Cardiac Chamber Hypertrophy following Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency

Article Outline

• Abstract
• Introduction
• Materials and Methods
  • Patients
  • Echocardiography
  • Statistical Analysis
• Results
  • Patient Characteristics
  • Complication and Outcome after HSCT
  • Cardiac Chamber Hypertrophy after HSCT
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Children with primary immune deficiency (PID) who receive hematopoietic stem cell transplantation (HSCT) often suffer from graft-versus-host disease (GVHD), which is commonly treated with corticosteroids (CS). CS may cause hypertension, development of cardiac chamber hypertrophy (CCH), and left ventricular outflow tract obstruction (LVOTO). We followed the development of CCH and LVOTO by serial echocardiograms in 10 children with PID before and 6 to 12 weeks after HSCT, and correlated their development with age of transplant, GVHD, use of CS and hypertension. CCH developed in all 4 children transplanted before 1 year of age who received high dose CS treatment for grade III or IV acute GVHD (aGVHD), but not in the 6 children who were transplanted at later ages or who had not received high-dose CS (P = .07). Significant correlation (P < .002) was found between CCH and blood pressure measurements that deviated above the 99th percentile. One child also suffered from severe LVOTO. CCH and LVOTO improved when CS treatment was discontinued and blood pressure normalized. We conclude that following HSCT, young children who suffer from aGVHD, treated with high CS doses, and have excessive hypertension are at risk of developing CCH.

Key Words: Immunodeficiency, Hematopoietic stem cell transplant, Corticosteroids, Hypertrophic, Cardiomyopathy

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Introduction 

Primary immune deficiency (PID) diseases are heterogeneous diseases that cause increased susceptibility to infections in infancy, some of which are fatal unless treated with allogeneic hematopoietic stem cell transplantation (HSCT). Despite prophylaxis, acute graft-versus-host-disease (aGVHD) occurs in 40% to 50% or 70% to 80% of patients with severe immunodeficiency who receive HSCT from family-related HLA identical donors or HLA-matched unrelated donors, respectively [1]. Corticosteroids (CS), often at high doses, have been used to effectively treat aGVHD [2]. Common side effects of CS, including hyperglycemia, hypertension, and increased susceptibility to infections, are well known. CS has also been associated with the development of cardiac chamber hypertrophy (CCH).

CCH is characterized by thickening of the left ventricle wall, particularly the interventricular septum, and is best identified by 2-dimensional echocardiogram (2DE). CCH is most commonly caused by inherited defects in sarcomere function with hypertrophic cardiomyopathy [3]. Similar CCH has been described in preterm, newborns, and infants treated with CS for lung disease or hypsarrhythmia, many of whom also suffered from hypertension 4, 5. CCH has also been reported in young recipients of kidney transplants, possibly because of hypertension [6]. CCH may result in left ventricular outflow tract obstruction (LVOTO) and life-threatening arrhythmias.

CCH has been reported, albeit rarely, after HSCT, typically in patients with conditions predisposing to cardiac complications such as malignant infiltration or inherited metabolic storage diseases 7, 8. CCH and LVOTO were described in a single patient with Krabbe disease, who received HSCT in the first month of life [9]. However, the development of such complications after HSCT was not prospectively studied in large groups of patients after HSCT.

Detailed in this report is the observation that CCH may be associated with CS treatment for GVHD in children with PID who undergo HSCT.

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Materials and Methods 

Patients 

Children diagnosed with PID according to the World Health Organization (WHO) classification, who received HSCT at the Hospital for Sick Children, Toronto, Canada, between March 1, 2003, and February 28, 2007, were included in this study. Patients were excluded if they did not have echocardiograms before and/or after HSCT. Upon diagnosis, and until discharge, patients were nursed in private laminar air flow-filtered rooms with strict reverse isolation procedures. Intravenous immunoglobulin infusions were given to maintain IgG levels in the normal range for age. High-calorie diet and prophylactic antibiotics for Pneumocystis jiroveci were given. Children diagnosed with Omenn's syndrome were treated with CS or Cyclosporine A (CsA) prior to HSCT. All patients received myeloablative conditioning with intravenous busulphan followed by cyclophosphamide, each for 4 days. Engraftment was supported with granulocyte-colony stimulating factor (G-CSF), which was continued until the absolute neutrophil counts (ANC) were >1 × 10⁹ cells/L on 3 consecutive days. After HSCT, the children received acyclovir, cotrimoxazole, and Penicillin to prevent infections. Blood samples were obtained weekly for DNA polymerase chain reaction for herpes viruses including Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

