Cardiovascular Disease After Hematopoietic Stem Cell Transplantation in Adults: JACC: CardioOncology State-of-the-Art Review.

Hematopoietic cell transplantation (HCT) is a potentially curative option for a wide variety of malignant and nonmalignant conditions. 1 First described in 1957, by the end of 2019, approximately 1.5 million people had undergone HCT, with a frequency of 84,000 transplants per year globally. 2 , 3 , 4 The increased transplantation activity over the last 4 decades has been driven by the global adoption of HCT accompanied by modifications to transplantation regimens facilitating procedures in patients who are older and have more comorbidities with a higher baseline cardiovascular risk. 5 Advances in patient and donor selection, reduced toxicity conditioning, and improved supportive care during transplantation have increased survival and decreased nonrelapse mortality. 6 , 7 These changes have led to a focus on competing causes of increased morbidity and mortality in which cardiovascular disease plays a leading role.

Characterizing cardiovascular disease in the adult HCT population can be difficult; each transplantation candidate is different and requires a personalized approach to cardiovascular assessment. In this review, we cover the breadth of what is known about cardiovascular disease in this population, focusing on acute and late complications, risk prediction, surveillance, and treatment of complications.

Autologous and Allogeneic Stem Cell Transplants

Autologous and allogeneic HCT have a variety of indications, as detailed in Figure 1 . 1 The overall processes in both types of transplantation are similar, but the main treatment effect and the indication for transplantation differ between transplantation types. Initially, stem cells are harvested from the patient (in autologous HCT) or donor (in allogeneic HCT). Patients then receive conditioning therapy to ablate the bone marrow to varying degrees. After conditioning, hematopoietic progenitor cells (CD34+ stem cells) are infused back into the patient to reconstitute the lymphohematopoietic system. In autologous transplantation performed for malignant diseases, the treatment effect is provided by the cytotoxic conditioning therapy, and HCT salvages the bone marrow and prevents potentially fatal myelosuppression. When autologous transplantation is used to treat autoimmune diseases, the HCT acts to reset the immune system. 8 In allogeneic transplantation, the main treatment effect is provided by the donor stem cells attacking the tumor cells (graft-versus-tumor effect) or through replacing dysfunctional bone marrow in nonmalignant diseases.

In allogeneic HCT, donors are matched through human leukocyte antigen (HLA) typing. Five loci (each with 2 alleles) are typed and compared, with matching described as a score out of 10. The loci are HLA-A, HLA-B, HLA-C, DRB1, and DQB1. Although allogeneic transplantation outcomes have been improved by the use of matched related donors, matched unrelated donors are frequently used because of the lack of siblings. 9 In some cases, mismatched related or unrelated donors are used. A mismatch of 1 allele or antigen is tolerable in unrelated donors, but sibling, parent, or children family donors can be half-matched (haploidentical). There is a greater risk of graft rejection, graft-versus-host disease (GVHD), and nonrelapse mortality as the mismatch increases. However, this has been mitigated by improvements in post-transplantation GVHD prophylaxis, such as the use of post-transplantation cyclophosphamide ( Table 1 , Supplemental Appendix ). 10 , 11

In contemporary practice, peripheral blood is the main source of stem cells for both types of transplantation. Before collection, cells are mobilized from the bone marrow by various methods. Granulocyte colony-stimulating factor (eg, filgrastim) is used for stem cell mobilization in autologous HCT patients and allogeneic HCT donors. C-X-C motif chemokine receptor 4 inhibitors, such as plerixafor, can be used to augment mobilization in select cases. In autologous HCT, chemotherapy (commonly cyclophosphamide) ( Table 1 ) followed by granulocyte colony-stimulating factor is an alternative method for mobilization when high numbers of stem cells are required and/or tumor burden needs to be decreased further. In certain diseases, such as lymphoma, the chemotherapy used for mobilization can also be part of a disease-specific treatment regimen.

In allogeneic HCT, other sources of stem cells include bone marrow harvesting and umbilical cord blood. For allogeneic HCT in the malignant setting, peripheral blood stem cells demonstrate faster engraftment, a superior graft-versus-tumor effect, and a reduced incidence of graft failure compared with cells derived from bone marrow but at the expense of an increased risk of chronic GVHD. 12 , 13 Umbilical cord blood requires less stringent HLA matching but is associated with delayed engraftment and an increased risk of infections. Often, a judgment is made before allogeneic HCT regarding the optimal donor and cell source that will give the best treatment effect.

