Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% amongst HCT recipients. While MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. DeFilipp et al.

# Introduction
Advances in hematopoietic cell transplantation (HCT) and supportive care have led to substantial improvements in transplant outcomes and an increased number of long-term HCT survivors [bib_ref] Prevalence of hematopoietic cell transplant survivors in the United States, Majhail [/bib_ref]. Transplant survivors are at considerable risk for developing significant late effects and experience mortality rates higher than the general population [bib_ref] Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term..., Bhatia [/bib_ref] [bib_ref] Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone..., Bhatia [/bib_ref]. One challenge faced in the post-HCT setting is the development of metabolic syndrome (MetS), with reported prevalence rates of 31-49% [bib_ref] High prevalence of metabolic syndrome after allogeneic hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] Prevalence of metabolic syndrome in long-term survivors of hematopoietic stem cell transplantation, Annaloro [/bib_ref] [bib_ref] Metabolic syndrome appears early after hematopoietic cell transplantation, Mcmillen [/bib_ref] [bib_ref] Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute..., Oudin [/bib_ref]. HCT recipients are predisposed to develop MetS through several mechanisms, including conditioning regimen-mediated damage to the neurohormonal system and vascular endothelium, as well as the immunological and inflammatory effects of allografting (including subsequent graft-versus-host disease (GVHD) and its therapy) [bib_ref] High prevalence of metabolic syndrome after allogeneic hematopoietic cell transplantation, Majhail [/bib_ref]. Individuals in the general population with MetS are twice as likely to develop cardiovascular disease than those without MetS [bib_ref] Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart,..., Grundy [/bib_ref]. A better understanding of MetS following HCT may prove to be significant, as HCT survivors are known to be at increased risk for cardiovascular morbidity and mortality. In the Bone Marrow Transplant Survivor Study (BMTSS), the risk of premature cardiovascular-related death following HCT was found to be increased 2.3-fold compared to the general population [bib_ref] Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term..., Bhatia [/bib_ref] [bib_ref] Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone..., Bhatia [/bib_ref]. Similarly, others have reported the risk of cardiovascular hospitalizations and mortality to be increased by 3.6-fold in HCT recipients compared to the general popuation [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref].
Intensive chemotherapy and radiation have been associated with MetS and contribute to the development of this syndrome post-HCT, especially in heavily pre-treated populations [bib_ref] Prevalence and risk factors of the metabolic syndrome in adult survivors of..., Oudin [/bib_ref] [bib_ref] Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute..., Gurney [/bib_ref]. has not yet been proven to impact cardiovascular risk after HCT. However, an understanding of the incidence and risk factors for MetS and cardiovascular disease following HCT provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. Therefore, a collaboration was established between the Center for International Blood and Marrow Transplant Research (CIBMTR) Late Effects and Quality of Life Working Committee and the European Group for Blood and Marrow Transplantation (EBMT) Complications and Quality of Life Working Party with the goal to review literature, including previously published guidelines for screening and preventive practices for HCT survivors [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation:..., Rizzo [/bib_ref] [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. We subsequently provide specific screening and preventive practice recommendations for MetS and cardiovascular disease appropriate to HCT recipients based on published evidence and expert opinion.

## Metabolic syndrome
MetS is a cluster of interrelated factors that increases the risk of cardiovascular disease, diabetes mellitus (DM), and all cause mortality . The International Diabetes Foundation (IDF) estimates that 25% of the world's adult population has MetS . The four core clinical measures are increased body weight/visceral adiposity, elevated lipids, raised blood pressure (BP), and hyperglycemia/insulin resistance (IR) . The individual diagnostic criteria of MetS have varied over time according to the different definitions applied. The diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) [bib_ref] Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart,..., Grundy [/bib_ref] , the IDF and the American Heart Association (AHA) and the World Health Organization (WHO) are shown in . A comparison of various definitions in terms of their predictive value established that the prevalence of MetS was significantly greater when using the criteria of the AHA and IDF compared with the NCEP ATPIII definition . However, the risks of cardiovascular events and death were markedly greater for participants who satisfied any of the criteria for diagnosis of MetS compared with healthy individuals. This supports other reports that found agreement between MetS components and cardiovascular risk factors in the general population [24, 25].

