Cardiovascular disease in survivors of hematopoietic cell transplantation

Abstract

Hematopoietic cell transplantation (HCT) is increasingly offered as a curative option for many patients with hematologic malignancies. Improvements in HCT strategies and supportive care have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing long-term debilitating chronic health conditions, including premature cardiovascular disease. These complications are more common than in the general population, and there are well-described associations between therapeutic exposures, traditional cardiovascular risk factors and subsequent cardiovascular disease risk. We present here an overview of the current state of knowledge regarding pathogenesis and risk factors for some of the more commonly occurring cardiovascular complications following HCT, highlighting existing surveillance recommendations and future directions for research to minimize cardiovascular morbidity in these survivors.

INTRODUCTION

Hematopoietic cell transplantation (HCT) is frequently offered as a curative option for a variety of malignant and benign conditions.¹ Improvements in HCT strategies and supportive care have contributed to an incremental improvement in survival of 10% per decade.^2–4 However, improved overall survival rates do not necessarily translate to full restoration of health. The growing population of long-term survivors has brought to the medical forefront chronic, debilitating conditions attributable to toxicity from pre-HCT exposures, HCT conditioning regimens, and graft versus host disease (GvHD).^5–7 These conditions include subsequent malignant neoplasms, cardiopulmonary dysfunction, endocrine dysfunction, chronic kidney disease, cataracts, osteonecrosis, and impairment in functional status due to persistent, chronic GvHD.^5–7

A recent report from the Bone Marrow Transplant Survivors Study (BMTSS) cohort reported that two out of three HCT survivors will develop a chronic health condition, and more than one-third will develop a condition that is severe/life-threatening, or fatal.⁵ The BMTSS cohort consists of 1022 individuals who received HCT at City of Hope or the University of Minnesota between 1974 and 1998, survived at least 2 years after transplantation, and completed a comprehensive questionnaire regarding a wide range of health-related outcomes; 309 siblings were recruited as a comparison group.^{5, 8} Compared with siblings, HCT survivors were twice as likely to develop a chronic health condition, and 3.5-times to develop severe/life-threatening conditions. Survivors with a history of chronic GvHD were nearly 5-times as likely to develop severe/life-threatening conditions.⁵

One of the more serious adverse events encountered in HCT survivors is the development of late-occurring cardiovascular events.^9–13 Table 1 provides an overview of these events, which include arterial disease (cerebrovascular disease [stroke, transient ischemic attack, cerebral arterial occlusion, symptomatic lacunar infarcts], coronary artery disease [myocardial infarction, atherosclerotic heart disease, angina pectoris]) or cardiac disease (cardiomyopathy, congestive heart failure [CHF], valvular disease, conductive abnormalities, and constrictive pericarditis). These complications are more common than expected,^{13, 14} and often occur earlier than would be expected for the general population.^{11, 12} In a recently conducted registry-based study, HCT survivors had significantly greater cumulative incidence and relative risk of cardiovascular death (incidence rate difference, 3.6, 95% CI 1.7–5.5; hazard ratio 3.4, 95% CI 2.1–5.4, respectively) when compared to sex- and age-matched individuals from the general population.¹³ Absolute differences and relative hazards were similarly increased for specific hospitalized complications, such as ischemic heart disease, cardiomyopathy/heart failure, stroke, other vascular diseases, and rhythm disorders.¹³ These findings are in line with other studies that have reported a 2–4 fold increased risk of cardiovascular death among HCT survivors compared with the general population.^{2, 15}

Table 1.

Characteristics of late-occurring cardiovascular disease (CVD) in HCT survivors

	Arterial disease	Cardiac disease
Cardiovascular complications	Cerebrovascular disease (stroke, transient ischemic attack, cerebral arterial occlusion, symptomatic lacunar infarctions) Coronary artery disease (myocardial infarction, atherosclerotic heart disease, angina pectoris)	Cardiomyopathy, Congestive heart failure Constrictive pericarditis Valvular heart disease Conduction abnormalities
HCT recipients at highest risk	Allogeneic HCT survivors	Autologous HCT survivors
Median time to CVD from HCT	4–9 years	2–3 years
Median age at first CVD	48–54 years old	50–52 years old
Clinical risk factors	Older age at HCT Cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity)	Female sex Cardiovascular risk factors (hypertension, diabetes)
Pre-HCT therapeutic risk factors	Radiation (Cerebrovascular disease - cranial, cervical; Coronary artery disease – chest)	Anthracycline chemotherapy Radiation (chest)
HCT-related risk factors	Graft versus host disease	-

We present here an overview of the current state of knowledge regarding pathogenesis and risk factors for some of the more commonly occurring cardiovascular complications following HCT, highlighting existing surveillance recommendations and future directions for research to minimize cardiovascular morbidity in HCT survivors.

