Several variables in the process of HCT can be associated with an increased risk of CVD. These include pre-transplant patient factors and co-morbidities, prior chemotherapy, high-dose conditioning chemotherapy, transplant-related medications, and GVHD itself.

Patients post-HCT are at increased risk for the development of cardiovascular factors such as metabolic syndrome including individual factors of hypertension, dyslipidemia, and type 2 diabetes mellitus [5,6,7]. Complications such as GVHD and its treatment may predispose allogeneic HCT compared to autologous HCT to these cardiovascular factors and longer-term cardiovascular events. Subsequent development of CVD in these patients can manifest most commonly as congestive heart failure, arrhythmias, and/or ischemic coronary artery disease.

Pre-Transplant Risk FactorsPatient Risk Factors

There are notable common shared risk factors between CVD and malignancy, including age, race/ethnicity, sex, lifestyle behavior, and genetic predisposition. HCT recipients often have elevated CV risk, as well as pre-existing CVD, particularly in an increasingly older and more co-morbid transplant population. The incidence of pre-HCT comorbidities such as hypertension, diabetes, and hyperlipidemia are reported to be as high as 25%, 5%, and 32% respectively [8, 9]. Pre-HCT risk factors are subsequently a strong predictor of post-HCT risk; several studies have demonstrated that conventional cardiovascular risk factors such as hypertension, obesity, dyslipidemia, and diabetes are significantly associated with increased risk of both early and late cardiac events [10,11,12].

Pre-Transplant Therapy

Direct cardiotoxicity from prior anthracycline chemotherapy exposure and radiation further predisposes patients to poor cardiovascular outcomes during and post-HC [13]. Armenian et al. demonstrated that a prior cumulative anthracycline dose ≥ 250 mg/m2, in conjunction with the presence of 2 or more comorbidities (specifically hypertension, renal insufficiency, and chronic lung disease) were significantly associated, up to a tenfold increased risk, with late cardiomyopathy and congestive heart failure [14].

Radiotherapy is also commonly used before HCT and can increase the risk of cardiac dysfunction, particularly when the heart is involved in the irradiation field. Pre-HCT exposure to chest radiation is associated with an increased risk of coronary artery disease (OR 9.5, P = 0.03) post-transplant [10, 15]. A retrospective study of long-term survivors of Hodgkin lymphoma exposed to radiation observed significant valvular defects in 42% of patients and conduction defects in 75% of patients. A peak oxygen uptake (VO2max) during exercise, a known predictor of mortality in heart failure, was significantly reduced (< 20 mL/kg/m2) in 30% of these long-term survivors. [16]

Although most data regarding pre-transplant therapy’s impact on transplant CV outcomes is with anthracyclines, it is also important to note that several novel and now commonly used agents have also been associated with cardiotoxicities. Agents such as bruton tyrosine kinase inhibitor and ibrutinib are associated with a 4.7-fold risk of atrial fibrillation and a 2.8-fold risk of hypertension [17, 18]. Proteasome inhibitors, classically part of the backbone of induction chemotherapy for multiple myeloma before transplant, have also been shown to be commonly associated with adverse cardiovascular events, with heart failure being the most common, followed by hypertension [19]. Immune checkpoint inhibitors (ICI) are increasingly used for hematologic malignancies, particularly in the relapsed/refractory setting, which may also be an indication for transplant. A recent retrospective study reported by Lin et al. observed an incidence of adverse cardiac events with ICIs of 12.5%, with the most common events being arrhythmias (9.3%), followed by myocarditis (2.1%), acute myocardial infarction (1.7%), pericarditis (1.2%), and cardiomyopathy (0.9%) [20]. The impact on subsequent post-HCT CVD outcomes, however, remains largely unknown.å

Pre-HCT Cardiac Risk AssessmentComorbidity Evaluation

The pre-transplant evaluation incorporates the HCT Comorbidity Index (HCT-CI), developed by Sorror in 2005, which scores 17 organ-specific comorbidities, including several cardiovascular (CV) conditions, to predict non-relapse mortality post-transplant [21]. This tool, validated in numerous studies, includes arrhythmia, congestive heart failure (CHF), coronary artery disease (CAD), cerebrovascular disease, valvular disease, diabetes, and obesity among its CV risk factors. Recent analyses have highlighted pre-transplant diabetes and CV disease as key predictors of non-relapse mortality, emphasizing the impact of pre-existing CV conditions on transplant outcomes [21,22,23,24, 7].