## Abdominal obesity
Obesity, defined as a body mass index (BMI) 30 kg/m 2 , affects 35% of adults in the United States [26] and 10-30% of adults in Europe . Obese persons have a higher risk of developing serious medical conditions, including hypertension (HTN), dyslipidemia, type 2 DM, coronary heart disease (CHD), and ischemic stroke, and have a higher mortality than the non-obese population . However, BMI is an insufficient measure of abdominal obesity. Waist circumference, which emphasizes visceral adipose deposits, is preferentially used in the evaluation of abdominal obesity when defining MetS (see as this distribution of fat accumulation independently confers cardiometabolic risk . Yet, as studies reporting waist circumference at the time of and following HCT are limited, BMI may act as a possible surrogate.
BMI 35 kg/m 2 (severely obese) is part of the HCT-specific Comorbidity Index since 2005, as this was determined to be a risk factor for increased non-relapse mortality (NRM) [bib_ref] Impact of pretransplant body mass index on the clinical outcome after allogeneic..., Fuji [/bib_ref]. While pre-transplant obesity can influence body composition following HCT, changes in waist circumference can be seen independent of pre-existing obesity. Despite what may be a normal BMI, HCT survivors are at an increased risk to develop sarcopenic obesity (increase in percent fat mass, decrease in lean body mass), which can significantly contribute to IR [bib_ref] Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation, Baker [/bib_ref] [bib_ref] Sarcopenia: characteristics, mechanisms and functional significance, Narici [/bib_ref]. A longitudinal study using dual X-ray absorptiometry (DXA) to calculate body fat mass index (BFMI) in 82 patients found the prevalence of a high BFMI was greater at 2-3 years following allo-HCT than in healthy controls [bib_ref] Longitudinal follow-up of body composition in hematopoietic stem cell transplant patients, Kyle [/bib_ref]. Corticosteroids, which remain the first line treatment of GVHD, contribute to sarcopenic obesity by promoting muscle atrophy and may contribute to obesity in the early post-HCT period [bib_ref] Metabolic syndrome in hematologic malignancies survivors: a meta-analysis, Li [/bib_ref]. Robust data on the changes in abdominal obesity following autologous HCT (auto-HCT) are lacking. One study evaluated metabolic and body composition changes in 32 patients with multiple myeloma who had received three lines of intensive treatment, including at least one HCT. At a median duration of 6 years from diagnosis, DXA identified sarcopenic obesity in 65% of patients [bib_ref] Endocrine, metabolic, nutritional and body composition abnormalities are common in advanced intensively-treated..., Greenfield [/bib_ref]. Importantly, the development of sarcopenic obesity following HCT has yet to be independently associated with increased cardiovascular mortality. In the pediatric population, a cross-sectional study evaluating 54 allo-HCT survivors and 894 healthy participants found a deficiency in lean mass (as identified by DXA) as compared to fat mass in HCT survivors [bib_ref] Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation, Mostoufi-Moab [/bib_ref]. A prospective, descriptive, cross-sectional study evaluating children and adolescents for the development of MetS post-HCT found that 73% of individuals with this diagnosis had a characteristic of abdominal obesity (abdominal circumference >75 th percentile by age and gender).

## Screening and preventive recommendations
The United States Preventive Services Task Force (USPSTF) and the National Heart, Lung, Blood Institute (NHLBI) recommend screening for obesity in all adults and children >2 years of age, though no recommendation is made regarding appropriate intervals for screening. Current guidelines for HCT recipients do not provide specific screening recommendations for abdominal obesity, though education and counseling regarding regular exercise, healthy weight, and dietary counseling are encouraged [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. Given the increase in abdominal obesity that can occur after HCT, clinicians should consider monitoring body composition at each visit, with regular measurement of height, weight, and waist circumference (at least yearly). Based on what is known in other populations, we recommend that patients with a BMI 30 kg/m 2 , waist circumference >102 cm (>40 inches) in men or >88 cm (>35 inches) in women, or significant increases in either of these measurements should be considered for intensive, multicomponent behavioral interventions. DXA may be used to assist evaluation and monitoring of changes in body composition in survivors of HCT.

