Long-Term Consequences of Hematopoietic Stem Cell Transplantation: Current State of the Science
2009; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês
10.1016/j.bbmt.2009.09.017
ISSN1523-6536
AutoresK. Scott Baker, Saro H. Armenian, Ravi Bhatia,
Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoHematopoietic cell transplantation (HCT) is an established curative option for a variety of hematologic malignancies. Liberalization in the indications for transplantation coupled with an increase in options in the source of the hematopoietic stem cells (HSCs) are responsible for the increasing number of HCTs performed annually [1Horowitz M.M. Uses and growth of hematopoietic cell transplantation.in: Blume K.G. Forman S. Appelbaum E.R. Thomas' Hematopoietic Cell Transplantation. Blackwell Publishing, Malden, MA2004: 9-15Google Scholar]. Advances in transplantation techniques and supportive care strategies have resulted in a significant improvement in survival, such that long-term survival has now become an expected outcome for patients undergoing HCT. However, exposure to chemotherapy prior to transplantation as well as at the time of transplantation, coupled with prolonged periods of immune suppression and the risk of disease recurrence, place this population at an increased risk of chronic health conditions, such as cardiac compromise, endocrine sequelae, and subsequent malignancies. Furthermore, premature death remains of significant concern among health care providers as well as patients who have successfully survived the immediate post-HCT period. The following sections will focus on long-term survival and causes of premature death among patients undergoing HCT; on the overall burden of morbidity suffered by long-term survivors, with special emphasis on the occurrence of metabolic syndrome in this population and its impact on cardiac dysfunction and the need to understand individual variability in the risk for post-HCT complications, as we move closer to personalized medicine. Long-term survival and premature deaths after allogeneic HCT were first examined for 6691 patients registered with the International Bone Marrow Transplant Registry (IBMTR) [2Socie G. Stone J.V. Wingard J.R. et al.Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.N Engl J Med. 1999; 341: 14-21Crossref PubMed Scopus (574) Google Scholar]. This study reported the overall survival (OS) for those who were disease-free for 2 or more years after allogeneic HCT to be 89% at 5 years. The risk of death after 5 years approached that of the general population for patients with severe aplastic anemia (SAA). Recurrent disease was the chief cause of premature death. However, registry studies such as this are limited by the dependence on passive reporting of events by the participating institutions. This limitation was overcome by the Bone Marrow Transplant Survivor Study (BMTSS), where a comprehensive evaluation of cause-specific late mortality was performed in patients treated with HCT by using central resources such as the National Death Index or Social Security Death Index, supplemented by information abstracted from medical records. Late mortality was evaluated in 1479 individuals who had survived 2 or more years after allogeneic HCT [3Bhatia S. Francisco L. Carter A. et al.Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.Blood. 2007; 110: 3784-3792Crossref PubMed Scopus (366) Google Scholar]. Median age at HCT was 25.9 years and the median length of follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% ± 1.9% for those who were disease-free at entry into the cohort, and the cohort was at a 9.9-fold increased risk of premature death compared with the general population. Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio [SMR] = 2.2). Relapse of primary disease and chronic graft-versus-host disease (cGVHD) were the leading causes of premature death. Late mortality in 854 individuals who had survived 2 or more years after autologous HCT for hematologic malignancies was also assessed in the BMTSS cohort [4Bhatia S. Robison L.L. Francisco L. et al.Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study.Blood. 