Cardiovascular Risk Stratification

The primary goal of pre-transplant assessment is to identify high-risk CV diseases through thorough history-taking and physical examination to determine a recipient's fitness to endure the HCT process, acknowledging the potentially cardiotoxic nature of conditioning regimens, rapid volume shifts, and increased oxygen demands. Studies have shown an increased risk of cardiovascular complications at an earlier age (median age 54) among hematopoietic cell transplantation (HCT) survivors, emphasizing the critical role of pre-existing conditions, and therapeutic exposures (notably anthracyclines), in elevating this risk. [7, 25, 26]

Risk factors are categorized into non-modifiable, such as age—with associations showing a 1.6–1.8-fold increased risk of cardiac dysfunction in patients over 60 treated with anthracyclines and/or trastuzumab—and modifiable, including hypertension, diabetes, dyslipidemia, obesity, and smoking [26]. Among HCT survivors treated with high-dose anthracyclines, Armenian et. al. reported up to fivefold risk of heart failure compared to age- and sex-matched individuals from the general population and additionally increased with pre-existing conditions, hypertension, and diabetes [7].

It underscores the importance of aggressive screening and management of cardiovascular risk factors, given the observed under-treatment of conditions like hypertension, dyslipidemia, and diabetes post-transplant. The findings advocate for tailored intervention strategies, including prospective studies to assess the effectiveness of standard cardiovascular risk management in HCT survivors. The necessity of lifestyle modifications to mitigate cardiovascular morbidity is also noted, alongside the challenges in tracking late adverse effects due to survivor mobility. [27]

Diagnostic Tools and Treatments

Echocardiography assesses cardiac function, including ejection fraction and valvular health, but may not detect early signs of cardiovascular function and coronary artery narrowing [7]. Additional evaluations might include resting electrocardiograms, computed tomography for coronary and aortic calcifications, and more specialized tests like coronary CT angiography or myocardial perfusion testing for those at high risk [7, 25]. Additional research is required to investigate the role of standardizing cardiac evaluation.

The American Society of Clinical Oncology (ASCO) underscores the importance of comprehensive history and physical examinations for patients previously treated with cardiotoxic drugs, advocating for regular evaluation of cardiovascular risk factors such as smoking, hypertension, diabetes, dyslipidemia, and obesity [26]. Heart-healthy lifestyle modifications are encouraged, alongside echocardiograms at 6- and 12-months post-cancer therapy for asymptomatic patients at increased cardiac risk [26].

For symptomatic individuals, a shared medical decision-making approach is recommended, with options including cardiac MRI or MUGA scans if echocardiography is not feasible. Early detection of cardiac dysfunction via serum cardiac biomarkers, such as troponins and natriuretic peptides, is advised, with referrals to cardiologists for patients exhibiting cardiac dysfunction. Elevations in cardiac markers may precede findings on echocardiogram. Recommendations extend to aerobic training for disease prevention and management, given its benefits on blood pressure, lipid levels, and insulin sensitivity.

Pre-HSCT treatment focuses on optimizing current cardiac conditions and addressing reversible diseases due to prolonged survival and treatment-induced late-occurring morbidity and mortality from cardiac causes [26].

Suggested interventions to mitigate the cardiovascular risk are prophylactic therapy before and during HCT to prevent anticipated injury; primary intervention by providing therapy to treat and prevent early signs of myocardial and/or cardiac vascular damage; secondary prevention by providing therapy after the detection of LVEF decline, and tertiary treatment by providing therapy after detection of heart failure or coronary artery disease [26]. Atorvastatin is a statin that is widely used to treat hyperlipidemia and has been studied on the risk of development of cardiac dysfunction. A double-blinded randomized clinical trial demonstrated that lymphoma patients receiving anthracycline-based chemotherapy treated with atorvastatin demonstrated a reduction of the incidence of cardiac dysfunction [28]. Similarly, sodium-glucose co-transported 2 inhibitors (SGLT2) demonstrated efficacy in patients with cancer therapy-related cardiac dysfunction or heart failure by demonstrating decreased heart failure exacerbation and all-cause mortality [29]. Management of cardiac dysfunction by chemotherapy has been studied but additional studies are required particularly for transplant patients due to their unique risk factors.