## Dyslipidemia
Dyslipidemia, defined as elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol or triglycerides, or low levels of high-density lipoprotein (HDL) cholesterol, is an important risk factor for CHD and ischemic stroke [bib_ref] Hypertriglyceridemia and its pharmacologic treatment among US adults--invited commentary, Thompson [/bib_ref]. The prevalence of dyslipidemia is high in the general population: in 2000, approximately 25% of adults in the United States had total cholesterol greater than 240 mg/dL (6.2 mmol/L) or were taking lipid-lowering medication [bib_ref] Primary prevention of CVD: treating dyslipidaemia, Fodor [/bib_ref]. A high prevalence of dyslipidemia has also been reported in European countries. Of the various dyslipidemias, low HDL (<40-50 mg/dL, <1.0-1.3 mmol/L) and hypertriglyceridemia (>150 mg/dL, >1.7 mmol/L) have been incorporated into the diagnostic criteria of MetS (see .
Survivors of allo-HCT are at an increased risk of post-transplant dyslipidemia. In a retrospective cohort study comparing incidence and risk factors for cardiovascular events, allo-HCT recipients had significantly higher risk of new-onset dyslipidemia (RR: 2.31; 95% CI, 1.15 to 4.65) compared to auto-HCT recipients [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref]. Single institution studies have estimated the incidence of hypercholesterolemia and/or hypertriglyceridemia following allo-HCT to be 43-73% [bib_ref] Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on..., Kagoya [/bib_ref] [bib_ref] Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation, Blaser [/bib_ref]. The onset of dyslipidemia post-HCT can be rapid, with the median interval to development of hypertriglyceridemia and hypercholesterolemia being 8 and 11 months following allo-HCT, respectively, in one single center experience [bib_ref] Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on..., Kagoya [/bib_ref]. Factors predicting development of post-HCT dyslipidemia include family history of hyperlipidemia, obesity, high-dose total body irradiation (TBI), grade II-IV acute GVHD, chronic GVHD, and chronic liver disease [bib_ref] Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute..., Oudin [/bib_ref] [bib_ref] Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on..., Kagoya [/bib_ref] [bib_ref] Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation, Blaser [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref]. In addition, immunosuppressant medications (e.g., sirolimus, calcineurin inhibitors, corticosteroids) not only increase lipid levels but also lead to significant drug-drug interactions with 3-hydroxy-3-methyl-gutaryl (HMG)-CoA reductase inhibitors (statins) via the cytochrome p450 pathway [bib_ref] Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management, Griffith [/bib_ref] [bib_ref] Treatment of dyslipidemia in allogeneic hematopoietic stem cell transplant patients, Marini [/bib_ref]. Data regarding the incidence of dyslipidemia following auto-HCT are limited. In a single center analysis evaluating late post-HCT cardiovascular complications in 1379 patients, which included both auto-and allo-HCT recipients, 1-year post-HCT dyslipidemia requiring treatment was associated with an increased risk for stroke (HR 7.4; 95% CI, 1.2-47) [bib_ref] Late cardiovascular complications after hematopoietic cell transplantation, Chow [/bib_ref]. In the pediatric population, the risk of hypercholesterolemia is high in childhood cancer survivors who underwent auto-HCT (HR = 3.2; CI 1.7-5.9) [bib_ref] Prevalence of cardiovascular risk factors in long-term survivors of childhood cancer: 16..., Felicetti [/bib_ref].

## Screening and preventive recommendations
The USPSTF strongly recommends screening for lipid disorders every 5 years in men 35 years, women 45 years, and persons 20 years at increased risk for CHD, while the NHLBI recommends screening in children between the ages of 9-11 years or earlier in those with family history. Current guidelines for HCT recipients recommend similar screening practice for dyslipidemia amongst the general population [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. We recommend standard-risk patients (including auto-HCT recipients without personal risk factors) should follow these guidelines. However, early onset of dyslipidemia following allo-HCT is not uncommon, especially in high-risk patients. Thus, we propose early assessment of exposures and risk factors in all HCT patients. For recipients of allo-HCT, we suggest an initial lipid profile 3 months after HCT. For high-risk patients with ongoing risk factors (including those on sirolimus, calcineurin inhibitors, corticosteroids), we suggest repeat evaluation every 3-6 months. In recipients without ongoing risk factors, we suggest repeat evaluation according recommendations for the general population. Non-pharmacologic management of dyslipidemia primarily involves lifestyle modifications such as diet (low saturated fat and low cholesterol), exercise (or other regular physical activities), weight reduction, smoking cessation, and limiting alcohol intake. Although not validated amongst HCT survivors, we recommend use of the Framingham risk score (http://cvdrisk.nhlbi.nih.gov) to assess cardiovascular risk and guide therapy decisions. The safety of lipid-lowering agents must be considered in the pediatric population, as the AHA recommends considering drug therapy for high-risk lipid abnormalities in boys 10 years of age and after onset of menses in girls, preferably after a 6 to 12 month trial of saturated fat-and cholesterol-restricted dietary management [bib_ref] Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific..., Mccrindle [/bib_ref].