Conditioning therapy for autologous HCT is myeloablative, whereas conditioning for allogeneic HCT includes myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), or nonmyeloablative conditioning. 14 MAC ablates the bone marrow using combination therapies, and RIC uses lower doses of the same agents ( Table 1 ). MAC regimens are associated with a reduced risk of relapse but are more toxic and generally have a higher risk of GVHD. For older patients, the increased nonrelapse mortality induced by MAC has made RIC the preferred option. 15 Although conditioning typically involves chemotherapy alone, the exact regimen used depends on the underlying disease, disease status, and comorbidities. In autologous HCT, the goal of treatment depends on the disease being treated ( Figure 1 ), but allogeneic HCT is always performed with curative intent.

Key Points

Autologous HCT uses MAC before stem cell infusion.

In autologous HCT performed for malignant disease, the main treatment effect is provided by the conditioning therapy.

Allogeneic HCT uses varying intensities of conditioning therapy (MAC, RIC, or nonmyeloablative conditioning), balancing the risk of toxicity with the risk of relapse.

In allogeneic HCT performed for malignant disease, the main treatment effect is caused by the graft-versus-tumor response.

Allogeneic transplantation recipients have different degrees of donor HLA matching, which impact the likelihood of developing GVHD.

Literature Review

We conducted a literature review on cardiovascular outcomes after HCT and cardiovascular risk prediction before HCT. The search strategies and full-text papers that we reviewed are included in the Supplemental Appendix . We excluded case reports, editorials, and review articles. Cardiovascular outcome definitions varied between studies, and many papers predated the contemporary definition of chemotherapy-related cardiac dysfunction. 16 , 17 , 18 , 19 , 20 Our recommendations for the cardiovascular care of HCT patients were constructed from critical review of relevant societal guidelines, position statements, and their supporting literature.

Most of the data describing cardiovascular complications after HCT originated from patients who underwent the procedure between 1980 and 2005. However, there is an emerging literature base describing patients treated in later eras. 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 The cardiovascular risk profile has changed over time; older eras are associated with higher doses of cardiotoxic therapies, whereas contemporary practice uses lower doses of cardiotoxic therapies but in patients who are older and have more comorbidities. Where possible, we include data derived from patients who underwent HCT after 2005, and a comparison is made to previous eras where appropriate. The results of the literature searches are synthesized into a narrative review.

Cardiotoxicity: Treatment Effects

Many parts of the HCT process have been implicated in cardiotoxicity, including treatment given before HCT (eg, anthracyclines and radiotherapy), constituents of the stem cell cryopreservation media (dimethylsulfoxide), conditioning therapy (including total body irradiation), and drugs used for GVHD prophylaxis such as alemtuzumab. 30 , 31 , 32 , 33 , 34 , 35 , 36 Often, different classes of drugs are used in combination before HCT and during conditioning, making it a challenge (and possibly incorrect) to attribute a particular adverse effect to a single treatment. Many HCT recipients receive treatment with anthracyclines before HCT, a class of drugs with a well-defined association to heart failure (HF) and cardiovascular morbidity and mortality. 37 , 38 , 39 , 40 Although the use of anthracyclines has declined, novel therapies used to treat hematologic cancers, such as proteosome inhibitors 41 and tyrosine kinase inhibitors, 42 , 43 are associated with cardiotoxicity independent of the HCT process.

In contemporary cohorts, different combinations of conditioning therapy have been associated with different risks of cardiotoxicity. In 1 study, fludarabine/melphalan was associated with the highest cumulative incidence of cardiovascular events at 100 days (7.2%) and 10 years (26%) after HCT. 28 The historical use of high-dose cyclophosphamide for transplantation conditioning has been associated with hemorrhagic myocarditis and acute HF in up to 28% of patients. 44 , 45 , 46 , 47 This is now uncommon because of the use of lower doses of cyclophosphamide in modern conditioning regimens. 48

There has been an increased use of cyclophosphamide for GVHD prophylaxis after allogeneic HCT. Three studies analyzed the incidence of cardiotoxicity with post- transplantation cyclophosphamide. 25 , 26 , 29 However, only 1 study found an increased incidence of short-term cardiac events in patients treated with post-transplantation cyclophosphamide (19%) compared with controls (6%). 25 The most common cardiovascular events within 100 days after starting post-transplantation cyclophosphamide were left ventricular systolic dysfunction (incidence of 14.3%), symptomatic heart failure (incidence of 5.1%), atrial arrhythmias (incidence of 3.1%-4.8%), and pericardial effusions (incidence of 1.5%). 25 , 29 A summary of the therapies used in HCT and their associated adverse cardiovascular outcomes is provided in Table 1 .