GVHD prophylaxis included CS (methylprednisolone) 2 mg/kg body weight/day and CsA with doses adjusted to maintain levels between 100 to 150 or 150 to 200 μmol/L, after HSCT from family related or unrelated donors, respectively. The severity of aGVHD was graded according to Glucksberg et al. Grade III or IV aGVHD was treated with 30 mg/kg/day methyleprednisolone (MP) for 3 days, which were reduced every 3 days to 20 mg/kg/day, 10 mg/kg/day, 5 mg/kg/day, 3.75 mg/kg/day, and 2 mg/kg/day. Subsequently, MP (or equal potency prednisone) was reduced by 25% on alternate days every 1 or 2 weeks for patients after HSCT from related or unrelated donors, respectively. When CS were given only on alternate days, CsA was reduced by 25% to 33% every 2 weeks, followed by gradual reduction of the remaining CS. Systolic blood pressures, determined when the patients were not active, crying, or febrile, were maintained below the 95th percentile for age with 1 or more of the following: amlodipine, nifedipine, enalapril, nadolol, or captopril. Acute GVHD (aGVHD) or chronic GVHD (cGVHD) were documented on every follow-up visit. None of the patients were lost to follow-up. This prospective study was approved by the Hospital for Sick Children, Toronto, Research Ethics Board.

Echocardiography 

All children had 2-dimensional echocardiograms (2DE) 2 to 3 weeks prior to HSCT and 6 to 12 weeks after HSCT. The echocardiograms were obtained with commercially available equipment (High Definition Imager 5000, Philips Medical Systems, Canada) using a 700-MHz transducer and analyzed by a single cardiologist (L.B). Measurements included right and left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and interventricular septum (IVS) and left ventricular posterior wall (LVPW) thicknesses corrected for body surface area, as previously described [10]. Left ventricular systolic function was assessed by fractional shortening and ejection fraction (EF). 2DE measurements were considered abnormal if the Z-scores were >3. The Z-score was calculated as: patient value minus normal population mean/population standard deviation [10]. Doppler ultrasound was used to determine LVOTO, which was defined as anatomic narrowing together with a measured systolic gradient of >15 mmHg. None of the children had evidence for familial hypertrophic cardiomyopathy or Pompe's disease, Friedreich's ataxia, or Noonan's syndrome, which have also been associated with CCH.

Statistical Analysis 

Correlation between patients' age at transplant, doses of MP, frequency and magnitude of hypertensive episodes, and development of CCH, as measured by LVPW and IVS Z-scores, were determined using Spearman Correlation Coefficient. Cumulative MP doses were calculating by multiplying the daily dose (in milligrams equivalent to MP) and duration of treatment between HSCT and the 2DE, divided by the patient's weights. Three systolic blood pressure measurements per day recorded in the patients' charts by the nursing team, at similar hours of the day between HSCT and the 2DE, were used to calculate the frequency and deviation from the 95th and 99th maximal blood pressure percentiles for age and height. Crossclassified comparisons were analyzed by the Fisher's exact tests. Differences were considered statistically significant if P < .05.

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Results 

Patient Characteristics 

Ten patients diagnosed with PID who received HSCT were included in this study. Mutations in the gamma common chain were the cause of the immunodeficiency in patients #1, #2, and #3. Four patients had mutations in the Ribonuclease Mitochondrial RNA Processing (patient #7), CD3δ (patient #8), adenosine deaminase (patient #9), or Wiskott-Aldrich syndrome genes (#10). Two patients suffered from Omenn's syndrome without identifiable mutations. Five were treated with CS prior to HSCT, including 3 with Omenn's phenotype (#4, #6, and #7). Patient #5 with Pneumocystis jiroveci pneumonia received 1 mg/kg/day MP for 2 weeks, and another child (#10) with Wiskott-Aldrich syndrome received a 3-day course of 4 mg/kg/day MP for low platelet counts. Prior to HSCT, 2DE demonstrated nonsignificant small patent foramen ovale in 2 children (# 4 and #8) and a mitral valve nodule in 1 patient (#9), which was determined to be noninfectious. All had normal LVPW and IVS thicknesses (Table 1) and normal ejection fraction prior to HSCT (not shown).

Table 1. Patient Characteristics

LVPW indicates left ventricle posterior wall thickness; IVS, interventricular septum thickness; HSCT, hematopoietic stem cell transplantation; M, months; HLA, human leukocyte antigen; MUD, matched unrelated donor; PBL, CD34⁺ from peripheral blood lymphocytes; GVHD, graft-versus-host disease; A, alive; W, well; CS, corticosteroid; GI, gastrointestinal tract.

HSCT was performed at a median age of 6 months (range: 5-19 months). Seven of the children received bone marrow from HLA-matched or mismatched unrelated donors, 1 patient received bone marrow from an HLA-identical family member, and 2 patients received CD34⁺ selected stem cells derived from peripheral blood lymphocytes (Table 1).