ARTERIAL DISEASE

Arterial disease in the transplant setting is related to an accelerated atherosclerotic process, attributed to pre-HCT and conditioning-related radiation, and compounded by the development of cardiovascular risk factors ([CVRFs]: hypertension, diabetes, dyslipidemia) in the early post-HCT period.^{16, 17} Atherosclerosis is primarily an inflammatory process where endothelial injury occurs decades before the clinical presentation of disease.^18–20 The cumulative incidence of arterial events such as clinically overt coronary artery disease or stroke among allogeneic HCT recipients is 10% at 15 years, and the risk exceeds 20% at 20 years.^{11, 12} In this population, median age at first myocardial infarction is as low as 53 years (range 35–66 years),^{10, 21} much earlier than would be expected for the general population (67 years)²² or that reported for autologous HCT survivors (61 years).^{10, 21}

The risk of developing CVRFs such as hypertension, diabetes, and dyslipidemia is especially high in allogeneic HCT recipients when compared to autologous HCT recipients as well as age- and sex-matched individuals in the general population.^{21, 23} In a recent retrospective cohort study,²¹ the ten-year cumulative incidence of hypertension, diabetes, and dyslipidemia in allogeneic HCT recipients was 37.7%, 18.1%, and 46.7%, respectively; the risk for multiple (≥2) CVRFs approached 40% (compared to 26% in autologous HCT survivors).

Conditioning with TBI has been associated with an increased risk for dyslipidemia and diabetes in pediatric^{24, 25} and adult²³ HCT survivors. The mechanism by which TBI increases the risk of these CVRFs is not clear. Previous studies in conventionally treated cancer survivors have shown that abdominal radiation may contribute to insulin resistance and/or metabolic syndrome, suggesting a role for radiation-induced pancreatic or hepatic injury.^{26, 27} The increased risk of diabetes and dyslipidemia among HCT survivors treated with TBI could potentially be due to the combined effects of abdominal radiation and post-HCT gonadal dysfunction.²⁸

Drugs used to manage GvHD can also increase the risk of CVRFs. Dyslipidemia has been reported in up to 80% of solid-organ transplantation patients on immunosuppressive agents, and insulin resistance and hypertension are frequently encountered side-effects of GvHD medications such as corticosteroids and calcineurin inhibitors.^{29, 30} History of GvHD has been associated with increased risk for all three CVRFs (hypertension: RR=9.1, p<0.01; diabetes: RR=5.8; p<0.01 dyslipidemia: RR=3.2, p<0.01).²¹ The risk of arterial disease is highest in patients with multiple CVRFs (cumulative incidence [CI]: 10–12% at 10 years);^{12, 21} pre-HCT exposure to cardiotoxic therapies including chest radiation further increases this risk to 15% at 10 years post-HCT.

Radiation-induced vascular injury is characterized by endothelial cell proliferation, intimal thickening, medial scarring, lipid deposits and adventitial fibrosis.³¹ In addition, chronic GvHD can lead to microvessel disease caused by the infiltration of alloreactive cytotoxic T lymphocytes.³² Biomarkers of endothelial injury such as von Willebrand Factor (vWF) show a close relation to chronic GvHD, suggesting that an immunological mechanism may contribute to the development of atherosclerosis in this population.^{32, 33} The already high prevalence of CVRFs in allogeneic HCT survivors likely accelerates the process of atherogenesis initiated by endothelial injury due to exposure to ionizing radiation, and/or chronic GvHD.^{16, 21} Taken together, these data form the basis of screening strategies for targeted surveillance as well as more aggressive management of cardiovascular risk factors.