Short- and Long-Term Cardiovascular Complications in Autologous and Allogeneic Transplantation

Most studies classify short-term cardiovascular complications after autologous and allogeneic HCT as events that occur within 100 days after transplantation, but there is variability between studies. 21 , 23 , 26 , 29 , 38 , 39 , 44 , 77 , 94 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 Although the 100-day time point has been used for both transplantation types, it originated from the historical time frame used to define acute GVHD after allogeneic HCT. Acute GVHD is now defined by disease features, not temporality. 121 Many studies classify long-term cardiovascular complications after autologous and allogeneic HCT as those occurring 1 to 2 years or more after transplantation rather than 100 days or more after transplantation. 22 , 24 , 37 , 51 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134

Cardiovascular outcome definitions vary between studies, and many papers were published before the contemporary definition of chemotherapy-related cardiac dysfunction. 16 , 17 , 18 , 19 , 20 We use the term HF to refer to symptomatic cardiac dysfunction occurring after HCT and asymptomatic left ventricular systolic dysfunction in which a left ventricular ejection fraction (LVEF) decline has been reported in the absence of symptoms.

With both types of transplantation, there is an increased risk of infection, relapse, and graft rejection within 100 days of HCT. Allogeneic HCT carries the additional risk of acute GVHD. Cardiovascular complications are relatively uncommon within 100 days after HCT. 28 Engraftment syndrome, occurring early after autologous and allogeneic transplantation, is associated with a proinflammatory state that can exacerbate underlying cardiovascular disease. 135 Patients often require intravenous fluid or blood products to support them through HCT, and large shifts in fluid balance can trigger cardiovascular complications such as arrhythmias and symptomatic heart failure. In the long-term, there is a higher incidence of adverse cardiovascular outcomes in HCT patients compared with the general population, particularly in allogeneic transplantation recipients. 28 , 126

The HCT population is a highly selected cohort because patients with pre-existing cardiovascular disease are less likely to be offered HCT, lowering the rate of cardiovascular adverse events. The most common adverse cardiac outcomes for each transplantation and associated risk factors are discussed later and are summarized in Table 2 . The results of the literature search are provided in the Supplemental Appendix .

Autologous HCT

Atrial fibrillation (AF) is the most common short-term cardiovascular event after autologous HCT, occurring in 2.8% to 8.5% of transplantations. 28 , 109 , 116 Most cases occur within 3 weeks after HCT, but it is also not uncommon in the long-term, with a 5-year cumulative incidence of 6.7%. 27 Risk factors for developing AF include conditioning with melphalan, increasing age, previous AF, and hypertension at the time of HCT. 77 , 109 , 116 , 136 Multiple myeloma is the most common indication for autologous HCT, and patients undergoing transplantation for multiple myeloma have an increased risk of developing AF or flutter, with the incidence ranging from 10% to 27% in the short-term. 108 , 137 Risk factors for AF specific to the multiple myeloma population included baseline renal dysfunction, hypertension, previous AF, left atrial dilatation, left ventricular dysfunction, and excess intravenous fluid administration in the first 14 days after HCT. 77 , 108 , 137

The cumulative incidence of HF within 100 days of autologous HCT is up to 1.1%, rising over time to 9.2% at 10 years after HCT. 28 , 77 Risk factors for developing HF include a high cumulative anthracycline dose before HCT, diabetes, and hypertension. 37 When LVEF is measured routinely after autologous HCT, short-term declines in LVEF appear to be relatively common. One study showed 10 of 32 patients had an LVEF decline of 10% or more to less than 50% up to 6 weeks after autologous HCT. 138 Two patients developed pulmonary edema (1 fatal), and 2 developed AF.