2005; 105: 4215-4222Crossref PubMed Scopus (183) Google Scholar]. Median age at HCT was 36.5 years and median length of follow-up was 7.6 years. OS was 68.8% ± 1.8% at 10 years, and the cohort was at a 13-fold increased risk for premature death when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT and in patients undergoing HCT for acute myelogenous leukemia (AML). Relapse of primary disease and subsequent malignancies were leading causes of premature death. Relapse-related mortality was increased among patients with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL). Total body irradiation (TBI) provided a protective effect. Control of the underlying disease and prolongation of life among HCT survivors is not necessarily accompanied by full restoration of health. HCT survivors are at risk for long-term treatment-related complications, such as endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise, and subsequent malignancies [5Armenian S.H. Sun C.L. Francisco L. et al.Late congestive heart failure after hematopoietic cell transplantation.J Clin Oncol. 2008; 26: 5537-5543Crossref PubMed Scopus (84) Google Scholar, 6Baker K.S. Ness K.K. Steinberger J. et al.Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study.Blood. 2007; 109: 1765-1772Crossref PubMed Scopus (248) Google Scholar, 7Brennan B.M. Shalet S.M. Endocrine late effects after bone marrow transplant.Br J Haematol. 2002; 118: 58-66Crossref PubMed Scopus (142) Google Scholar, 8Choi M. Sun C.L. Kurian S. et al.Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation.Cancer. 2008; 113: 1580-1587Crossref PubMed Scopus (63) Google Scholar, 9Fraser C.J. Bhatia S. Ness K. et al.Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study.Blood. 2006; 108: 2867-2873Crossref PubMed Scopus (206) Google Scholar, 10Leiper A.D. Non-endocrine late complications of bone marrow transplantation in childhood: part II.Br J Haematol. 2002; 118: 23-43Crossref PubMed Scopus (49) Google Scholar, 11Majhail N.S. Ness K.K. Burns L.J. et al.Late effects in survivors of Hodgkin and non-Hodgkin lymphoma treated with autologous hematopoietic cell transplantation: a report from the bone marrow transplant survivor study.Biol Blood Marrow Transplant. 2007; 13: 1153-1159Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 12Rizzo J.D. Curtis R.E. Socie G. et al.Solid cancers after allogeneic hematopoietic cell transplantation.Blood. 2009; 113: 1175-1183Crossref PubMed Scopus (310) Google Scholar, 13Sanders J.E. Chronic graft-versus-host disease and late effects after hematopoietic stem cell transplantation.Int J Hematol. 2002; 76: 15-28Crossref PubMed Scopus (42) Google Scholar, 14Socie G. Salooja N. Cohen A. et al.Nonmalignant late effects after allogeneic stem cell transplantation.Blood. 2003; 101: 3373-3385Crossref PubMed Scopus (319) Google Scholar, 15Wingard J.R. Vogelsang G.B. Deeg H.J. Stem cell transplantation: supportive care and long-term complications.Hematology Am Soc Hematol Educ Program. 2002; : 422-444Crossref PubMed Scopus (63) Google Scholar]. Understanding the burden of morbidity because of these treatment-related complications is important to the health care providers and policy makers in identifying and procuring resources for the long-term care of individuals with a high burden of morbidity, to the researchers in identifying common etiologic pathways that lead to the overall morbidity, and to the HCT survivors in making an informed decision regarding the quality-of-life concerns long-term after HCT. The burden of morbidity because of chronic health conditions was evaluated in HCT survivors and a healthy sibling comparison group participating in the BMTSS [16Sun C.-L. Francisco F. Kawashima T. et al.Burden of long-term morbidity after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS).Blood (ASH Annu Meet Abstr). 2007; 110: 832Google Scholar]. HCT survivors and siblings completed a 255-item questionnaire, which covers the following general areas: diagnosis of physical health conditions with age at diagnosis (endocrinopathies; central nervous system compromise; cardiopulmonary dysfunction; gastrointestinal and hepatic sequelae; musculoskeletal abnormalities; and subsequent malignancies); diagnosis and extent of cGVHD; access to and use of medical care; and sociodemographic characteristics (education, marital status, employment, household income, and insurance). The reliability and validity of the BMTSS questionnaire has been tested, and the responses have demonstrated a high level of sensitivity and specificity, confirming that survivors are able to report the occurrence of adverse medical conditions with accuracy [17Louie A.D. Robison L.L. Bogue M. Hyde S. Forman S.J. Bhatia S. Validation of self-reported complications by bone marrow transplantation survivors.Bone Marrow Transplant. 