## Hypertension
HTN, defined as a systolic BP 140 mmHg or diastolic BP 90 mmHg, is a worldwide epidemic affecting approximately ~25% of adults [bib_ref] Global burden of hypertension: analysis of worldwide data, Kearney [/bib_ref]. Of note, the blood pressure criteria used in most definitions of MetS is systolic BP 135 mmHg or diastolic BP 85 mmHg (or drug treatment for HTN) (see , which is classified as pre-hypertension according to the report from the Eighth Joint National Committee (JNC 8) [bib_ref] evidence-based guideline for the management of high blood pressure in adults: report..., James [/bib_ref].
An analysis of the BMTSS showed that after adjustment for age, sex, race, and BMI, allo-HCT recipient were 2.06 times (95% CI, 1.39-3.04) more likely to report HTN as compared to sibling donors or auto-HCT recipients, who had a similar risk (OR, 0.96; 95% CI, 0.65-1.44) [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. Similarly, a retrospective, single-institution evaluation of 265 long-term transplant survivors reported that allo-HCT recipients have an increased risk of HTN (RR: 2.50; 95% CI, 1.19 to 5.27) compared to auto-HCT patients [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref]. A direct cause and effect relationship of conditioning regimen, acute or chronic GVHD and HTN was not established [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. Two large retrospective studies did not show a significant difference in the incidence of HTN in allo-HCT recipients with or without GVHD [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref] [bib_ref] Male survivors of allogeneic hematopoietic stem cell transplantation have a long term..., Pophali [/bib_ref]. It appears that HTN is related to use of certain GVHD therapies (e.g., calcineurin inhibitors, steroids) rather than GVHD induced pro-inflammatory cytokine response and endothelial damage. Although pediatric patients are less likely than adults to have pre-transplant HTN as well as any risk factors for HTN, an analysis of 1-year survivors of allo-HCT found a similar incidence of post-HCT HTN in adult (68%) and pediatric (73%) HCT survivors [bib_ref] Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic..., Majhail [/bib_ref]. In multivariate analyses, exposure to cyclosporine increased the risk of HTN post-HCT (RR: 1.6; 95% CI, 1.1-2.5), but only within the first 2 years, suggesting this may revert once medications are stopped.

## Screening and preventive recommendations
The USPSTF recommends BP assessment every 3 to 5 years in adults aged 18-39 years with normal BP (<130/85 mm Hg) who do not have other risk factors and annually in adults aged 40 years and for those who are at increased risk for high BP. In children, the NHLBI recommends BP assessment yearly after the age of 3 years, interpreted for age, sex, and height. Current guidelines for HCT recipients recommend at least annual BP assessment in children and BP assessment every other year in adults [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. We recommend BP assessment for HCT recipients at every clinic visit (at least yearly). The JNC 8 report recommends initiating pharmacologic treatment for BP of 150/90 mmHg in persons 60 years of age (to a BP goal of <150/<90 mmHg) and for BP of 140/90 in persons 30-59 years of age (to a BP goal of <140/<90) [bib_ref] evidence-based guideline for the management of high blood pressure in adults: report..., James [/bib_ref]. In the absence of HCT-specific evidence, these goals can be used to guide management of HCT recipients, but other factors such as end organ compromise (cardiac or renal failure) and therapy with calcineurin inhibitors also need to be taken into account.