Arterial disease is uncommon after autologous HCT. The cumulative incidence of myocardial infarction within 100 days of HCT is 0.2%, rising to 2.7% at 10 years. 28 The cumulative incidence of stroke is lower, at 0.1% within 100 days of HCT, rising to 0.6% at 10 years. 28 Ventricular arrhythmias are uncommon after autologous HCT, with a 10-year cumulative incidence of 0.6%. 28 Pericardial disease is rarely encountered after autologous HCT.

Autologous transplantation recipients have an elevated risk of developing hypertension, diabetes, and dyslipidemia compared with matched controls. In 1 study of patients who survived 1 year or more after transplantation, the 10-year cumulative incidence of developing 2 or more cardiovascular risk factors was 26%. 139

Allogeneic HCT

AF is the most common cardiovascular complication after allogeneic HCT. The short-term incidence is 2.5% to 9%, 21 , 29 , 38 , 110 , 113 , 119 , 140 rising to 6.9% to 10.6% at 5 years after HCT. 22 , 24 , 28 Risk factors for the development of AF after allogeneic HCT include conditioning with melphalan, increasing age, prior AF, and the use of HLA-unrelated donors. 77 , 119

HF is uncommon in the short-term after allogeneic HCT, affecting 1.1% to 2.3% of patients. 21 , 26 , 27 , 28 , 29 , 38 , 105 , 114 , 140 , 141 The cumulative incidence increases over time, reaching 8.2% at 10 years after HCT. 28 Risk factors for the development of HF include a high cumulative dose of anthracycline, increasing age, GVHD, pre-existing hypertension, and diabetes. 26 , 27 , 29 , 38 , 114 Similar to autologous HCT, when LVEF is measured routinely after allogeneic HCT, declines in LVEF are common. In 1 study, 23 of 136 patients had a decline in LVEF of 10% or more to less than 53% within 100 days after allogeneic HCT, and 11 developed symptomatic HF. 27 In the long-term, another study of allogeneic HCT recipients found that 44% had declines in their LVEF, and 28% were symptomatic. 20 Declines in LVEF also occur with the use of post-transplantation cyclophosphamide. One study with a median follow-up of 243 days found that 21.9% of patients developed a fall in LVEF of 10% or more to less than 53%; however, the majority of these patients (94%) also had sepsis. 26 More research is needed to determine which patients with early declines in LVEF will develop clinically significant HF.

Arterial disease within 100 days after allogeneic HCT is uncommon. 28 Although the cumulative incidence of stroke remains low at 2.4% up to 10 years after HCT, the risk of myocardial infarction increases with a 10-year cumulative incidence of 6.5%. 28 The incidence of long-term arterial events after allogeneic HCT is comparable across transplantation eras. 133 , 142 Certain risk factors for arterial disease are common in the allogeneic HCT population, including hypertension, dyslipidemia, diabetes, obesity, and smoking. 124 , 127

GVHD after allogeneic HCT has been postulated to cause accelerated atherosclerosis by alloreactive cytotoxic T lymphocytes infiltrating arterial walls, leading to increased lipid deposition. 134 , 143 , 144 Despite this, GVHD has not been shown to be independently associated with arterial events after adjustment for other important variables such as age and cardiovascular comorbidities. 126 , 127 , 133 , 142 However, GVHD is associated with an increased risk of developing a cardiac event after allogeneic HCT (HR = 1.68), and acute GVHD is associated with an increased risk of cardiovascular death (HR = 4.0). 28 , 127 Chest-directed radiation is associated with vascular injury and an increased risk of coronary artery disease in older transplantation cohorts (OR: 5.2). 124 , 125 , 145 In contemporary practice, the risk of arterial disease secondary to radiotherapy has been attenuated by advances in treatment that result in a reduced mean heart dose. 28 , 145

Although pericardial effusions occur after allogeneic HCT, they are uncommon in adults. The short-term incidence ranged from 0.8% to 1.7%, rising to 3.0% to 3.1% within 5 years after HCT. 22 , 29 , 106 However, 1 study of haploidentical HCT recipients receiving post-transplantation cyclophosphamide found that 13.6% had a pericardial effusion within the first year after transplantation. 26 The mortality associated with tamponade in this population is low because most patients have timely intervention. 26 , 106 Risk factors include increasing age, chronic GVHD, and multiple transplantation procedures. 106 Although ventricular tachycardia and conduction system disorders occur, they are uncommon in both the short- and long-term ( Table 2 ).

