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  Ventricular Diastolic Dysfunction in Sickle Cell Anemia IsCommon But Not Associated With Myocardial Iron Deposition Jane S. Hankins, MD, MS 1, M. Beth McCarville, MD 2, Claudia M. Hillenbrand, PhD 2, Ralf B.Loeffler, PhD 2, Russell E. Ware, MD, PhD 1, Ruitian Song, PhD 2, Matthew P. Smeltzer, MS 4,and Vijaya Joshi, MD 3 1 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 2 Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 3 Department of Pediatrics – Division of Cardiology, University of Tennessee, Memphis, TN 4 Department of Biostatistics St. Jude Children's Research Hospital, Memphis, TN  Abstract Background— Cardiac failure from myocardial iron deposition is a severe complication in patients with transfusion-related iron overload. Progressive heart damage from iron overload cancause left ventricular systolic and diastolic dysfunction in patients with hematologic disorders.Since non-transfused patients with sickle cell anemia (SCA) have a high incidence of diastolicdysfunction, we investigated the relationships among transfusional iron burden, myocardial irondeposition, and diastolic ventricular dysfunction by T2*-MRI and tissue Doppler echocardiography in iron-overloaded children with SCA. Procedure— Children ( ≥ 7 years) with SCA and iron overload (serum ferritin >1000 ng/ml or  ≥ 18 lifetime transfusions) were eligible. Serum ferritin and hepatic iron content (HIC) weremeasured and participants underwent nonsedated T2*-MRI of the heart, echocardiogram,electrocardiogram, and multi-uptake gated acquisition (MUGA) scan. Age-matched normativeechocardiographic data were used for comparison. Results— Among 30 children with SCA (median age, 13 years) and iron overload, mean (±SD)HIC and serum ferritin were 10.8 mg Fe/g (±5.9 mg Fe/g) and 3089 ng/mL (±2167 ng/mL),respectively. Mean T2*-MRI was 33 msec (±7 msec, range 22-49). Echocardiography showed ahigh prevalence of diastolic dysfunction (77% and 45% abnormally low mean mitral annular velocity and mean tricuspid annular velocity, respectively); however, echocardiogram and MUGAscan findings were not significantly associated with HIC or T2*-MRI. Conclusions— Diastolic dysfunction is not associated with transfusional iron burden or myocardial iron deposition among children with SCA. Diastolic dysfunction likely results fromdisease pathophysiology and severity rather than iron overload. Keywords T2*MRI; echocardiography; multi-uptake gated acquisition; diastolic dysfunction; systolicdysfunction; sickle cell disease Corresponding author : Jane Hankins, MD, MS St Jude Children's Research Hospital - Department of Hematology 262 DannyThomas Place - MS # 800 Memphis TN 38105 Tel. (901) 595-4153/ Fax (901) 595-2952 jane.hankins@stjude.org.  NIH Public Access Author Manuscript Pediatr Blood Cancer  . Author manuscript; available in PMC 2011 September 1. Published in final edited form as: Pediatr Blood Cancer  . 2010 September ; 55(3): 495–500. doi:10.1002/pbc.22587. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    INTRODUCTION Cardiac failure is a major complication for patients with hematological disorders who haveincreased body iron burden because of repeated blood transfusions. Myocardial irondeposition leads to progressive heart dysfunction and remains the leading cause of death in patients with beta thalassemia major (TM).[1;2] Myocardial hemosiderosis can also occur inother hematological diseases treated with repeated blood transfusions such as Diamond– Blackfan anemia, myelodysplasia, and, in some cases, sickle cell anemia (SCA).[3]The severity of cardiac dysfunction depends on the amount of iron deposited in themyocardium[4] and the overall body iron burden; hepatic iron content (HIC) persistentlygreater than 15 mg Fe/g of dry weight liver is associated with cardiac morbidity.[5] Leftventricular systolic dysfunction (decreased ejection fraction) is a late finding of heart diseasefrom iron accumulation, since cardiac iron deposition is associated with the duration of  blood transfusions.[3] In contrast, left ventricular diastolic dysfunction occurs earlier in thedevelopment of overall cardiac dysfunction (heart failure), and its presence is anindependent risk factor for mortality among adults with SCA.[6]Diastolic dysfunction, measured by tissue Doppler imaging (TDI) echocardiography, has been documented in patients with hematological diseases; left ventricular diastolicdysfunction occurs in 9.7–18% of patients with SCA without iron overload.[6;7] Patientswith TM having high ferritin values also have restrictive left ventricular fillingabnormalities, suggesting ventricular diastolic impairment.[8] Small-scale studies havesuggested a relationship between iron overload and diastolic dysfunction in SCA. Childrenwith SCA receiving blood transfusions have a higher left ventricular myocardial performance index (LVMPI – a measure of combined left ventricular systolic and diastolicfunction) than control patients with SCA not receiving transfusion.