## Insulin resistance/diabetes mellitus
DM, which affects almost 10% of the adult population worldwide, is characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of DM is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. The American Diabetes Association (ADA) defines DM as a fasting plasma glucose 126 mg/dl (7 mmol/L), a hemoglobin A1C (HbA1C) 6.5%, a 2-hour plasma glucose 200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test, or a random glucose 200 mg/dl (11.1 mmol/L) in a patient with classic symptoms or hyperglycemia or hyperglycemic crisis. Impaired fasting glucose (IFG, fasting glucose 100-126 mg/dL (5.6-7 mmol/L)) or DM are used in most definitions of MetS . The treatment of DM may reduce the progression of microvascular and cardiovascular disease [bib_ref] Lifestyle interventions for patients with and at risk for type 2 diabetes:..., Schellenberg [/bib_ref] [bib_ref] Effect of regression from prediabetes to normal glucose regulation on long-term reduction..., Perreault [/bib_ref]. Although randomized trials have failed to demonstrate an unequivocal benefit, the identification of patients by screening allows for earlier intervention with potential reduction in complications [bib_ref] Screening for type 2 diabetes mellitus: a systematic review for the U.S...., Selph [/bib_ref] [bib_ref] Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge):..., Simmons [/bib_ref].
While hyperglycemia and impaired glucose tolerance (IGT) are well-recognized complications of cancer and GVHD treatment (corticosteroids), data regarding the long-term risk of DM in HCT survivors are limited [bib_ref] Diabetes mellitus after hematopoietic stem cell transplantation, Griffith [/bib_ref]. In the BMTSS, both allo-HCT (OR, 3.65; 95% CI, 1.82-7.32) and auto-HCT (OR: 2.03; 95% CI, 0.98-4.21) recipients were more likely to report DM than sibling donors [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. The incidence of post-HCT DM was 30% among 1-year allo-HCT recipients in both adult and pediatric populations [bib_ref] Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic..., Majhail [/bib_ref]. In this study, exposure to high-dose corticosteroids (cumulative prednisone dose of > 0.25 mg/kg/day) increased the likelihood of developing DM (RR, 3.6; 95% CI, 1.7-7.5) and for having persistent DM at 2 years post-HCT (RR, 4.1; 95% CI, 1.0-18.2). While data regarding the incidence of IR in survivors of adult HCT are lacking, the incidence of IR for pediatric HCT survivors has been estimated to be 10-52% in single center studies [bib_ref] Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in..., Taskinen [/bib_ref] [bib_ref] Early and progressive insulin resistance in young, non-obese cancer survivors treated with..., Bizzarri [/bib_ref] [bib_ref] Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and..., Mostoufi-Moab [/bib_ref]. These reports suggest an increased risk for IR/DM in survivors of both allo-and auto-HCT compared to patients treated with chemotherapy alone or untreated siblings, even when off immunosuppressive treatments. Preliminary data from a cross sectional study including 151 HCT survivors (76.8% allo-HCT) and 92 sibling controls found HCT survivors who had received TBI conditioning to be significantly more likely to have IR than their sibling controls, but there was no increased risk of IR for those patients who had a history of acute or chronic GVHD (personal communication, Baker KS). Multiple studies found high-dose TBI as a risk factor for IR and IGT, in addition to older age and lipodystropic body type [bib_ref] Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and..., Mostoufi-Moab [/bib_ref] [bib_ref] Risk factors for diabetes mellitus and impaired glucose tolerance following allogeneic hematopoietic..., Hirabayashi [/bib_ref] [bib_ref] Disorders of glucose homeostasis in young adults treated with total body irradiation..., Chemaitilly [/bib_ref]. While data have not demonstrated an increased risk of diabetes to be directly associated with history of GVHD, further study is warranted.