In patients who survive 1 year or more after allogeneic HCT, the 10-year cumulative incidence of developing 2 or more cardiovascular risk factors (hypertension, diabetes, and/or dyslipidemia) can be as high as 40%. 139 In patients on immunosuppression after allogeneic HCT, the incidence of dyslipidemia can be as high as 80%. 146 , 147 Stage II to IV GVHD has been associated with an increased risk of developing cardiovascular risk factors (hypertension risk ratio [RR]: 9.1, diabetes RR: 5.8, and dyslipidemia RR: 3.2), partly because of the effect of medications used to treat GVHD ( Table 1 ). 139 Total body irradiation has been associated with increased rates of diabetes and dyslipidemia, possibly through radiation-induced pancreatic or hepatic dysfunction, combined with gonadal dysfunction after HCT. 88 , 90 , 91 , 92 , 93 , 97 , 98 , 99 , 139

Cardiovascular and all-cause mortality

Cardiovascular death remains low in both the short-term and long-term, with a 5-year cumulative incidence of 0.2% for autologous transplantation and 1.4% for allogeneic transplantation. 28 , 126 The leading cause of mortality in both types of transplantation is the relapse of the primary disease. 37 , 122 , 124 , 132 , 140 In long-term survivorship cohort studies, late mortality after both allogeneic and autologous transplantation has improved. However, life expectancy decreased compared with the general population, and recent reports of improvements in life expectancy were not because of a reduction in death from cardiovascular disease. 6 , 7

Indirect causes of cardiovascular disease secondary to autologous and allogeneic HCT

Both autologous and allogeneic HCT are associated with toxicity in other organs and tissues, which may contribute to cardiovascular disease. This includes thrombotic microangiopathy causing systemic and pulmonary hypertension and pericardial effusions, hepatic veno-occlusive disease leading to fluid overload and HF, and sepsis leading to arrhythmias and depression of myocardial contractility. 151 , 152 , 153 , 154

Damage to other organs can also have a long-term impact on the risk of cardiovascular disease. Hypertension can be aggravated by renal disease accrued during the course of the transplantation, and cardiometabolic derangements occur secondary to gonadal dysfunction, thyroid disease, and liver cirrhosis. 155 Depression and anxiety are also prevalent before, during, and after autologous and allogeneic HCT, impacting patient lifestyle choices, engagement with treatment, and physical conditioning. 156 , 157

Key Points

Atrial arrhythmias are the most common short-term complication in autologous and allogeneic HCT.

After autologous HCT, the main long-term complications are HF and atrial arrhythmias.

After allogeneic HCT, the main long-term complications are atrial arrhythmias, HF, and myocardial infarction.

Autologous and allogeneic HCT recipients have an elevated risk of hypertension, dyslipidemia, and diabetes after transplantation.

Clonal Hematopoiesis of Indeterminant Potential

Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an age-dependent risk factor for both cardiovascular disease (predominantly coronary artery disease) and cancer. 158 , 159 CHIP refers to the clonal expansion of stem and progenitor cells caused by a somatic variant endowing the cells with a survival and proliferation advantage. Numerous genes are implicated in CHIP, and the mechanisms linking different variants to coronary artery disease vary between genes. 158 , 160

CHIP-related sequence variants are prevalent in autologous HCT recipients, occurring in 29.9% of patients treated for lymphoma and 21.6% to 22.8% of patients treated for myeloma. 161 , 162 , 163 The presence of CHIP in patients who undergo autologous HCT for lymphoma and multiple myeloma indicate a worse overall survival rate compared with controls, with an increased incidence of cardiovascular disease. 161 , 162 , 163 In 1 study of patients with multiple myeloma treated with autologous HCT who had 1 CHIP-related sequence variant, the 5-year incidence of cardiovascular disease was noted to be 21.1% compared with 8.4% in controls. 163 Donors are not routinely screened for CHIP-related sequence variants, and there is no evidence to suggest an increased incidence of cardiovascular disease after allogeneic transplantation from donors with these variants. 164

Key Points

Patients who require autologous HCT for lymphoma or myeloma and have CHIP-related sequence variants may be at an increased risk of cardiovascular disease.