CARDIAC DISEASE

Congestive heart failure (CHF) is a well-described occurrence during the immediate post-HCT period.^34–36 Mortality attributed early CHF ranges from 1% to 9%, whereas morbidity ranges from 5% to 43%. Risk factors for early CHF include reduced pre-HCT ejection fraction (EF), conditioning with high-dose cyclophosphamide (HD-CY) and TBI.^34–37 Information related to late-occurring CHF (1+ year post-HCT) is now emerging, and the risk appears to be especially high for autologous HCT recipients – cumulative incidence estimated at 5% at 5 years, approaching 10% at 15-years post-HCT.¹⁴ Autologous HCT survivors are at a nearly fivefold risk of CHF when compared to age- and sex-matched individuals from the general population.¹⁴ Outcome following post-HCT CHF is poor, with less than 50% surviving five years after diagnosis of CHF.^{9, 14}

Studies have demonstrated that the risk of late-occurring CHF is primarily due to pre-HCT exposure to anthracyclines.^{9, 14} Anthracycline-related cardiotoxicity is dose-dependent, and there are well-established factors that modify this association, such as young age at exposure to anthracyclines, being female, and radiation to the chest. The underlying mechanism for the higher risk of anthracycline-related CHF in female cancer survivors is not clear. Differences in body composition between males and females could alter the disposition, and hence metabolism of anthracyclines, since the drug does not reach a high concentration in adipose tissue.^{38, 39} For females with higher percentage of body fat for the same body surface area, equivalent doses of anthracyclines could lead to greater concentrations in non-adipose tissues such as the heart and lead to more cardiotoxicity than their male counterparts. Lastly, as in arterial disease, the risk of anthracycline-related cardiotoxicity increases significantly among those who develop conventional CVRFs such as hypertension and diabetes.^{13, 14, 17, 21, 40}

Hypertension is the most common risk factor for CHF in the general population, and carries the highest population attributable risk for CHF.⁴¹ In animal models, there is evidence that hypertension may accelerate chronic myocardial injury known to occur after anthracycline exposure.⁴² On the other hand, the pathophysiology of CHF in survivors with diabetes is more complex and may be caused by unrecognized (silent) myocardial infarction or metabolic derangement due to hyperglycemia.⁴³ In a recent study,¹⁴ the presence of hypertension among survivors with past exposure to high-dose anthracyclines (≥250 mg/m²) was associated with a 35-fold increased risk of CHF, and the risk was nearly 27-fold for those who developed diabetes when compared to survivors without these health conditions. The findings from this study provide further evidence that CVRFs are important modifiers of CHF risk, highlighting target populations for aggressive intervention.

These clinical modifiers notwithstanding, there are also emerging data to suggest that there is marked inter-individual variability in the risk of anthracycline-related CHF after HCT. The pathogenesis of anthracycline-related CHF includes oxidative stress and intracardiac metabolic derangements induced by anthracycline metabolites that are known to be cardiotoxic.^{44, 45} Susceptibility due to inherited genetic variation in these pathways could explain the inter-individual variability in risk of anthracycline-related CHF. Using a candidate gene approach, a recent study⁴⁶ identified variants in genes involved in free radical generation (RAC2), iron homeostasis (HFE), and anthracycline metabolism (ABCC2) to be independent predictors of post-HCT CHF risk. In fact, a combined clinical (female sex, hypertension, pre-HCT chest radiation exposure) and genetic (RAC2 [rs13058338], 7508T→A; HFE [rs1799945], 63C→G; ABCC2 [rs8187710], 1515G→A) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone, accurately predicting the likelihood of CHF in up to 80% of HCT survivors in the study.⁴⁶ These data, when confirmed in an independent cohort, could form the basis for novel approaches for prevention in at-risk HCT survivors; these would include targeted screening (e.g. female sex, pre-HCT chest radiation exposure, presence of at risk genotype), behavior modification (e.g. adoption of healthy lifestyle, aggressive management of CVRFs such as hypertension), and early pharmacologic intervention (ACE inhibitors or beta blockers) for high risk survivors with early evidence of cardiac dysfunction after HCT.

Other cardiac complications reported in HCT survivors include constrictive pericarditis, valvular heart disease, and conduction abnormalities.^{13, 17} The risk for many of these conditions is due to past exposure to chest radiation. In conventionally treated survivors of Hodgkin lymphoma treated with chest radiation, up to 60% have been reported to have valvular fibrosis or insufficiency, while conduction defects are present in as many as 75%.⁴⁷ A recent report from a large cohort of long-term HCT survivors found that the cumulative incidence of conduction abnormalities approached 10% at 10 years post-HCT, and this incidence was significantly greater than that of matched controls (3.5%, p<0.001).¹³ The cumulative incidence for conduction disorders as well as many other cardiovascular complications continued to increase years after HCT, highlighting the importance lifelong surveillance in this growing population of high risk survivors.