## Screening and preventive recommendations
The most common tests to screen for diabetes are fasting plasma glucose, two-hour plasma glucose during an oral glucose tolerance test, and HbA1C. The USPSTF recommends screening for abnormal blood glucose (HbA1C, fasting plasma glucose or oral glucose tolerance test (OGTT)) every 3 years in adults aged 40-70 years who are overweight or obese. The NHLBI recommends screening with a fasting glucose every 2 years after the age of 10 years in overweight children with other risk factors. Current guidelines for HCT recipients recommend screening for type 2 DM every 3 years in adults aged 45 years or in those with sustained higher BP (>135/80 mm Hg) and fasting glucose at least every 5 years pediatric survivors [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref] , which should be appropriate for standard-risk patients. For highrisk patients with ongoing risk factors (including those on systemic corticosteroids), we recommend screening for abnormal blood glucose (HbA1C or fasting plasma glucose) 3 months after HCT with repeat evaluation every 3-6 months. For patients with IFG, we encourage weight reduction and increased physical activity while patients with type 2 DM should implement lifestyle therapy and pharmacotherapy, if necessary, to achieve nearnormal HbA1C (<7%).

## Coronary heart disease
More people die from cardiovascular disease each year than from any other cause. Cardiovascular disease is caused by disorders of blood vessels and is closely related to atherosclerosis, where endothelial lesions occur up to decades before clinical manifestations [bib_ref] Inflammation, atherosclerosis, and coronary artery disease, Hansson [/bib_ref] [bib_ref] Inflammation and atherosclerosis: novel insights into plaque formation and destabilization, Stoll [/bib_ref]. Risk factors for arteriosclerosis in the general population are well established and include smoking, arterial HTN, obesity, DM, dyslipidemia, familial history of CHD, physical inactivity, male gender and elevated C-reactive protein [bib_ref] Prediction of lifetime risk for cardiovascular disease by risk factor burden at..., Leip [/bib_ref].
Several studies have attempted to assess the incidence of cardiovascular disease after HCT, with or without a comparison to a control population. A retrospective multicenter EBMT analysis showed that 3.6% of long-term allo-HCT survivors transplanted between 1990 and 1995 had a cardiovascular event in at least one arterial territory observed [bib_ref] Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter..., Tichelli [/bib_ref]. The cumulative incidence of a first cardiovascular event 15 years after HCT was 6% (95% CI, 3%-10%). One study reported a cumulative incidence of 7.5% for the first cardiovascular event at 15 years post allo-HCT, as compared with 2.3% post auto-HCT [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref]. In multivariate analysis, allo-HCT, in addition to at least 2 of 4 cardiovascular risk factors (HTN, dyslipidemia, DM, and obesity) was associated with a higher incidence of cardiovascular events (RR: 12.4; P=.02). In a retrospective cohort study, 2-year HCT survivors experienced an increased incidence of cardiovascular death (adjusted incidence rate difference, 3.6 per 1000 person-years (95% CI, 1.7 to 5.5) when compared with the general population [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref]. In this study, an increased cumulative incidence was also found for ischemic heart disease, cardiomyopathy or heart failure, stroke, vascular diseases, and rhythm disorders and an increased incidence of related conditions that predispose toward more serious cardiovascular disease (HTN, renal disease, dyslipidemia, and DM). In another study, HCT recipients had significantly higher rates of cardiomyopathy (4.0% vs. 2.6%), stroke (4.8% vs. 3.3%), dyslipidemia (33.9% vs. 22.3%) and DM (14.3% vs. 11.7%) (P<.05 for all comparisons) than the general population, though lower rates of ischemic heart disease (6.1% vs. 8.9%; P<.01) [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref]. In the BMTSS, survivors of both allo-and auto-HCT were not more likely to report arterial disease, myocardial infarction or stroke than sibling donors [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. One series, which included 42.7% allo-HCT recipients, reported an incremental increase in 10-year incidence of cardiovascular disease by number of cardiovascular risk factors (4.7% (no factor), 7.0% (one risk factor), 11.2% (2 risk factors), P<.01); the risk was especially high (15.0%) in patients with multiple risk factors and pre-HCT exposure to anthracyclines or chest radiation [bib_ref] Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of..., Armenian [/bib_ref]. In the adult population, it is important to acknowledge that an increasing number of older patients are undergoing allo-HCT with reduced intensity conditioning and that future studies are needed to assess the incidence of cardiovascular complications in this population.
In children with acute lymphoblastic leukemia, high-dose TBI and cranial irradiation correlated with multiple adverse cardiovascular factors including central adiposity, HTN, IR and dyslipidemia [bib_ref] Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with..., Chow [/bib_ref] [bib_ref] Hyperinsulinemia in children and adolescents after bone marrow transplantation, Lorini [/bib_ref]. Some studies have analyzed the correlation with GVHD and either found a correlation [bib_ref] Late altered organ function in very long-term survivors after allogeneic hematopoietic stem..., Rovo [/bib_ref] or not [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref] [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref] and if so, more likely with acute than chronic GVHD [bib_ref] Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter..., Tichelli [/bib_ref] [bib_ref] Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of..., Armenian [/bib_ref].

## Screening and preventive recommendations
In the general population, a person's 10-year risk for CHD is determined based on age, gender, and conventional CHD risk factors such as smoking, HTN, and dyslipidemia (Framingham risk score, http://cvdrisk.nhlbi.nih.gov)) [bib_ref] Forecasting the Future of Cardiovascular Disease in the United States: A Policy..., Heidenreich [/bib_ref]. Overall, the benefits of screening with resting or exercise electrocardiography (ECG) or for non-traditional risk factors, including coronary artery calcification on electron-beam computerized tomography (EBCT), have not been clearly demonstrated to outweigh harms. The USPSTF recommends against screening with ECG in asymptomatic adults with low risk for CHD and concludes that there is insufficient evidence to assess the balance of benefits and harms of screening with resting or exercise ECG in asymptomatic adults at intermediate-or high-risk for CHD events. Similarly, the USPSTF finds insufficient evidence to assess the balance of benefits and harms of using non-traditional risk factors to screen asymptomatic men and women with no history of CHD to prevent CHD events. Current guidelines for HCT recipients do not provide specific screening recommendations for coronary heart disease [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref]. Decisions about screening in adults at increased risk should be made on a case-by-case basis and after careful discussion with the patient about the risks and benefits of screening. Although little data are available about specific interventions in the HCT populations, we recommend a similar approach.