More research is required to understand the associations between CHIP-related sequence variants and cardiovascular disease after transplantation.

Cardiovascular Assessment and Risk Prediction

The goal of baseline cardiovascular assessment is to identify patients at highest risk of cardiovascular disease, optimize their risk factors, and facilitate the safe delivery of the HCT ( Central Illustration ). Baseline assessment includes clinical examination and a comprehensive history. There should be a focus on cardiovascular risk factors and underlying cardiovascular disease, with measurement of body mass index, blood pressure, lipids, and glycosylated hemoglobin (HbA 1c ). Healthy lifestyle modification should be advised, including smoking cessation. Because of a lack of evidence in HCT cohorts, the management of hypertension, dyslipidemia, and diabetes should follow general guidelines.

A baseline 12-lead electrocardiogram should be performed to identify arrhythmias, and the Fridericia formula should be used to calculate the corrected QT interval. 19 Three small studies found that increased QT dispersion before HCT was associated with HF after transplantation, but this effect may have been transient and related to cyclophosphamide cardiotoxicity. 111 , 165 , 166

The role of cardiac biomarker assessment before transplantation is unclear. Several small studies suggest that serial measurement of natriuretic peptides or troponin T early after HCT may be useful for detecting cardiotoxicity. 105 , 167 , 168 Patients who undergo HCT are susceptible to hemodynamic changes through alterations in fluid balance secondary to the infusion of large volumes of intravenous fluid and blood products, and most have recently completed induction chemotherapy or were undergoing consolidation therapy. These factors impair the baseline interpretation of natriuretic peptides (N-terminal pro–B-type natriuretic peptide or B-type natriuretic peptide) and cardiac troponin levels. Because of this, baseline assessment of natriuretic peptides and cardiac troponin is not recommended in asymptomatic patients. 169 , 170

Imaging in the adult population

Cardiac imaging should be used to determine left ventricular systolic function and identify structural heart disease before transplantation. 19 Most centers use echocardiography because of wide availability and lesser costs. 171 When feasible, 3-dimensional LVEF measurement with echocardiography is preferred over 2-dimensional LVEF measurement because of reduced variability and better correlation with cardiac magnetic resonance (CMR). 172 , 173

Speckle tracking techniques such as global longitudinal strain have a role in identifying subclinical myocardial damage, 174 and there is evidence to support the use of global longitudinal strain in light-chain cardiac amyloidosis as a prognostic marker for patients who undergo HCT. More data are required to define its use after HCT performed for other diseases. 175

In select cases in which echocardiography is nondiagnostic, CMR should be used over nuclear techniques to minimize radiation dose and provide an assessment of cardiac structure and function. There is no evidence to suggest that routine stress testing or cardiac computed tomography should be used before HCT in the absence of ischemic symptoms.

Reduced LVEF, cardiovascular disease risk, and mortality

Studies investigating the association between a reduced LVEF before HCT and both adverse cardiovascular outcomes and transplantation-related mortality have mixed results ( Supplemental Appendix ). 16 , 18 , 21 , 38 , 52 , 115 , 117 , 129 , 132 , 176 , 177 , 178 , 179 Many of these studies included mixed allogeneic and autologous HCT populations. 18 , 117 , 129 , 176 , 177 , 179

Several studies have shown an increased incidence of short-term adverse cardiovascular outcomes (including arrhythmia, HF, and myocardial infarction) and mortality in those with a reduced baseline LVEF. 16 , 21 , 38 , 176 Other studies have shown no increase in short-term cardiotoxicity or mortality in those with a reduced LVEF. 18 , 52 , 117 , 132 , 177 , 178 In the long-term, 2 studies have shown no increase in the incidence of HF 129 or mortality 115 with reduced LVEF before HCT.

