. Will this happen again?

(47:14): [Dr. Vlad Zaha] Successful management of GVHD is quite remarkable in sort of quieting down the immunologic storm. And cardiovascular management, in parallel to that, can have some excellent results. Once the GVHD is addressed, maintaining the state of the cardiovascular system is definitely easier. So, there is that transition phase of management of GVHD and the GVHD itself that are causing that increased risk. So, coming on the other side of the GVHD, what will be important is to maintain that surveillance state and maintain the treatments that have instituted for the heart to maintain heart function and to decrease the long-term risks.

(48:16): [Marsha Seligman] And someone would like to know, can high dose chemo damage or weaken the heart valve?

(48:27): [Dr. Vlad Zaha] That's a good question that is sort of very specific about the valves. So the valves in the heart are the structures that allow the blood to flow in one direction. And by that, maintain the efficiency of the pump. The specific interventions in treatments that are damaging the valves are radiation treatments because of the process of scarring, or sclerosis as we call it, that can slowly, gradually evolve over time. The chemotherapy agents are designed to control or to kill all the rapidly growing cells. While the valves don't have rapid growing cells, they are less affected by the chemical treatments for malignancies. But again, depending on the type of therapy that is approached, there may be a need for radiation treatment that will expose the valves. The way to address that is to monitor for the development of changes over time with cardiovascular imaging and to optimize the blood flow by a good control of the blood pressure and by maintaining aerobic activity.

(50:03): [Marsha Seligman] The next question says, "Hi, Dr. Zaha. I know cycling is great for general cardio fitness, but does it help in reducing the cardiovascular complications associated with HSCT?"

(50:17): [Dr. Vlad Zaha] Yes, that is an excellent question. And cycling... And I would say expanding a little bit on the question... cycling is an excellent aerobic activity. And it is one that is probably easier to do for some patients because they can have a stationary bike and they can perform that activity in the comfort of their space. And during all the COVID time was, was much more accessible for many patients. So cycling is also very good because the intensity can be adjusted, right? So there can be high intensity intervals. There can be more endurance type of exercise. And it will be limited by someone's ability to breathe and exercise at that time. It also allows to see what is the progression of capacity to perform exercise. So definitely, cycling is a very good exercise. At the same time, the choice of exercise is, as long as it's aerobic exercise, so walking, dancing, biking, swimming, they are all good exercises that would be good at that stage.

(51:44): [Marsha Seligman] The next question says, "My previous LDL before HSCT was 100. I am 14 months post-HSCT, and LDL is 176. When should I be treated with medicine to bring it down?"

(52:01): [Dr. Vlad Zaha] This is a very good question, and it points exactly to the role of our baseline assessment and the follow-up assessments. And some of the changes that are happening in metabolism, and specifically in the cholesterol metabolism can be exacerbated either in the short-term, during the state of the higher inflammatory state, sort of the whole system is revved up following the transplant. And the decision of treatment will have to take in consideration the personal risk profile factors that have not been considered in the current preventive cardiology models, such as left chest radiation, the utilization of other chemotherapies that have been during the stem cell transplant and the need for long-term treatment sometimes. Again, not considered by the current preventive cardiology models. And also, the personal risk factors in the family.

(53:18): The number that was mentioned here would have to be placed in the context, and then followed up longitudinally. So we know that higher LDL numbers over time, so a longer exposure if you want, to these higher numbers is detrimental even in young patients. So it would be potential benefit to have a medical treatment to normalize those numbers, and as long as there is no interaction with other medications that may be limiting at least for some time.

(54:04): [Marsha Seligman] The next question says, "I am three years post-allogeneic transplant. I had mild hypertension before transplant, resolved with weight loss. Now, my blood pressure varies usually 110 to 120 systolic, but sometimes goes up to the 130s to 140s. Should I treat?"

(54:24): [Dr. Vlad Zaha] That's a very good question. And one of the aspects that is important to realize about the blood pressure measurement is that what we are focusing on in the guidelines are the blood pressure measurements at rest in, as much as possible, standardized conditions. And what that means, and based on the professional association recommendations, is to be resting for 10, 15 minutes in a quiet room in a sitting position with a back rest, and with feet on the ground without having an interaction with someone. And then having a couple measurements of the blood pressure. And then identifying what is the lowest blood pressure. That would be a truly resting condition, in a quiet room without being rushed in.

(55:18): So, if that situation is going to lead to numbers that are more than 130, the systolic blood pressure consistently, the guidelines recommend to start the process of treating the blood pressure. And in the first phase, that involves optimization of what we call the lifestyle factors. And then if changes in the lifestyle factors, involving again exercise and healthy nutrition, are not helpful, there should be a close follow up with medical professional to start medical therapy.

(56:06): [Marsha Seligman] We are running out of time, so this is going to have to be our last question. It is, "The day I left the hospital from my second BMT, I had atrial tachycardia and had to have electro cardioversion. Was this most likely due to the melphalan? Does it need further follow up? I am now six months post-BMT, and it has not been a problem since?

(56:35): [Dr. Vlad Zaha] Very good question. We see sometimes what we call isolated arrhythmias that are happening during the process of transplant. And in some patients, they don't come back. They don't occur back. Again, it is a good practice to follow up and have an electrocardiogram checked at the surveillance visits following sort of long-term successful transplant. And that would surface any specific electrical problems in the heart.

(57:16): [Marsha Seligman] Closing. On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Zaha, for your very helpful remarks. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.