2000; 25: 1191-1196Crossref PubMed Scopus (63) Google Scholar]. The prevalence and severity of chronic health conditions reported by individuals who had undergone HCT between 1976 and 1998 and survived 2 years (n = 1022), and their siblings (n = 309) is described here. A severity score (grades 1 [mild] through 4 [life-threatening]) was assigned to each health condition using the Common Terminology Criteria for Adverse Events (version 3). The mean age at enrollment was 43.1 years and 44.8 years for survivors and siblings, respectively. Among HCT survivors, 66% had at least 1 chronic condition, and 18% had a severe or life-threatening condition; comparable figures in siblings were 39% and 8%, respectively (P < .001). HCT survivors were 3.5 times more likely to develop severe/life-threatening conditions (95% confidence interval [CI], 2.3-5.4), when compared with age- and sex-matched siblings. The prevalence of any chronic health condition was significantly higher among allogeneic HCT recipients when compared with autologous HCT recipients (any chronic health conditions: 71.1% versus 60.7%, P = .001; grade 3 or 4 conditions: 20.6% versus 15.5%, P = .04). The cumulative incidence of a chronic health condition among patients, who had survived the first 2 years after HCT was 32% (95% CI, 30%-35%) and 59% (95% CI, 56%-62%) at 2 and 10 years after HCT, respectively. HCT survivors are more likely to report difficulty in holding jobs (allogeneic HCT survivors report a 14-fold increased risk compared with the siblings, whereas autologous HCT recipients report a 9-fold increase risk). Furthermore, HCT survivors report greater difficulty in obtaining health insurance (7-fold greater difficulty) or life insurance (9-fold greater difficulty) compared with the sibling comparison group [3Bhatia S. Francisco L. Carter A. et al.Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.Blood. 2007; 110: 3784-3792Crossref PubMed Scopus (366) Google Scholar, 4Bhatia S. Robison L.L. Francisco L. et al.Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study.Blood. 2005; 105: 4215-4222Crossref PubMed Scopus (183) Google Scholar]. BMTSS data reveals that long-term survivors of HCT are at a 2.9-fold increased risk of reporting severe or life-threatening cardiovascular disease when compared with age- and sex-matched siblings [16Sun C.-L. Francisco F. Kawashima T. et al.Burden of long-term morbidity after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS).Blood (ASH Annu Meet Abstr). 2007; 110: 832Google Scholar]. Furthermore, female recipients of autologous HCT are at a 4.4-fold increased risk of premature death from cardiac causes when compared with age-matched general population [4Bhatia S. Robison L.L. Francisco L. et al.Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study.Blood. 2005; 105: 4215-4222Crossref PubMed Scopus (183) Google Scholar]. The next few sections focus on the magnitude of risk and pathogenetic risk factors for the development of cardiovascular complications in HCT survivors. Metabolic syndrome is a constellation of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, and is associated with a substantially increased risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD) [18Reusch J.E. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome.Am J Cardiol. 2002; 90: 19G-26GAbstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 19Trevisan M. Liu J. Bahsas F.B. Menotti A. for the Risk Factor and Life Expectancy Research Group. Syndrome X and mortality: a population-based study.Am J Epidemiol. 1998; 148: 958-966Crossref PubMed Scopus (352) Google Scholar, 20Lakka H.M. Laaksonen D.E. Lakka T.A. et al.The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.JAMA. 2002; 288: 2709-2716Crossref PubMed Scopus (3901) Google Scholar]. Data from the third National Cholesterol Education Program Adult Treatment Panel III (NHANES) (ATP III) [21Park Y.W. Zhu S. Palaniappan L. Heshka S. Carnethon M.R. Heymsfield S.B. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994.Arch Intern Med. 2003; 163: 427-436Crossref PubMed Scopus (1692) Google Scholar, 22Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5594) Google Scholar] (Table 1) show that the prevalence of metabolic syndrome in the U.S. population of adults is 21.7%, with little difference by sex. A comparative analysis of NHANES III with NHANES 1999 to 2000 has shown that the age adjusted prevalence of metabolic syndrome in the United States has increased from 24.1% in to 26.7% (P = .088) [23Ford E.S. Giles W.H. Mokdad A.H. Increasing prevalence of the metabolic syndrome among U.S. Adults.Diabetes Care. 2004; 27: 2444-2449Crossref PubMed Scopus (1201) Google Scholar].Table 1ATP III Criteria for Metabolic Syndrome—Indicated by 3 or More Positive FindingsCriterionAdultsAdolescents∗ATP III criteria modification for adolescents (aged 12–19 years) as described by Cook et al [24].High Triglyceride Level, mg/dL≥150≥110Low HDL-C level, mg/dL Males<40≤40 Females 102≥90th Percentile Females>88≥90th PercentileHigh fasting glucose level, mg/dL≥100†American Diabetes Association 2003 definition lowers abnormal fasting glucose level to 100 mg/dL [73] and this change has been incorporated into the current definition of metabolic syndrome [74].