All of the studies were retrospective and have a high likelihood of selection bias; patients were carefully selected and must have been clinically stable despite an impaired LVEF. In practice, patients are excluded from HCT if they have an impaired LVEF, although the cutoff varies across centers, ranging from 50% or less to 35% or less. 171 It is possible that some patients may have been excluded from HCT based on measurement error because of the imprecision inherent to 2-dimensional LVEF assessment with echocardiography. 172 , 180 Some centers use RIC if the ejection fraction is impaired; however, only 2 studies evaluating outcomes in patients with an LVEF below 50% used RIC in patients with a reduced LVEF. 18 , 117 In 1 of these studies, 81.6% received RIC, and there was a significantly lower 1-year overall survival in patients with an LVEF <43%. 18 There is also evidence to suggest that impaired cardiac reserve measured through changes in LVEF with exercise had a stronger association with short-term mortality than resting LVEF. 179

The discrepancy in the study outcomes suggests that some patients with a reduced LVEF may have been able to safely undergo HCT. However, because of the lack of data, the decision to perform HCT with an LVEF of 50% or less and/or the use of RIC is based on expert consensus of hematologists and cardiologists at individual transplant centers.

Cardiopulmonary exercise testing

Cardiopulmonary exercise testing (CPET) represents an integrative approach to the assessment of cardiorespiratory fitness and cardiac reserve. CPET allows dynamic, noninvasive assessment of the hematopoietic, pulmonary, cardiovascular, skeletal muscle, and neural systems. Patients may have baseline impairments beyond left ventricular dysfunction that have a systemic impact on their ability to tolerate the physiological demands of HCT, including anemia, infections, large fluid volume shifts, and insults secondary to the conditioning regimen. 181

Three small pilot studies have shown that CPET in the HCT population is feasible (completion rates of 91%-95%) and safe. 182 , 183 , 184 Patients with impaired maximal respiratory oxygen uptake are at higher risk of mortality and an increased length of hospital stay within the first 100 days after HCT. 184 CPET may have a role before HCT in identifying patients who would benefit from prehabilitation and/or rehabilitation to improve cardiac reserve 185 and after HCT in the ongoing assessment of patients with exertional cardiovascular symptoms within 12 months after HCT by unmasking impairments in cardiorespiratory fitness. 186 , 187 Future work should determine if CPET is better than resting LVEF measurement at predicting adverse cardiovascular outcomes and transplantation-related mortality.

Risk stratification scores

Before transplantation, the most widely used risk stratification tool to predict nonrelapse mortality and overall survival is the hematopoietic cell transplantation comorbidity index. 171 , 188 The hematopoietic cell transplantation comorbidity index covers various organ systems and has categories for arrhythmia, HF, coronary artery disease, and valve disease. The score is not validated for the assessment of cardiovascular-specific risk, and the discriminatory performance of the score is modest for the prediction of nonrelapse mortality and overall survival. 188

Cardiovascular risk prediction scores have also been proposed to detect acute and long-term cardiotoxicity ( Supplemental Appendix ). 29 , 125 , 189 Recently, Vasbinder et al 40 developed the Cardiovascular Registry in Bone Marrow Transplantation (CARE-BMT) score for cardiovascular risk stratification in adult autologous and allogeneic transplantation recipients. The model includes 8 variables available at the time of transplantation and was used to predict a composite of cardiovascular death, myocardial infarction, HF, stroke, AF, or flutter and sustained ventricular tachycardia at 100 days, 5 years, and 10 years after HCT. The model performed well in the validation cohort across both types of transplantation. Two genome-wide association studies identified single-nucleotide variations that were associated with an increased risk of both early (<1 year) 128 and late (≥1 year) 122 cardiomyopathy. However, external validation is needed to incorporate these into clinical risk prediction models.

Key Points

Baseline cardiovascular risk assessment should include a comprehensive history and examination, body mass index assessment, blood pressure measurement, lipid profile, and HbA 1c .

Twelve-lead electrocardiography and transthoracic echocardiography (or CMR) should be performed before HCT in all patients.

The decision to perform HCT in patients with an LVEF of 50% or less is based on expert consensus within individual transplant centers.

More research is needed to determine the utility of CPET before and after HCT.

Cardiovascular-specific risk scores have been developed but require validation and are not in routine clinical use.