## Ischemic stroke
Stroke is the fourth leading cause of death in the United States, whereas globally it is the second most common cause of mortality and the third most common cause of disability [bib_ref] Deaths: leading causes for, Heron [/bib_ref] [bib_ref] Global and regional mortality from 235 causes of death for 20 age..., Lozano [/bib_ref]. Globally, stroke incidence from ischemia is 68% and 32% from hemorrhagic stroke (intracerebral and subarachnoid combined) [bib_ref] Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010:..., Krishnamurthi [/bib_ref]. Pediatric stroke is a top ten cause of death in children, occurring at 11 per 100,000 children per year, with acute ischemic stroke accounting for half of all cases [bib_ref] Heart disease and stroke statistics-2009 update: a report from the American Heart..., Carnethon [/bib_ref] [bib_ref] Management of stroke in infants and children: a scientific statement from a..., Roach [/bib_ref] [bib_ref] Etiology of stroke in children, Riela [/bib_ref].
The cumulative incidence of stroke after adult HCT has been reported in single center series to be 1-5% at a median of 4-10 years following HCT [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref] [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] [bib_ref] Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with..., Chow [/bib_ref] [bib_ref] Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a..., Sun [/bib_ref]. In one study of 3833 HCT survivors of 1 year (71.3% allo-HCT), the prevalence of stroke at a median of 10.8 years since HCT was slightly higher than in a matched general population sample (4.8% vs 3.3%) [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref]. Reported risk factors for stroke include hyperlipidemia, suboptimal physical activity, HTN treatment before HCT, BMI  30 kg/m 2 at HCT, and recurrence of the original disease [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] [bib_ref] Late cardiovascular complications after hematopoietic cell transplantation, Chow [/bib_ref]. The risk of stroke did not differ statistically between autoor allo-HCT, gender, age at HCT, TBI dose, smoking history, donor type, stem cell source, fruit or vegetable intake, and prior cranial radiation [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] [bib_ref] Late cardiovascular complications after hematopoietic cell transplantation, Chow [/bib_ref] [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. A history of chronic GVHD was associated with an increased risk of stroke among 5-year HCT survivors (OR, 2.0; 95% CI, 1.1-3.6) in one study [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] , while it was not statistically associated with risk of stroke in the other studies. Although ischemic stroke is an indication for HCT in sickle cell disease (SCD), reports indicate that there is no increased risk post-HCT in this population. In one report of pediatric SCD patients, 2 had TIAs after allo-HCT but not stroke [bib_ref] Cerebral vascular abnormalities in pediatric patients with sickle cell disease after hematopoietic..., Bodas [/bib_ref]. Similarly, another study of pediatric SCD matched related allo-HCT patients did not report stroke in those with successful engraftment [bib_ref] Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for..., Walters [/bib_ref]. Adult SCD may have a higher risk of stroke and allo-HCT studies in the adult population are ongoing.
While the reported incidence of stroke in HCT survivors is low, it may be under recognized due to under reporting. Central nervous system complications -such as stroke, posterior reversible encephalopathy syndrome (PRES) and seizures -also occur frequently in the early post-HCT follow-up with significant impact on patient survival [bib_ref] Central Nervous System Complications and Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation, Bhatt [/bib_ref]. Beside the well-known PRES, calcineurin inhibitors may cause a reversible cerebral vasoconstriction syndrome that can progress to cerebral infarction [bib_ref] Reversible cerebral vasoconstriction syndrome resulted in cerebral infarction after allogeneic stem cell..., Imataki [/bib_ref]. Furthermore neurovascular complication -including stroke and transient ischemic attacks (TIA) -occur commonly upon initial presentation of thrombotic microangiopathies presentation and cryptogenic stroke may develop before the onset of alarming hematologic abnormalities [bib_ref] Pearls and oy-sters: acute ischemic stroke caused by atypical thrombotic thrombocytopenic purpura, Rojas [/bib_ref] [bib_ref] Progressive multifocal cerebral infarction in a young kidney transplant recipient due to..., Haghikia [/bib_ref].

## Screening and preventive recommendations
The risk of a first stroke can be assessed by a global risk assessment tool such as the American Heart Association/American College of Cardiology Cardiovascular Risk Calculation online tool for adults (http://my.americanheart.org/cvriskcalculator), which has also been endorsed by the American Academy of Neurology [bib_ref] Guidelines for the primary prevention of stroke: a statement for healthcare professionals..., Meschia [/bib_ref]. The USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. Preventive practice includes performing moderate to vigorous aerobic physical activity for at least 40 minutes 3-4 times a week, statin therapy according to 10 year calculated cardiovascular risk, implementation of a Mediterranean diet, HTN therapy, and weight loss in overweight and obese patients. Current guidelines for HCT recipients do not provide specific screening recommendations for stroke [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref]. In the absence of HCT-specific evidence, these goals represent appropriate guidelines for HCT recipients.