Complication and Outcome after HSCT 

aGVHD grade III or higher was diagnosed in 1 and 6 patients after HSCT from family-related or -unrelated donors, respectively (Table 1). Another patient suffered skin grade I GVHD 32 days after transplant. aGVHD of the skin was diagnosed clinically, whereas aGVHD of the gastrointestinal system and liver, which occurred in 4, were confirmed by biopsies. aGVHD improved rapidly in all 7 patients following 3 days of high-dose CS. All the children who received high dose CS required 2 or more antihypertensive medications.

Patient #2 was the only patient who did not survive. Five months after HSCT, while still receiving weaning doses of CS, CsA, amlodipine, and nadolol, he presented with vomiting and low-grade fever. He rapidly deteriorated despite broad-spectrum antibiotic treatment. Autopsy showed extensive myocarditis and diffuse skeletal muscles myositis suggestive of toxic shock-like syndrome. No infectious etiology was identified.

Cardiac Chamber Hypertrophy after HSCT 

CCH was diagnosed in 4 children after HSCT. Three months after HSCT, patient #2 was found to have CCH without LVOTO. Although sequential echocardiograms are not available, autopsy performed 2 months later showed persistent hypertrophy. Patient #4 was found to have marked CCH and LVOTO with a gradient of up to 85 mmHg across the aortic outlet, 3 months after HSCT. CS doses and CsA were rapidly tapered over 6 weeks and propanolol was added. Repeat 2DE 3 months later demonstrated marked improvement of the CCH and LVOTO (Figure 1A). However, 14 months after the HSCT, a short viral illness induced extensive sclerodermatous GVHD involving the skin and lungs, which was treated with 30 mg/mg/kg MP for 3 days. Echocardiogram was performed 3 weeks later, demonstrated worsening of the CCH and LVOTO, which again improved with propanolol treatment and reduction of CS (Figure 1B). Patient #7 suffered severe aGVHD, which initially responded to high doses of CS. Exacerbation of the aGVHD, which occurred during reduction of CS in the first 2 months after HSCT, was treated with mycophenol mofetil (MMF), antithymocyte immunoglobulin, and daclizumab. CCH was found 2 months after transplant, with no evidence of LVOTO. Patient #10 was found to have CCH without LVOTO, 6 weeks after HSCT. Because of persistent low-grade skin and gastrointestinal GVHD, CS treatment was gradually reduced over 8 months, with improvement of the left ventricular hypertrophy. Importantly, despite the development of CCH, Left ventricular ejection fractions were normal in all children (63% to 82%) and repeated electrocardiograms did not demonstrate abnormal heart rate in any child. Also, right and left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and fractional shortening remained normal after HSCT (data not shown).

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• Figure 1 

  Echocardiograms of patient #4. (A) Echocardiogram long axis views of the left ventricle demonstrating a thickened interventricular septum (left), which improved 3 month later (right). (B) Schematic representation of left ventricular posterior wall (open squares) and interventricular septum thickness (open triangles), in centimeters, and corticosteroids treatment (filled shapes) in doses equivalent to methylprednisolone, before and after hematopoietic stem cells transplantation.

CCH developed in all 4 children transplanted before 1 year of age who received high-dose CS treatment for grade III or IV aGVHD, but not in the 6 children who were transplanted at a later age or who had not received high-dose CS (P = .07). There was negative correlation between patients' age and LVPW or IVS Z-scores, r = −0.53 and −0.39, respectively, which did not reach statistical significance. There was no significant correlation between LVPW or IVS Z-scores and total amount of CS (Table 2), or between the frequency and the cumulative blood pressure above the 95th percentile and CCH (data not shown). Positive correlation was found between LVPW and IVS Z-scores and the frequency of blood pressure above the 99th percentile, r = +0.55 and +0.48, although they did not reach statistical significance (Table 2). In contrast, correlation between LVPW or IVS Z-scores and cumulative blood pressure measurements above the 99th percentile, r = 0.88 and 0.87, respectively, were statistically significant (P = .0008 and .0012, respectively).

Table 2. Cardiac Chamber Hypertrophy after Hematopoietic Stem Cell Transplantation

2DE indicates 2-dimensional echocardiogram; HSCT, hematopoietic stem cell transplantation; LVPW, left ventricle posterior wall thickness; IVS, interventricular septum thickness; MP, methylprednisolone; BP, blood pressure; Mm, millimeter; CCH. cardiac chamber hypertrophy; LVOTO, left ventricular outflow tract obstruction.

Italic data are significantly elevated (Z > 3) LVPW and IVS compared to normal controls adjusted for body surface area.