CURRENT RECOMMENDATIONS FOR LONG-TERM MONITORING

Given the increased burden for serious cardiovascular and other organ system morbidity following HCT, various recommendations for long-term health monitoring relevant to HCT survivors have been issued. These include international consensus-based guidelines from HCT-specific professional organizations,⁴⁸ as well as from pediatric oncology groups that address unique HCT-related exposures.^{49, 50} Select screening recommendations, including those issued by the US Preventative Services Taskforce⁵¹ for the general population, are included in Table 2.

Table 2.

ACC/AHA recommendations for cardiac and vascular tests for cardiovascular disease risk assessment in asymptomatic adults

Resting electrocardiogram	A resting electrocardiogram is reasonable for cardiovascular risk assessment in asymptomatic adults with hypertension or diabetes (Class IIa recommendation). A resting ECG may be considered for cardiovascular risk assessment in asymptomatic adults without hypertension or diabetes (Class IIb recommendation).
Transthoracic echocardiography	Echocardiography to detect LVH may be considered for cardiovascular risk assessment in asymptomatic adults with hypertension (Class IIb recommendation). Echocardiography is not recommended for cardiovascular risk assessment in asymptomatic adults without hypertension (Class III recommendation: no benefit).
Carotid Intima-Media Thickness on Ultrasound	Measurement of carotid artery IMT is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk. Published recommendations on required equipment, technical approach, and operator training and experience for performance of the test must be carefully followed to achieve high quality results (Class IIa recommendation).
Brachial/Peripheral Flow- Mediated Dilation	Peripheral arterial flow-mediated dilation studies are not recommended for cardiovascular risk assessment in asymptomatic adults (Class III: no benefit).
Pulse wave velocity and other arterial abnormalities: measures of arterial stiffness	Measures of arterial stiffness outside of research settings are not recommended for cardiovascular risk assessment in asymptomatic adults (Class III: no benefit).
Ankle-brachial index	Measurement of ABI is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (Class IIa recommendation).
Exercise electrocardiography	An exercise ECG may be considered for cardiovascular risk assessment in intermediate-risk asymptomatic adults (including sedentary adults considering starting a vigorous exercise program), particularly when attention is paid to non-ECG markers such as exercise capacity (Class IIb recommendation).
Stress echocardiography	Stress echocardiography is not indicated for cardiovascular risk assessment in low- or intermediate-risk asymptomatic adults (Class III recommendation: no benefit).
Myocardial perfusion imaging (MPI)	Stress MPI may be considered for advanced cardiovascular risk assessment in asymptomatic adults with diabetes or asymptomatic adults with a strong family history of CAD or when previous risk assessment testing suggests high risk of CAD, such as a CAC score of 400 or greater (Class IIa recommendation). Stress MPI is not indicated for cardiovascular risk assessment in low- or intermediate-risk asymptomatic adults (Class III recommendation: no benefit).
CT-based imaging	Measurement of CAC is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10% to 20%10-year risk); Class IIa recommendation Measurement of CAC may be reasonable for cardiovascular risk assessment in persons at low to intermediate risk (6% to 10% 10-year risk); Class IIb recommendation Persons at low risk (<6% 10-year risk) should not undergo CAC measurement for cardiovascular risk assessment; Class III recommendation: no benefit.
Magnetic resonance imaging (MRI) of plaque	MRI for detection of vascular plaque is not recommended for cardiovascular risk assessment in asymptomatic adults (Class III recommendation: no benefit).

Recommendations: Class I – benefit⋙risk; procedure should be performed. Class IIa – benefit≫risk; additional studies with focused objectives needed; it is reasonable to perform procedure. Class IIb –benefit ≥ risk; additional studies with broad objectives needed; additional registry data would be helpful; procedure may be considered. Class III – no benefit, may cause harm.