## Recommendations for screening and preventive practices
While evidence demonstrating the benefits of screening and preventive practices in HCT survivors is lacking, this review of MetS and cardiovascular disease emphasizes the high incidence of cardiovascular risk factors and the related morbidity and mortality experienced by HCT recipients. Based on this data, we present published guidelines for general population and HCT survivors [fig_ref] Table 2: Screening guidelines for metabolic syndrome and cardiovascular risk factors for adult and... [/fig_ref] as well as our consensus recommendations on the screening and preventive practices [fig_ref] Table 4: CIBMTR/EBMT screening guidelines and preventive practice recommendations for metabolic syndrome and cardiovascular... [/fig_ref] for MetS and cardiovascular disease. We also present risk factors to consider when screening for components of metabolic syndrome in transplant recipients [fig_ref] Table 5: Risk factors to consider when screening for components of metabolic syndrome in... [/fig_ref]. HCT survivors with no identifiable risk factors should be counseled to have a healthy lifestyle and to follow the well-established screening recommendations for the healthy population. However, high-risk patients with ongoing risk factors should be more closely monitored.
Although not addressed formally in this manuscript, endocrine abnormalities, such as male hypogonadism, premature menopause, and hypothyroidism can occur following HCT and may contribute to MetS cardiovascular risk. Health care providers should be aware of these risks and evaluate for these conditions in HCT survivors, especially in the presence of MetS or those with risk factors.
A number of online tools are available to help providers assess risk in patients. In addition to the Framingham risk score (http://cvdrisk.nhlbi.nih.gov), the AHA released a mobile application in 2013 (http://tools.acc.org/ASCVD-Risk-Estimator) to estimate 10-year and lifetime risks for atherosclerotic cardiovascular disease in healthy subjects considering age, ethnicity, gender, systolic BP, history of smoking and DM, total and HDL cholesterol. However, these calculators were designed for the general population and have limitation by age, ethnicity, and/or comorbid conditions. Furthermore, it is important to acknowledge that these tools have not been validated in HCT survivors and thus potentially underestimate risk in this population.

# Conclusion
We provide a consensus recommendations for screening and preventive measures for MetS and cardiovascular disease in recipients of HCT. Such effort by the CIBMTR and EBMT Late Effects Working Groups is intended to raise awareness of the cardiovascular risk in HCT survivors and lead to practices that will decrease related mortality. This document does not discuss strategies to achieve these practices (e.g. survivorship clinics, rehabilitation or exercise programs) given the differences in health care environments between different countries, but efforts to facilitate such strategies to be developed at the local or national level are needed.
[table] Table 2: Screening guidelines for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients amongst the general population and HCT survivorsBiol Blood Marrow Transplant. Author manuscript; available in PMC 2016 November 14. [/table]
[table] Table 3: Preventive practice recommendations for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients amongst the general population and HCT survivors * [/table]
[table] Table 4: CIBMTR/EBMT screening guidelines and preventive practice recommendations for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients amongst the general population and HCT survivors Weight, height, and BMI assessment at every clinic visit (at least yearly) Waist circumference measurement yearly Consider DXA to assess sarcopenia Provide advice regarding intensive, multicomponent behavioral interventions focused on achieving and maintaining healthy weight by reducing caloric intake and increasing physical activityDyslipidemiaFor all allo-HCT recipientes, initial lipid profile 3 months after HCT. For high-risk patients with ongoing risk factors (including those on sirolimus, calcineurin inhibitors, corticosteroids), repeat evaluation every 3-6 months.For standard-risk patients, lipid profile assessment every 5 years in males aged 35 years and females aged 45 years. The interval for screening should be shorter for people who have lipid levels close to those warranting therapy.Lifestyle modifications and lipid lowering therapies to achieve relative reductions in LDL is the primary goal In adults, the decision to initiate lipid lowering therapy should include assessment of overall risk of heart disease (http://cvdrisk.nhlbi.nih.gov).Non-pharmacologic treatments may also be tried for mild hypertension and include moderate dietary sodium restriction, weight reduction in the obese, avoidance of excess alcohol intake, and regular aerobic exercise. Treatment is indicated for readings >140/90 in adults on two separate visits at least 1 week apart, unless hypertension is mild or can be attributed to a temporary condition or medication (eg, cyclosporine). Hyperglycemia For high-risk patients with ongoing risk factors (including those on systemic corticosteroids), screen for abnormal blood glucose (HbA1C or fasting plasma glucose) 3 months after HCT with repeat evaluation every 3-6 months. For standard-risk adult patients, screening for abnormal blood glucose every 3 years in adults aged 45 years or in those with sustained higher blood pressure (>135/80 mm Hg) For standard-risk pediatric patients, fasting glucose at least every 5 years; if abnormal, screen annually For IFG, encourage weight reduction and increased physical activity. For type 2 DM, lifestyle therapy, and pharmacotherapy, if necessary, should be used to achieve near-normal HbA1C (<7%). Abbreviations: BMI: body mass index; CIBMTR: Center for International Blood and Marrow Transplant Research; DM: diabetes mellitus; DXA: dual X-ray absorptiometry; EBMT: European Group for Blood and Marrow Transplantation; HbA1C: hemoglobin A1C; HCT: hematopoietic cell transplantation; IFG: impaired fasting glucose; LDL: low-density lipoprotein; TG: triglycerides [/table]
[table] Table 5: Risk factors to consider when screening for components of metabolic syndrome in transplant recipients TBI as part of pre-transplant conditioning  Development of acute or chronic GVHD [/table]