Acute CV Complications of Hematopoietic Stem Cell Transplantation

Feb 16, 2021   |  Thomas D. Ryan, MD, FACC; seth rotz, MD; Salim Hayek, MD, FACC

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  • Cardiovascular risk factors, prior exposure to cardiotoxic agents, and high-dose chemotherapy administered during hematopoietic stem cell transplantation (HSCT) conditioning contribute synergistically to post-HSCT cardiovascular complications.
  • Reduced intensity conditioning regimens associated with less cardiotoxicity are being used more frequently, particularly in older patients.

Introduction
HSCT is a potentially curative treatment for many malignancies, hemoglobinopathies, metabolic diseases, bone marrow failure syndromes, and primary immune deficiencies.1-3 In brief, HSCT accomplishes disease eradication through high-dose chemotherapy with or without radiation, leading to ablation of a patient's bone marrow, known as conditioning, followed by transplantation of either donor-derived stem cells (allogeneic HSCT), or patient-derived stem cells collected prior to conditioning (autologous HSCT). Complications can affect multiple organ systems and are results of the cytotoxic effects of the conditioning regimen, resulting cytopenias, and graft-versus-host disease in patients undergoing allogeneic HSCT. Cardiovascular complications of HSCT such as cardiomyopathy, arrhythmias, pulmonary hypertension, and pericardial effusions are increasingly recognized.4

Mechanisms of Cardiotoxicity in HSCT
Pre-HSCT cardiotoxic exposures (e.g., prior therapeutic exposure) and pre-existing cardiovascular disease are significant contributors to post-HSCT cardiovascular morbidity. In addition, cardiac adverse events have been attributed to different components of HSCT itself such as total body radiation ablative therapy combined with a multi-drug conditioning regimen, with many of the drugs employed associated with cardiovascular toxicity: cyclophosphamide,5 cytarabine,6 carmustine,7 and melphalan.8 Further, the dimethylsulfoxide used to preserve stem cells may also contribute to cardiac events (Table 1).9 This includes pulmonary hypertension, vascular disease, hypertension, cardiometabolic effects, arrhythmia, myocardial ischemia, and prolongation of the QT interval.10-13 Cardiovascular complications may also arise as consequences of other HSCT-related comorbidities such as sepsis,14 graft-versus-host disease,15-17 thrombotic microangiopathy,18,19 and hepatic veno-occlusive disease.20

Table 1: Causality and Mechanisms of Acute Cardiac Complications of HSCT*

Therapeutics Associated Cardiovascular Complications
Total body irradiation21,22 Pericarditis, congestive heart failure
Calcineurin inhibitors23 Hypertension
Cyclophosphamide5,24-28 Congestive heart failure, hemorrhagic myocarditis, pericarditis
Cytarabine6,29 Dysrhythmia, congestive heart failure, pericarditis
Carmustine7 Myocardial ischemia
Melphalan8,30 Dysrhythmia, congestive heart failure
Dimethylsulfoxide9 Bradycardia, cardiac arrest
Alemtuzumab (anti-CD52 antibody)31 Congestive heart failure, dysrhythmia, tachycardia
Vinca alkaloids29 Dysautonomia
Common Transplant Complications Associated Cardiovascular Complications
Graft-versus-host disease15-17,32 Pericardial effusion, bradycardia, dysrhythmia, coronary artery
disease, cardiomyolysis
Thrombotic microangiopathy17-19 Systemic hypertension, pulmonary hypertension, pericardial effusion
Sepsis14 Systolic dysfunction/myocardial depression, tachyarrhythmias
Hepatic veno-occlusive disease20 Fluid overload leading to decompensated heart failure
*Other drugs used to treat complications of HSCT may also have cardiac toxicity (e.g., certain antibiotics) but are not listed here. Additionally, other HSCT complications not included may exacerbate known cardiac disease (e.g., pulmonary complications leading to right heart dysfunction).

Risks of Short-Term Cardiotoxicity During HSCT
Adult Recipients
Myriad short-term cardiovascular complications may occur during or in the short term after HSCT.4 One challenge in determining the incidence of cardiac complications is the lack of standardized diagnostic criteria or surveillance techniques and heterogeneous populations. Overall, severe cardiac complications are generally rare. A retrospective study of 2,821 patients (median age 22, 58% male) status post-HSCT (55% autologous) between 1977 and 1997 identified 26 patients (0.9%, 19 adults and 7 children) who experienced major or lethal cardiotoxicity in the first 100 days post-HSCT. This included death from a cardiovascular cause, congestive heart failure requiring inotropic support, cardiac tamponade, or significant electrocardiographic abnormalities.31,33 These findings are difficult to extrapolate to other populations, notably older patients with increased incidence of cardiovascular risk factors and less cardiovascular reserve who represent a growing segment of the HSCT-eligible population as the population ages and use of the therapy is more common.