It is important to note that different evidence standards may have been applied to the creation of these guidelines. HCT and oncology-specific guidelines often lack the same degree of high-quality evidence that is required to inform US Preventative Services Taskforce guidelines for the general population. HCT/oncology-guideline recommendations are more likely to be based on retrospective observational studies focused on studying disease incidence and risk factors rather than optimal screening strategies.⁴⁹ At the same time, given the unique exposures experienced by HCT survivors, many elements of general population oriented guidelines are inadequate, particularly as some cardiovascular outcomes are unique to HCT and cancer survivors. For example, anthracycline-related cardiomyopathy, for which long-term screening with echocardiograms or other imaging modality is recommended by professional societies,^52–54 would not be discussed by general population screening guidelines. Exposures and outcomes related to radiotherapy exposures would similarly not be covered by general population guidelines. As a result, clinicians should carefully review the targeted populations in each of the guidelines prior to any implementation into routine clinical practice.

The cost-effectiveness and cost-utility of various screening strategies may also differ significantly based on the specific population referenced.^{55, 56} While the assumption behind screening is that detection of subclinical disease would result in interventions that may delay or even prevent the onset of clinically apparent disease, this hypothesis has not been tested among HCT and cancer survivors. As such, oncology/HCT-specific recommendations typically have had to rely on expert consensus when determining surveillance strategies.^48–50 A discussion of more specific screening methods for both arterial and cardiac disease follows.

FUTURE DIRECTIONS: EARLY SCREENING AND DETECTION

Arterial disease

In the general population, primary prevention of arterial disease such as coronary artery disease (CAD) is often guided by a cluster of laboratory and clinical risk factors (e.g. Framingham Risk Score [FRS]) that categorizes individuals as being at low-, intermediate-, or high-risk for CAD according to 10-year CAD risk (low: <10%, intermediate: 10–20%, high: >20% risk).²² However, while clear recommendations exist for those at high risk (pharmacologic interventions) and low risk (life-style modification), the guidelines for prevention strategies are imprecise for individuals who are at intermediate risk (i.e., whether this group qualifies for pharmacologic interventions in addition to life-style modifications).²² It is important to note that the risk of CAD among allogeneic HCT recipients on average is comparable to individuals in the general population with low to intermediate risk, with select subgroups having much higher risk.^{11–13, 21} As mentioned earlier, HCT survivors also appear on average to develop CAD at an earlier age than in the general population, requiring heightened awareness among clinicians.^{10, 21} Cardiac catheterization has long been considered the gold standard for assessing diseased arteries. However, it has limited value in screening for asymptomatic disease because, although it accurately depicts vessel lumen size, it is invasive, and cannot detect significant plaque accumulation in the absence of stenosis.^{57, 58} This has led the development of less invasive methods, reviewed below.

Computer tomographic (CT)-based imaging: in non-oncology populations, CT-based imaging (coronary artery calcium scoring, CT angiography [CTA]) has emerged as an accurate, non-invasive measure of CAD risk in the intermediate group, helping to identify individuals with higher risk who may warrant more aggressive (e.g.: pharmacologic) therapy, while limiting interventions to lifestyle measures alone in those at lower risk.^{57, 58}

Over the last decade, multiple retrospective cohort studies have demonstrated the strong independent prognostic value of coronary artery calcium in predicting CAD events.²² As a result, the recent American College of Cardiology Foundation/ American College of Cardiology Guidelines for assessment of cardiovascular risk in asymptomatic individuals contain, for the first time, a Class IIa (benefit ≫ risk) indication for coronary artery calcium in screening intermediate risk individuals.²² Screening with coronary artery calcium is associated with a decrease in downstream health related costs when compared to no screening (37% and 25% reduction in invasive procedures and medication costs, respectively).⁵⁹ Lipid-lowering therapy based on an arterial calcium score (>400) has also been shown to significantly lower the incidence of cardiovascular events (8.7% vs. 15%, p<0.05) when compared to placebo,⁶⁰ independent of other cardiovascular risk biomarkers such as CRP.

CT-angiography (CTA) allows a more direct, yet still non-invasive, measurement of total plaque in the coronary arteries.^{57, 58} Each of the 17 coronary segments are visually assessed and classified on the basis of stenosis severity, and each plaque is classified as calcified, non-calcified, or mixed. As discussed above, while the extent of coronary artery calcification provides valuable prognostic information regarding CAD risk, significant atherosclerosis may be present in the absence of calcium.^{19, 20} Non-calcified plaque, unlike calcified plaque, results in outward remodeling of the vessel wall, causing ulceration and subsequent plaque disruption.²⁰ CTA enables visualization of ulcerated lesions as well as accurate assessment of plaque morphology. There is a paucity of studies evaluating the utility of coronary artery calcium or CTA in assessment of coronary atherosclerosis in cancer survivors at high risk for CAD. This lack of information has, in turn, impeded the routine clinical use of these screening strategies in survivors at highest risk for CAD.