Aerobic training is a cornerstone of disease prevention and treatment and decreases lipids, improves insulin sensitivity, and lowers blood pressure [7]. HSCT recipients require an average of 4 or more weeks of inpatient hospital stay which leads to muscle loss and decreased exercise capacity impacting cardiopulmonary fitness. Given the propensity of deconditioning among HSCT patients due to treatment-related complications, the American College of Sports Medicine (ACSM), recommends home-based exercise regimens, allowing recovery of the immune system before returning to gym facilities [30]. Studies indicate that initiation of exercise before and during transplantation can be safely performed [30]. Physical therapy leads to higher rates of engraftment and shorter duration of total parenteral nutrition as well as a decreased need for blood transfusions [30]. Contraindications to exercise include but not limited to are unstable angina, decompensated heart failure, ventricular arrhythmia, pulmonary hypertension, and severe valve disease but referral to cardio-oncology can result in referral to cardiac rehabilitation which is in a supervised environment [30].

Post-Transplant Cardiac Events

Cardiac events post-hematopoietic cell transplantation (HCT) are generally categorized based on their occurrence: early (within 100 days) and late (> 100 days post-transplant). Conditioning-regimen-mediated damage to the neurohormonal system and vascular endothelium as well as immunological and inflammatory effects of allografting predispose to the development of cardiovascular disease. Atrial fibrillation has been highlighted as a major post-transplant concern, with studies by Tonorezos et al. and Chang et al. illustrating its association with increased mortality risk [22, 31, 32]. Additional complications include pericarditis, dyslipidemia, type 2 diabetes mellitus, valvular heart disease, and right ventricular systolic dysfunction, underscoring the need for vigilant cardiovascular monitoring and intervention [33,34,35,36,37,38,39].

Graft-versus-host disease (GVHD) has been linked to the development of cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia. Rackley et al. identified acute GVHD as independently associated with hypercholesterolemia and hypertriglyceridemia post-allogeneic transplant [40]. Its inflammatory nature also correlates with increased thrombosis risk and potential microvascular disease exacerbation [41]. Pharmacologic therapy for the prevention and treatment of GVHD may also have an impact on cardiovascular complications. GVHD prevention standards include steroids, calcineurin inhibitors (tacrolimus/cyclosporine), sirolimus, and methotrexate or mycophenolate. Sirolimus may elevate hypertriglyceridemia and hyperlipidemia risk, while mycophenolate mofetil (MMF) and corticosteroids have been linked to hyperlipidemia [42]. High-dose post-transplant cyclophosphamide (PT-Cy) has also emerged as an effective GVHD prevention strategy [41], but also has been associated with cardiotoxicity, although data can be conflicting. Medications like ruxolitinib and ibrutinib used to treat acute and chronic GVHD have been associated with a 4.7–5.8-fold increase in atrial fibrillation risk and a 2.8-fold increase in hypertension and hyperlipidemia risk, respectively [41].

PT-Cy use decreases the incidence of GVHD but has been suggested to be associated with cardiac events within the first 100 days post-transplantation, negatively impacting overall survival. Historically, Cy-related acute cardiotoxicity, which includes endothelial injury, arrhythmias, and heart failure, often occurs within 10 days of administration. Dulery et al. found that the incidence of early cardiac events was significantly higher in patients receiving post-transplant cyclophosphamide (PT-Cy) at 19%, compared to 6% in those who did not [37]. These events encompassed left ventricular systolic dysfunction, acute pulmonary edema, pericarditis, arrhythmias, and acute coronary syndrome. Risk factors for increased early cardiac event incidence included PT-Cy administration, advanced age, a sequential conditioning regimen, and prior cyclophosphamide exposure before HCT37 [37, 38]. Additional data is needed to further understand the potential increased cardiotoxicity with PT-Cy but underscores the importance of careful monitoring with PT-Cy in higher-risk patients.

Studies investigating PT-Cy-associated cardiac toxicity illustrate the challenges in evaluating and mitigating cardiac risk among stem cell transplant recipients [39, 40]. Two studies by Yeh et al. and Perez-Valencia et al. investigated the cardiac toxicities following allogeneic HCT and the use of PT-Cy for GVHD prophylaxis [38, 39]. Yeh et. al., studied 585 patients and found a 6.5% incidence of cardiac toxicities post-allo-HCT, slightly higher in PT-Cy recipients (7.4%) compared to non-PT-Cy recipients (5.8%) [39]. Significant predictors of cardiac toxicity included age over 55 and pre-existing conditions such as hypertension and diabetes. This toxicity correlated with poorer one-year survival outcomes, although PT-Cy use was also linked to some improvement in outcome as well [39, 40]. The Perez-Valencia et al. study reported an 8.4% incidence of early cardiac events (ECEs) within 180 days post-transplant, with a higher incidence in patients receiving PT-Cy, particularly when combined with TBI [38]. ECEs, including heart failure and pericardial complications, were associated with higher mortality and lower survival rates. Both studies highlight the importance of cardiac risk assessment and monitoring in patients undergoing allo-HCT with PT-Cy, especially when combined with TBI [38, 39].