Arrhythmias occur commonly in the HSCT setting. Estimates of incidence ranges between 2% and 10% of adult recipients.34-41 Atrial fibrillation and flutter are the most frequently described arrhythmias, with supraventricular tachycardia occurring in up to 5.1% of patients.35,38-41 Although lethal arrhythmias are rare, the occurrence of arrhythmias has been associated with in-hospital and 1-year mortality.36,42

Congestive heart failure is generally considered a long-term complication of HSCT,43,44 but new onset left ventricular dysfunction or exacerbations of pre-existing congestive heart failure can also occur in the short term. New onset heart failure occurs in approximately 0.4-2.2% of recipients.21,34,37,45 However, inclusion criteria (e.g., presence of pre-HSCT cardiomyopathy), diagnostic criteria (echocardiographic screen versus clinically diagnosed decompensated heart failure), and duration of follow-up can differ significantly between centers or studies, leading in some cases to reported incidence of upwards of 20%.46

Beyond arrhythmia, ventricular dysfunction, and symptomatic heart failure, other cardiovascular disease can occur peri-HSCT, although less frequently. Myocardial infarction and severe pericardial effusion/tamponade also may occur during the course of HSCT and immediately after, though in general these are rare events.21,33,34

Pediatric Recipients
Although cardiac disease is an important cause of early post-HSCT morbidity, data regarding the frequency of acute cardiac complications in this population are limited compared with data for adult patients.4,47 In a prospective evaluation screening program of 227 pediatric patients undergoing HSCT at a single center, 32% of patients developed a new abnormality by echocardiogram in the first 100 days post-transplantation. Findings included new left ventricular systolic dysfunction in 6%, pericardial effusion in 27%, and elevated right ventricular pressure (>35% systemic pressure) in 9%.48 Whether these findings lead to clinically important disease is not well appreciated. Pulmonary hypertension is a potentially fatal complication of HSCT and often presents nonspecifically in children and young adults undergoing HSCT.18 Echocardiographic abnormalities are particularly common in pediatric patients who become critically ill after HSCT, and a team-based screening approach involving providers from bone marrow transplantation, cardiology, and intensive care can allow for early detection and timely intervention.49 Pericardial effusions occur for a number of reasons post-HSCT,17,22,48,50,51 and approximately 3-4% of pediatric patients will require pericardial drain placement in the first 100 days after HSCT.17,48

Pre-HSCT Evaluation
The perceived risks of HSCT-related cardiotoxicity have led to the incorporation of a cardiovascular evaluation in the pre-transplant assessment of HSCT. Although practice varies across centers, patients with a pre-transplant left ventricular ejection fraction of less than 35% are often denied HSCT. The data surrounding the association between pre-transplant ejection fraction and short-term outcomes do not support this practice.4 When cardiovascular complications arise after HSCT, their management is dependent on the status of the patient, the predicted outcome, and other cardiovascular comorbidities.

Conclusion
Cardiac complications may occur in both pediatric and adult patients after HSCT. Pre-HSCT cardiac comorbidities are common, particularly in adults. Pediatric patients undergoing HSCT for certain genetic conditions are at risk for idiosyncratic cardiac events during transplantation (e.g., beta thalassemia, Hurler syndrome). Even in patients undergoing HSCT with no known cardiac disease, use of radiation and anthracycline chemotherapy as part of pre-HSCT malignancy treatment may predispose to events occurring during and after HSCT. Cardiac disease, unless very severe, should not be a specific barrier to utilizing HSCT and can often be managed with a multidisciplinary team. However, to establish specific practice guidelines, further research and/or expert opinion statements are needed to standardize the approach to evaluating and managing cardiovascular disease associated with HSCT.

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Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pericardial Disease, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Statins, Acute Heart Failure, Pulmonary Hypertension, Echocardiography/Ultrasound, Hypertension

Keywords: Stroke Volume, Cardiovascular Diseases, Retrospective Studies, Pericardial Effusion, Anthracyclines, Cardiotoxicity, Bone Marrow Transplantation, Atrial Fibrillation, Cardiac Tamponade, Hypertension, Pulmonary, Critical Illness, Mucopolysaccharidosis I, beta-Thalassemia, Expert Testimony, Prospective Studies, Ventricular Pressure, Ventricular Function, Left, Risk Factors, Heart Failure, Ventricular Dysfunction, Left, Echocardiography, Myocardial Infarction, Cardiomyopathies, Neoplasms, Tachycardia, Supraventricular, Critical Care, Hematopoietic Stem Cell Transplantation, Hospitals, Patient Care Team, Melphalan, Carmustine, Dimethyl Sulfoxide, Graft vs Host Disease, Hepatic Veno-Occlusive Disease, Bone Marrow, Cytarabine, Transplantation Conditioning, Whole-Body Irradiation, Anemia, Myocardial Ischemia, Cyclophosphamide, Thrombotic Microangiopathies, Arrhythmias, Cardiac, Metabolic Diseases, Hemoglobinopathies, Pharmaceutical Preparations, Sepsis, Disease Eradication


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