Recognizing the limitations in resources and availability of diagnostic procedures across treatment centers, organizations such as the ACC/AHA have established recommendations²² for alternative screening strategies in asymptomatic individuals at risk for CAD. These recommendations take into consideration the FRS risk classification of the individual as well as specific comorbidities that may modify their overall risk (Table 2). As in CT-based imaging, the prognostic utility of many of these diagnostic tests in HCT survivors is not known, and their role in routine CAD surveillance in this population remains to be determined.

Blood biomarkers

Extensive research supports the use of certain blood biomarkers for CAD risk prediction in non-oncology populations.⁶¹ Increased high-sensitivity C-reactive protein (hs-CRP) levels are associated with CAD risk across a wide age range and in different ethnic groups.⁶¹ While the predictive power of hs-CRP is partially affected by conventional risk factors such as hypertension, diabetes, obesity, or inflammatory processes (e.g.: infection, GvHD), it may play a role in further stratifying individuals at lowest risk for CAD.⁶¹ Hs-CRP <1 μg/ml in conjunction with low CAC score (<100) has been used to reclassify individuals into “very low risk” categories.^{62, 63} Other markers of endothelial injury such as vWF may provide additional insight into the etiopathogenesis of vascular injury in HCT survivors. Vascular endothelial cells have been recognized as an important target for alloreactive cytotoxic T-lymphocytes in patients with GvHD.³³ Studies in small numbers of HCT patients have shown that chronic GvHD can result in decreased microvessel density and loss of microvessels - changes that correlate with increased vWF from endothelial cells.^{17, 33} Future studies will need to evaluate the predictive value of blood biomarkers such as hs-CRP or vWF for identification of early arterial disease in HCT survivors with either resolved or ongoing GvHD, facilitating the implementation of novel prevention strategies in high risk subsets of survivors.

Cardiac disease

It is increasingly recognized that therapy-induced CHF is a progressive disorder, with a variable period of asymptomatic left ventricular (LV) dysfunction that precedes clinically overt CHF.⁴⁰ Traditionally, detection of anthracycline-related cardiotoxicity has relied upon echocardiographic screening using resting EF and shortening fraction (SF).⁶⁴ However, these parameters are derived from crude ventricular measurements, are load-dependent, and have increasingly been recognized as late-occurring changes in myocardial function.⁶⁵ Often, by the time changes in EF and SF are detected, functional deterioration proceeds rapidly and is essentially irreversible, emphasizing the need for biomarkers (echocardiographic and blood) that would facilitate identification of cardiac damage at an earlier stage.

Echocardiographic imaging

Myocardial performance index (MPI) is a Doppler-derived echocardiographic parameter that provides global assessment of systolic and diastolic function.^{66, 67} MPI is attractive as an echocardiographic index because it is independent of heart rate and blood pressure; it provides information regarding diastolic and systolic function; it does not rely on geometric assumptions; and it is highly reproducible in non-oncology populations at risk for CHF.⁶⁶ MPI has been shown to be predictive of CHF in elderly men with normal EF,⁶⁸ and has been shown to predict clinical response to medical treatment for individuals with both systolic heart failure and heart failure with preserved EF.⁶⁷ Studies in oncology patients are limited; however there is emerging evidence that this index can serve as a useful pre-clinical marker of LV dysfunction and subsequent CHF risk.^{69, 70}

Two-dimensional speckle tracking echocardiography (STE) has emerged as an alternative to tissue Doppler imaging in non-oncology populations, allowing more accurate measurements of LV regional myocardial systolic performance.⁷¹ Strain is a dimensionless parameter representing global or segmental myocardial deformation, relative to original dimensions within a given systolic frame.^{71, 72} Frame-by-frame tracking of speckles of bright signal within the myocardium allows assessment of temporal displacement throughout the cardiac cycle, quantifying the amount of myocardial deformation in a certain direction of cardiac motion (longitudinal, circumferential or radial). In non-oncology as well as in oncologic populations at risk for LV dysfunction, STE has been successfully used to monitor subclinical disease.^73–75 Future studies will need to evaluate the utility of STE-based screening and interventions in long-term survivors of HCT with past cardiotoxic exposures.