≥100†American Diabetes Association 2003 definition lowers abnormal fasting glucose level to 100 mg/dL [73] and this change has been incorporated into the current definition of metabolic syndrome [74].High blood pressure, mmHg≥130/85≥90th Percentile∗ ATP III criteria modification for adolescents (aged 12–19 years) as described by Cook et al 24Cook S. Weitzman M. Auinger P. Nguyen M. Dietz W.H. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994.Arch Pediatr Adolesc Med. 2003; 157: 821-827Crossref PubMed Scopus (1745) Google Scholar.† American Diabetes Association 2003 definition lowers abnormal fasting glucose level to 100 mg/dL [73Genuth S. Alberti K.G. Bennett P. et al.Follow-up report on the diagnosis of diabetes mellitus.Diabetes Care. 2003; 26: 3160-3167Crossref PubMed Scopus (73) Google Scholar] and this change has been incorporated into the current definition of metabolic syndrome [74Grundy S.M. Brewer Jr., H.B. Cleeman J.I. et al.Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition.Circulation. 2004; 109: 433-438Crossref PubMed Scopus (4109) Google Scholar]. Open table in a new tab The BMTSS demonstrated that, after adjustment for age, sex, and body mass index (BMI), allogeneic HCT survivors were 3.7 times (95% CI: 1.8-7.3) more likely to report diabetes and 2.1 times (95% CI: 1.4-3.0) more likely to report hypertension compared to siblings. Allogeneic HCT survivors were also more 2.3 times more likely to report hypertension (95% CI: 1.5-3.7) when compared with autologous recipients; finally, TBI was associated with an increased risk of diabetes (odds ratio [OR] = 3.4, 95% CI: 1.6-7.5). In the adolescent population in the United States, the prevalence of metabolic syndrome (Table 1) was 4.2% (6.1% in males and 2.1% in females) [24Cook S. Weitzman M. Auinger P. Nguyen M. Dietz W.H. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994.Arch Pediatr Adolesc Med. 2003; 157: 821-827Crossref PubMed Scopus (1745) Google Scholar], with an increase to 6.8% per the NHANES 1999-2000 (P = .02) [25Cook S. Auinger P. Weitzman M. Increasing prevalence of the metabolic syndrome among US adolescents.Pediatr Res. 2004; 55: 592aCrossref PubMed Scopus (66) Google Scholar]. More importantly, nearly 30% of overweight adolescents meet the criteria for metabolic syndrome. There is preliminary evidence to suggest that childhood cancer survivors are at an increased risk for premature development of metabolic syndrome [26Talvensaari K.K. Lanning M. Tapanainen P. Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome.J Clin Endocrinol Metab. 1996; 81: 3051-3055Crossref PubMed Scopus (201) Google Scholar, 27Talvensaari K. Knip M. Childhood cancer and later development of the metabolic syndrome.Ann Med. 1997; 29: 353-355Crossref PubMed Scopus (38) Google Scholar, 28Nuver J. Smit A.J. Postma A. Sleijfer D.T. Gietema J.A. The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures.Cancer Treat Rev. 2002; 28: 195-214Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. In adult survivors of childhood ALL, various factors, including female sex [29Oeffinger K.C. Mertens A.C. Sklar C.A. et al.Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study.J Clin Oncol. 2003; 17: 1359-1365Crossref Scopus (349) Google Scholar], genetic predisposition [30Shaw M.P. Bath L.E. Duff J. Kelnar C.J. Wallace W.H. Obesity in leukemia survivors: the familial contribution.Pediatr Hematol Oncol. 2000; 17: 231-237Crossref PubMed Scopus (37) Google Scholar], exposure to steroids [31Reilly J.J. Brougham M. Montgomery C. Richardson F. Kelly A. Gibson B.E. Effect of glucocorticoid therapy on energy intake in children treated for acute lymphoblastic leukemia.J Clin Endocrinol Metab. 2001; 86: 3742-3745Crossref PubMed Scopus (84) Google Scholar], and cranial radiation therapy [29Oeffinger K.C. Mertens A.C. Sklar C.A. et al.Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study.J Clin Oncol. 2003; 17: 1359-1365Crossref Scopus (349) Google Scholar, 32Sklar C.A. Mertens A.C. Walter A. et al.Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation.Med Pediatr Oncol. 2000; 35: 91-95Crossref PubMed Scopus (184) Google Scholar, have been implicated in the development of obesity and other conditions characteristic of metabolic syndrome. The Childhood Cancer Survivor Study (CCSS) reports that childhood cancer survivors who have received >20 Gy of cranial radiation are 2.6-fold (females) and 1.9-fold (males) more likely to be obese, when compared with age- and race-matched siblings. The risk for obesity is greatest among females exposed to radiation exceeding 20 Gy at 0 to 4 years of age [29Oeffinger K.C. Mertens A.C. Sklar C.A. et al.Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study.J Clin Oncol. 2003; 17: 1359-1365Crossref Scopus (349) Google Scholar]. Although the total dose of TBI exposure in HCT protocols is typically in the range of 10 to 14 Gy, the dose rate is higher, which may have a greater impact at the cellular level than a higher dose given over a longer time period [33Down J.D. Boudewijn A. van Os R. Thames H.D. Ploemacher R.E. Variations in radiation sensitivity and repair among different hematopoietic stem cell subsets following fractionated irradiation.Blood. 1995; 86: 122-127PubMed Google Scholar]. In addition to significantly higher weight and body fat, childhood cancer survivors have been shown to have higher fasting plasma glucose and insulin levels, and lower serum high density lipoprotein (HDL) cholesterol [26Talvensaari K.K. Lanning M. Tapanainen P. Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome.J Clin Endocrinol Metab. 1996; 81: 3051-3055Crossref PubMed Scopus (201) Google Scholar]. A combination of obesity, hyperinsulinemia, and low HDL cholesterol was seen in 16% of the survivors, but in none of the controls (P = .01). Of the survivors with indicators of metabolic syndrome, 50% had received cranial radiation, and also had markedly reduced spontaneous growth hormone (GH) secretion. Similar results were found in survivors of allogeneic HCT performed in childhood. Hyperinsulinemia, impaired glucose tolerance (by oral glucose tolerance test), hypertriglyceridemia, low HDL cholesterol, and abdominal obesity were more common among the HCT patients than among either the non-HCT group of leukemia patients or healthy controls [34Taskinen M. Saarinen-Pihkala U.M. Hovi L. Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood.Lancet. 2000; 356: 993-997Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar]. Core signs of metabolic syndrome were found in 39% of HCT survivors versus 8% of leukemia controls and 0% of healthy controls. Fifty-two percent of HCT patients were found to have hyperinsulinemia and 43% had abnormal glucose metabolism, compared to none of the healthy controls (P = .0002, and .001 respectively). Variables associated with hyperinsulinemia in the HCT patients were time from transplantation (P = .01), presence of cGVHD (P = .01), and hypogonadism (P = .04). Another study found that the patients who received TBI had a significantly higher first phase insulin response and insulinemia/glycemia ratio on glucose tolerance testing compared to patients who received only lymphoid radiation, no radiation, or controls [35Lorini R. Cortona L. Scaramuzza A. et al.Hyperinsulinemia in children and adolescents after bone marrow transplantation.Bone Marrow Transplant. 1995; 15: 873-877PubMed Google Scholar], suggesting that TBI may play a role in the development of insulin resistance. Presence of metabolic syndrome places survivors at an elevated risk for a number of adverse health outcomes, such as overt diabetes and cardiovascular disease, which when combined with prior exposure to cardiotoxic agents such as chest radiation and anthracyclines and cyclophosphamide (Cy) [36Sorensen K. Levitt G. Bull C. Chessells J. Sullivan I. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity.J Clin Oncol. 1997; 15: 61-68PubMed Google Scholar, 37Colvin M. Hilton J. Pharmacology of cyclophosphamide and metabolites.Cancer Treat Rep. 1981; 65: 89-95PubMed Google Scholar] could have a potentially devastating consequence on the survivors [28Nuver J. Smit A.J. Postma A. Sleijfer D.T. Gietema J.A. The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures.Cancer Treat Rev. 2002; 28: 195-214Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. Preclinical and clinical evidence of the impact of the components of metabolic syndrome on radiation-related atherosclerotic heart disease and anthracycline-related congestive heart failure is described in detail in the following section. Atherosclerosis is a complex process involving inflammation and cellular proliferation in arterial walls. The development and progression of atherosclerosis is mediated by a variety of growth factors, cytokines, thrombotic factors, and vasoactive substances. Insulin resistance is a suspected causal pathway because of its clinical association with increased rates of macrovascular disease and subsequent cardiovascular morbidity and mortality [38Reaven G.M. Banting lecture 1988. Role of insulin resistance in human disease.Diabetes. 