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Discussion 

Herein we describe the first series of 4 patients who after HSCT developed CCH indistinguishable from hypertrophic cardiomyopathy. The hypertrophic cardiomyopathy phenotype is common among children with inherited defects of myocardial function, Pompe's disease, Friedreich's, ataxia, or Noonan's syndrome. However, the contribution of such inherited syndromes and mutations in the sarcomere to the development of CCH in the children under our care is unlikely, as there were no other affected family members, and 3 of the 4 patients with CCH had mutations in genes that do not result in cardiac involvement. The remaining patient had Omenn's syndrome, which has previously been associated with ventricular hypertrophy in 1 patient prior to HSCT, possibly secondary to abnormal lymphocytes infiltrating the heart [11]. In contrast, our patient with Omenn's syndrome developed CCH after HSCT, when T cell receptor analysis already demonstrated normal expansion (data not shown). Thus, the cardiac hypertrophy in our patients was not likely inherited or directly related to the immunodeficiency, but rather related to the procedure or treatment that these children received.

Anthracyclines and mediastinal irradiation given prior to HSCT have been reported to cause cardiac complications including arrhythmia and heart failure but not the development of cardiac hypertrophy [12]. Similarly, high doses of Cy can result in restrictive cardiomyopathy but not CCH per se [13], which suggests that the CCH in our cohort was not because of the transplant itself.

There are several common factors in the management of the children described herein, which may help understand the development of CCH. All the patients who developed CCH had received the transplant before 1 year of age, experienced aGVHD, were treated with CsA and high doses of CS, and suffered from hypertension. aGVHD of the heart is rare, and usually manifests as pericardial effusions, rhythm abnormalities, or coronary arteriosclerosis, but not CCH [14]. Treatment with the calcineurin inhibitors CsA or Tacrolimus after solid organ transplantations have been associated with CCH, possibly by exacerbating hypertension; however, the CsA doses used to prevent solid organ rejection are typically greater than those given after HSCT [15]. In addition, by interfering with NFAT signaling, calcineurin inhibitors have actually been proposed for prevention and treatment of CCH [16]; therefore, it is unlikely that they were the major factor in development of CCH in our cohort. Therefore, we suspect that 1 or more of the remaining factors contributed to the appearance of CCH. The association between high doses of CS and CCH is well established, primarily in preterm infants or in the first few weeks of life, many of whom also suffer from hypertension 4, 5, 17. CCH has also been reported in very few older children treated with CS [18], although not after HSCT. CS may contribute to the development of CCH by 1 or more mechanisms. Steroids may directly stimulate glucocorticoid and mineralocorticoid receptors in muscle cells, increase Ca²⁺ currents, or alter gene expression, which may lead to myocyte hypertrophy 19, 20. Alternatively, CS and CsA induced hypertension may cause pressure overload, which stimulates myocyte hypertrophy [21]. Support for the contribution of hypertension to the CCH in this cohort is the correlation that we found between accumulative blood pressure beyond the 99th percentile and heart wall thickness, which is similar to the reports of left ventricular wall thickening in patients with malignant hypertension [22]. Clonidine, often used to treat hypertension, may further potentiate the effects of CS on the development of cardiac hypertrophy [23]. However, such mechanisms are unlikely to have contributed to CCH in our cohort, as patients were not treated with alpha-adrenergic agonists. Thus, our data suggests that HSCT complicated by aGVHD and treated with high doses of CS, directly or in concert with some of the factors described above, and hypertension, particularly in young children, is associated with the development of CCH.

Medications used to prevent or treat GVHD after HSCT have many adverse effects, to which we now add the possible development of CCH. However, as also demonstrated in our cohort, aggressive treatment of aGVHD is still the most common cause of death after HSCT in children with PID and other nonmalignant diseases 1, 24. Furthermore, we demonstrated reversal of the CCH and LVOTO upon improvement of the GVHD, discontinuation of CS, and control of hypertension, and none of the children experienced life-threatening arrhythmia. Therefore, we suggest that while continuing the use of CS for aGVHD after HSCT for PID, follow-up echocardiograms should be performed to detect the development of CCH, enabling appropriate adjustment of the immunosuppressive therapy.

Many children, other than those with PID, undergo HSCT and frequently receive immune suppression with CS or CsA and suffer from hypertension; however, we are unaware of previous reports of CCH in such patients. Patients with severe immune defects typically present and are transplanted, at a much younger age than most pediatric malignancies or other inherited disease. Furthermore, because GVHD is the most common cause of morbidity and mortality after transplant for severe immune defects, it is often treated more aggressively and with higher doses of steroids than in patients transplanted for other etiologies [1]. Therefore, to determine whether the development of CCH is unique to our cohort, to patients with severe immune deficiency, or is overlooked in other populations, larger prospective studies in young children receiving HSCT for other etiologies will be required.

In conclusion, we demonstrate increased frequency of CCH after HSCT for PID in children <1 year of age who developed aGVHD, were treated with high doses of CS, and who suffered from hypertension.

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Acknowledgments 

This work was supported in part by the Jeffrey Modell Foundation, by the Canadian Centre for Primary Immunodeficiency, and by the Donald and Audrey Campbell Chair of Immunology (CMR).

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