Blood Biomarkers

Serum cardiac troponins (cTn’s) are specific and sensitive biomarkers of myocyte injury, have established diagnostic and prognostic value in acute coronary syndrome, and have been successfully used as biomarkers to monitor acute anthracycline-related cardiotoxicity.⁷⁶ However, previous studies have failed to demonstrate a clear association between cTn and chronic LV dysfunction in cancer survivors due, in part, to the low-sensitivity of conventional testing kits.^{77, 78} As a result, there is currently no indication for the routine use of cTn in long-term monitoring of asymptomatic LV dysfunction at risk cancer survivors. Other serum markers such as natriuretic peptides (BNP, NT-proBNP) can be used as reliable markers of chronic cardiac remodeling.^{79, 80} They serve as independent risk factors for adverse cardiovascular events, and are being increasingly advocated as objective markers to monitor and adjust decongestive treatment in non-oncology populations with CHF.^{80, 81} However, due to inter-patient variability of natriuretic peptide values in cancer survivors with asymptomatic LV dysfunction, the establishment of an appropriate cutoff for abnormal values has been difficult, limiting their use in the routine follow-up of cancer survivors to date.

Conventional cardiovascular risk factors

Finally, as discussed earlier, CVRFs such as obesity, hypertension, dyslipidemia, and diabetes remain important considerations for both arterial and cardiac disease. Not surprisingly, patients who carry these risk factors into transplant appear to be at particularly high risk of subsequent cardiovascular complications.^{10, 12} For a small proportion of patients, CVRFs that develop after HCT may be transient, resolving soon after discontinuation of chronic immunosuppressive medications.^{23, 82} However, for many survivors, these CVRFs persist long after cessation of immunosuppressive therapy, emphasizing the importance early interventions to reverse the long-term cardiovascular disease risk in these survivors.^{10, 12, 82}

The latency between HCT and serious cardiovascular disease-related hospitalization or death can be as short as 6 years.¹³ As such, the window of opportunity for intervention and control of CVRFs is limited. In certain HCT survivor populations, more aggressive screening and early treatment may be indicated. As a result, current published guidelines (Table 2) recommend regular assessment of cardiovascular risk factors starting 1-year post-HCT, with specific recommendations for particular conditions based on exposures or presence of concurrent risk factors.^{48, 49} It is important to note that should adverse risk factors be detected, survivors may need to have more frequent assessments than the baseline frequencies shown in Table 3. Several groups have issued recommendations regarding possible management and treatment strategies specific to HCT survivors.^{29, 83, 84} However, additional studies, ideally prospective, are needed to determine the optimal frequency of any screening interval among HCT survivors as well as the efficacy and cost-effectiveness of recommendations in general.

Table 3.

Select published recommendations for cardiovascular disease and risk factor surveillance.