Early Cardiac Events

Atrial fibrillation and atrial flutter are the most common cardiac events occurring within the first 100 days of HCT, with an estimated incidence of 2–10% [14,15,16,17,18]. Congestive heart failure has also been reported as a predominant early post-transplant complication with an incidence of 2.2% [43,44,45]. While arrhythmias are associated with longer-term 1-year mortality, acute cardiovascular death from any cause is rare [24]. Other cardiovascular events such as pericardial effusion, pericarditis, and myocarditis are also uncommon (< 1%) but are associated with inferior survival [26, 46, 47].

Several studies have demonstrated risk factors associated with early cardiovascular events [26, 46, 47]. Patients with an ejection fraction of less than 50% had 5.3 higher odds of a cardiovascular event within the first 100 days than patients with an ejection fraction of > 60% (p = 0.02) [43]. While patients aged ≥ 55, hypertension and a history of cardiovascular disease, arrhythmia, and diabetes were noted to be significant predictors of the development of cardiac toxicity by day 100 after allogeneic HCT; of note, the cardiac toxicity did not significantly vary between patients receiving PT-Cy and non-PT-Cy GVHD prophylaxis [39]. The underlying pathophysiology for early cardiac complications is multifactorial but can be attributed to inflammation, oxidative stress, calcium homeostasis alteration, and programmed cell death mechanisms which lead to endothelial dysfunction, myocardial damage, apoptosis, and calcium overload [48]. Specifically in allogeneic HCT, the release of proinflammatory cytokines in GVHD can lead to leukocyte activation, endothelial injury, and vascular leakage which can lead to cardiac complications such as arrhythmias as well as the rare occurrences of pericardial effusion and pericarditis [48, 49].

The incidence of short-term cardiovascular events was similar between myeloablative, reduced intensity, and nonmyeloablative conditioning regimens among allogenic recipients [26]. Prior exposure to anthracycline of 250 mg/m2 was associated with increased short-term cardiovascular events among autologous recipients compared to allogenic recipients [26].

Late Cardiac Effects

Advancements in transplantation and supportive care have led to an increase in long-term HCT survivors but also revealed late adverse effects, notably cardiovascular disease, and metabolic syndrome. The leading causes of non-disease-related mortality among HCT survivors are solid tumor malignancies and cardiopulmonary diseases [50]. In the Bone Marrow Transplant Survivor Study, the risk of premature cardiovascular-related death following HCT was 2.3-fold for allogenic HCT recipients and 1.3 for autologous HSCT recipients compared to the general population [47, 49]. In a retrospective cohort study of both autologous and allogeneic HCT recipients compared to age-matched controls from the general population by Chow et al., several risk factors for increased risk of cardiovascular death were identified, including age ≤ 60 years at the time of transplant, mobilized peripheral blood stem cells, relapse of the primary disease, as well as the presence of multiple risk factors, (e.g. hypertension, dyslipidemia, diabetes, and renal disease) [49]. HCT recipients had greater all-cause mortality compared to the general population comparator group with an incidence rate difference of 39.1 (95% CI, 33.7–44.6) and cardiovascular death with an incidence rate difference 3.6 (95% CI 1.7–55) [49].

The prevalence of cardiovascular risk factors was also found to be significantly higher among HCT patients compared with the general population in a study by Armenian et al., as such that 10 years post-HCT the incidence of hypertension was 37.7%, diabetes 18.1%, and dyslipidemia 46.7% [47]. De-novo development of hyperlipidemia and hypertriglyceridemia following allo-HCT was estimated at 43–73% [47]. This is further pronounced with pre-existing cardiovascular risk factors, significantly elevating the risk of CVD, with a five-fold increase for a single factor and a 20-fold increase for multiple factors [51] Even controlling for age, cardiotoxic therapeutic exposures, and stem cell source, patients with multiple cardiovascular risk factors were at 1.5-fold higher risk of developing CVD [41,