Cardiovascular Care of HCT Recipients

The role of prehabilitation and rehabilitation in HCT

Patients who undergo HCT physically decondition because of the intensity of the treatment, potential complications, and prolonged bed rest (typically 4 weeks or more). There is limited evidence for any role of pharmacologic cardioprotection. The OVERCOME (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) trial showed a modest benefit of enalapril and carvedilol administered before chemotherapy, preventing a decline in LVEF of −3.1% at 6 months after chemotherapy. However, this endpoint was driven by patients who received chemotherapy for acute leukemia, not those who underwent autologous HCT for a variety of indications. 190

HCT recipients already have an increased risk of cardiovascular disease and mortality, and there has been interest in the role of physical exercise before (prehabilitation) and after (rehabilitation) HCT to attenuate this risk. Contemporary data surrounding exercise interventions have been summarized in reviews by Mohananey et al 185 and Scott et al. 191 Overall, exercise interventions improve aerobic capacity and muscle strength while increasing quality of life and reducing fatigue in HCT survivors.

Sarcopenia is common after HCT and is associated with reduced progression-free and overall survival. 192 , 193 Several studies have reported reduced loss of lean body mass with exercise interventions. 185 Classic cardiac rehabilitation (eg, following percutaneous coronary intervention or coronary artery bypass grafting) typically incorporates psychosocial assessment, lifestyle modification, and nutritional assessment. These components are highly relevant to the HCT population and should be incorporated into prehabilitation and rehabilitation programs.

The HCT cohort provides unique challenges regarding exercise prescription. These include defining the safe level and intensity of exercise for patients with bone lesions in myeloma and secondary metastasis from other malignancies, identifying the optimal location for exercise in patients at risk of neutropenia, defining the optimal duration and timing of exercise, and determining the best mix of aerobic and resistance training. More research is needed to generate exercise programs tailored to individual patients and their underlying disease, with supporting evidence that these programs improve quality of life and reduce cardiovascular disease and mortality in HCT survivors.

Management of toxicities

The management strategy for cardiovascular disease occurring in the HCT population is outlined in Table 3 . The acute management of cardiovascular complications is also discussed in a recent American Heart Association scientific statement. 194

Monitoring during the first 12 months and long-term surveillance

Given the increased incidence of cardiovascular complications across different patient cohorts, long-term surveillance is required for those deemed to be at high risk of complications. Recommendations for surveillance include the International Late Effects of Childhood Cancer Guideline Harmonization Group for childhood, adolescent, and young adult patients; the European Society of Cardiology (ESC) cardio-oncology guidelines; and individual position and scientific statements for the adult population. 19 , 194 , 202 , 203

Guidelines from the ESC and the American Society of Clinical Oncology recommend different surveillance strategies based on cardiovascular disease risk. 19 , 204 High-risk patients include those with allogeneic HCT, pre-existing cardiovascular disease, multiple poorly controlled cardiovascular risk factors, GVHD, previous cancer treatment including high doses of chest-directed radiotherapy, doxorubicin-equivalent dosages at 250 mg/m 2 or higher, and the use of alkylating agents or total body Irradiation during transplant conditioning. According to these expert consensus statements, all patients are recommended to have a physical examination, 12-lead electrocardiography, and a review of cardiovascular risk factors (including body mass index, blood pressure, lipids, and HbA 1c ) 3 and 12 months after HCT and then yearly thereafter. Those at high risk (ie, those with 1 or more of the high-risk features) are recommended to have a repeat transthoracic echocardiogram 12 months after HCT. 204 An additional echocardiogram at 3 months after HCT can be considered in high-risk patients as per ESC guidance. 19

Conclusions

The HCT population is at risk of a variety of cardiovascular complications. The risk varies between patients and is influenced by several factors including comorbidities, age, type of transplantation, and treatment before transplantation. Adult patients are susceptible to a variety of cardiovascular diseases, and it can be challenging to identify those at increased risk. The evidence for risk stratification based on LVEF measurement before HCT and biomarkers is weak, and many of the treatment recommendations for cardiovascular complications are extrapolated from general population guidance. Long-term follow-up is based on surveillance for cardiomyopathy and modification of cardiovascular risk factors. More prospective studies in the HCT population are needed to inform risk prediction and the short- and long-term management of cardiovascular complications.

Funding Support and Author Disclosures

Dr Dobson has received speaker fees from Bristol Myers Squibb, Cogora, and Boston Scientific outside the submitted work. Dr Wright has received consultancy and speaker fees from Boston Scientific and Medtronic outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Footnotes

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center .

Appendix

For supplemental tables, please see the online version of this paper.

Appendix

Supplemental Material

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