Condition (screening)	General population US Preventive Services Task Force (2013)51 [Evidence Grade*]	CIBMTR, ASBMT, EBMT, APBMT, BMTSANZ, EMBMT, SBTMO48	Children’s Oncology Group49, 53 [Evidence Score†]
Diabetes/impaired glucose tolerance (Fasting glucose)	Screening asymptomatic adults with blood pressures >135/80 mmHg [Grade B‡]. No recommendations on optimal interval, or for children.	Screening every 3 yrs after age 45 or earlier if blood pressure >135/80 mmHg.	2 yrs after completing therapy and every 2 yrs in cancer survivors exposed to specific treatments, including total body irradiation or cranial radiotherapy [Scores 1-2A]
Dyslipidemia (Fasting lipids)	All males ≥35 yrs and females ≥45 yrs [Grade A]. Males 20–34 yrs and females 20–44 yrs if at increased CAD risk [Grade B]. Insufficient evidence on optimal screening intervals, or for children.	Screening every 5 yrs starting age 35 for males, age 45 for females. Screening recommended starting age 20 for higher risk patients (smoking, diabetes, hypertension, obesity, positive family history heart disease).	2 yrs after completion of therapy and every 2 yrs if exposed to total body irradiation or cranial radiotherapy, or if other risk factors present [Scores 1-2B]
Heart disease (Lifestyle factors, e.g. diet, physical activity, obesity, tobacco)	Limited evidence of counseling efficacy in the general population. Therefore clinicians may choose to selectively counsel patients without known diagnoses on initiating behavior changes (diet, physical activity) [Grade C]. Obesity screening for all people ≥6 years, and behavioral interventions for those with obesity [Grade B]. Screening for tobacco use among adults and promoting tobacco cessation for any users [Grade A].	Recommend education and counseling for all survivors.	Same as general population.
Heart disease (Electrocardiogram/ECG)	Not recommended for screening individuals at low risk for CAD [Grade D]. Insufficient evidence for higher risk individuals.	May be indicated for high risk patients (chest/mediastinal radiotherapy, history of amyloidosis, preexisting cardiovascular disease).	2 yrs after completing therapy [Score 1]
Heart disease (Echocardiogram)	Not addressed.	May be indicated for high risk patients (chest/mediastinal radiotherapy, history of amyloidosis, preexisting cardiovascular disease).	Every 1–5 years depending on age of exposure, cumulative anthracycline dose, and/or chest radiotherapy [Score 1]
Heart disease (other markers)	Insufficient evidence for newer biomarkers such as hs-CRP, ankle- brachial index, carotid IMT	Not addressed.	Not addressed.
Hypertension (blood pressure)	Recommended for all people ≥18 years [Grade A‡]. Insufficient evidence on optimal screening interval, or for children.‡	Routine assessment every 2 yrs	Annually if treatment risk factors present [Score 1]
Arterial disease (ankle brachial index, carotid artery imaging)	Not recommended for screening [Grade D‡].	Not addressed.	Consider carotid or subclavian vessel imaging 10 yrs after exposure if ≥40 Gy radiotherapy exposure to respective regions [Score 2A]

Abbreviations: CAD, coronary heart disease; CHF, congestive heart failure; CIBMTR, Center for International Blood and Marrow Transplant Research; ASBMT, American Society for Blood and Marrow Transplantation; EBMT, European Group for Blood and Marrow Transplantation; APBMT, Asia-Pacific Blood and Marrow Transplantation Group; BMTSANZ, Bone Marrow Transplant Society of Australia and New Zealand; EMBMT, East Mediterranean Blood and Marrow Transplantation Group; BBTMO Sociedade Brasileira de Transplante de Medula Ossea.

^*USPSTF evidence grading: (A) High certainty of substantial net benefit. Recommended; (B) High certainty of moderate net benefit or moderate certainty of moderate to high net benefit. Recommended; (C) Moderate certainty of small net benefit. Up to clinical judgment; (D) Moderate or high certainty of no net benefit or possible harm. Not recommended.

^†COG evidence scoring: (1) Uniform consensus of high-level evidence; (2A) Uniform consensus of lower-level evidence; (2B) Non-uniform consensus of lower-level evidence.

^‡In process of being re-reviewed/updated by taskforce as of September 2013.

Efforts to promote smoking cessation and a healthy lifestyle also should be strongly encouraged for all HCT survivors. In other cancer survivor populations, adherence to lifestyle recommendations has been associated with a reduction in all-cause and cardiovascular disease-related mortality.⁸⁵ There are preliminary data among HCT survivors that healthier lifestyle characteristics may attenuate the risk of cardiovascular conditions as well, including lower risks of dyslipidemia and diabetes being associated with a diet richer in fruits and vegetables, and lower risks of hypertension and diabetes being associated with greater physical activity.⁸⁶ Interventions that foster and support such lifestyle changes have been tested in cancer survivors with some short and medium term improvements observed.^{87, 88}

SUMMARY

There is convincing evidence that long-term HCT survivors are at risk for clinically significant cardiovascular disease, and the risk increases with time from HCT. Current screening and follow-up guidelines for HCT survivors are largely consensus-based, due to the paucity of studies examining cost-effective approaches to cardiovascular disease surveillance. There is a large body of evidence in non-oncology populations that medical interventions in the asymptomatic setting may delay the onset of clinically apparent cardiovascular disease. Future studies in HCT survivors will to need examine the utility of novel diagnostic imaging and blood biomarkers in routine follow-up for cardiovascular disease prevention, taking into consideration the important role traditional cardiovascular risk factors play in the development of clinically apparent disease.