1988; 37: 1595-1607Crossref PubMed Google Scholar]. Insulin resistance is associated with endothelial dysfunction and impaired insulin-mediated nitric oxide-dependent vasodilation [39Petrie J.R. Ueda S. Webb D.J. Elliott H.L. Connell J.M. Endothelial nitric oxide production and insulin sensitivity. A physiologic link with implications for pathogenesis of cardiovascular disease.Circulation. 1996; 93: 1331-1333Crossref PubMed Scopus (272) Google Scholar]. Endothelial dysfunction occurs early in the pathogenesis of atherosclerosis and is associated with many cardiovascular pathologic disease states. Strong evidence exists showing the association between arterial stiffness and atherosclerosis, cardiovascular disease, and mortality [40Valente A.M. Strong W. Sinaiko A.R. Obesity and insulin resistance in young people.Am Heart J. 2001; 142: 440-444Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 41van Dijk R.A. Dekker J.M. Nijpels G. Heine R.J. Bouter L.M. Stehouwer C.D. Brachial artery pulse pressure and common carotid artery diameter: mutually independent associations with mortality in subjects with a recent history of impaired glucose tolerance.Eur J Clin Invest. 2001; 31: 756-763Crossref PubMed Scopus (33) Google Scholar]. Radiation therapy, including TBI, may lead to arterial stiffness and, therefore, potentially to atherosclerosis. In an ongoing study we have measured insulin resistance, fasting glucose, insulin, lipids, anthropometry, blood pressure, and carotid artery compliance and distensibility in 106 survivors of HCT performed in childhood (current age 26.6 years) and 72 healthy sibling controls (current age 23.7 years). Preliminary analysis found 2 or more components of metabolic syndrome were present in 37% survivors and only 13.9% controls (OR, 2.7, 95% CI 1.2-5.9, P = .02). HCT survivors who had TBI with or without cranial radiation had significantly higher total cholesterol, LDL cholesterol, triglycerides, and insulin, and lower HDL cholesterol levels, and they were also more insulin resistant. However, for the subjects who did not receive any radiation prior to or during HCT, there were no differences in any of the cardiovascular risk factors compared to controls. Carotid artery distensibility was decreased in survivors who received TBI compared to controls with an even greater negative impact in those who received TBI and pre-HCT cranial radiation. These findings are concerning, and suggest that even at a relatively young age, and independent of obesity, HCT survivors of childhood hematologic malignancies have increased cardiovascular risk factors present as well as adverse vascular changes, which are associated with exposure to TBI, with or without cranial radiation. These abnormalities may ultimately contribute to a higher risk of early cardiovascular morbidity and mortality, and thus early screening and management of modifiable cardiovascular risk factors should be considered in HCT survivors. CHF is a well-described sequela during the immediate post-HCT period. Mortality attributed early CHF ranges from 1% to 9%, whereas morbidity ranges from 5% to 43% [42Hertenstein B. Stefanic M. Schmeiser T. et al.Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant.J Clin Oncol. 1994; 12: 998-1004Crossref PubMed Scopus (123) Google Scholar, 43Fujimaki K. Maruta A. Yoshida M. et al.Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction.Bone Marrow Transplant. 2001; 27: 307-310Crossref PubMed Scopus (70) Google Scholar, 44Murdych T. Weisdorf D.J. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977-1997.Bone Marrow Transplant. 2001; 28: 283-287Crossref PubMed Scopus (118) Google Scholar]. Risk factors for early CHF include reduced pre-HCT ejection fraction (EF), conditioning with high-dose (HD) Cy and TBI [44Murdych T. Weisdorf D.J. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977-1997.Bone Marrow Transplant. 2001; 28: 283-287Crossref PubMed Scopus (118) Google Scholar, 45Braverman A.C.
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