[9;10] In these reports,systolic function was normal and the high LVMPI was thought to be secondary to diastolicleft ventricular dysfunction, however exclusive measures of diastolic function were not performed. No previous studies on SCA have investigated the relationships between myocardial irondeposition measured by magnetic resonance imaging (MRI), transfusional iron burden, and diastolic ventricular dysfunction. We investigated the relationships between the degree of myocardial iron accumulation and ventricular diastolic function by comparing heart T2*-MRI measurements with echocardiogram tissue Doppler findings in iron-overloaded children with SCA ( ≥ 7 years old) who received medical care at St. Jude Children's ResearchHospital (St. Jude). DESIGN AND METHODS Patient Selection and Data Collection This prospective study was approved by the St. Jude Institutional Review Board. Study participants or their legal guardians provided signed informed consent before any study-related activity; all children signed an informed assent. Children with SCA receivingmedical care at St. Jude were eligible to participate in the study if they were 7 years or older and had a diagnosis of iron overload. Patients were defined as having iron overload if theyhad serum ferritin values of 1000 ng/mL or more within 3 months of enrollment or had received 18 or more lifetime erythrocyte transfusions.[11;12] Patients who had anycontraindication for MRI testing (e.g., presence of ferromagnetic material in the body),could not tolerate MRI without sedation, or were pregnant were not enrolled in the study. Inaddition, patients with history of prior heart surgery were not included in the presentanalysis. Hankins et al.Page 2 Pediatr Blood Cancer  . Author manuscript; available in PMC 2011 September 1. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    Medical records of patients were reviewed for transfusion history prior to study enrollment,use of cardiac medication at the time of enrollment, and symptoms of heart failure. Study participants underwent a nonsedated T2*-MRI exam of the heart followed byechocardiogram, complete blood count, reticulocyte count, chemistries, electrocardiogram(EKG), multi-uptake gated acquisition (MUGA) nuclear scan, and one single serum ferritinmeasurement, all within 30 days. The hemoglobin (Hb) concentration value closest to theechocardiogram exam (usually the pre-transfusion Hb) was ascertained. To calibrate theT2*-MRI technique for assessing liver iron content, participants also underwent a percutaneous liver biopsy with HIC quantitation, and these findings have already beenreported.[13] Echocardiogram and MUGA Scan All studies were performed using GE Vivid 7 ultrasound equipment with 3.5 or 2.5 MHztransducers. Standard transthoracic 2D images were obtained. M Mode analysis was donefrom a parasternal long axis projection of the left ventricle (LV). Color flow Doppler,spectral Doppler, and tissue Doppler measurements were obtained. LV dimension, systolicfunction, and LV mass measurements were made using the M Mode data. Measurementswere made with the internal equipment electronic calipers on the digital image, or for videotape, the image was calibrated by using reference lines on the video screen image.Measurement of systolic function included estimation of the LV shortening fraction (LVSF).The left ventricular dimensions, systolic function, and LV mass were estimated from the MMode according to guidelines of the American Society of Echocardiography.[14] In order tocompare our results to published data in patients with SCA, the LVMPI (or Tei) wasobtained. LVMPI was calculated from the mitral valve inflow and the LV outflow obtained close in time. The mitral closing to opening time ( a ) was measured at the end of the intervalfrom the end to the onset of the mitral inflow velocity profile. The LV ejection time ( b ) wasmeasured from the onset to the end of the LV outflow velocity profile. LVMPI wascalculated by the formula ( a  – b )/ b .[15] Mean values were obtained by averaging the 3 best-quality signals from a sequence. Tissue Doppler was done from the apical projection withthe presets from the equipment. For each velocity, an average of 3 beats was used. The peak mitral annular velocity ( e ′ ) and early filling of the left ventricle ( e ) were measured fromdigital image videotape by using the echo machine calibration tool and electronic calipers.The e / e ′  ratio was used as a measure of global left ventricular diastolic function. The peak tricuspid annular velocity was used as a measure of right ventricular diastolic function.Decreasing e ′  (and therefore increasing e / e ′  ratio) values reflect the decreasing relaxationability (increasing stiffness) of the left ventricle, whereas decreasing peak tricuspid annular velocities reflect increasing right ventricular stiffness.Cardiac gated nuclear medicine blood pool studies (MUGA scan) were performed on patients in a resting state. An in vivo  method of labeling red blood cells was employed.Patients were intravenously administered 3 mg of sodium pertechnetate 30 min beforeinjecting 99m technetium at a dose of 15mCi times their body surface area (maximum dose20mCi). Patients were placed in a supine position on the gamma camera (Siemens Duet,Chicago, IL) and 45° left lateral oblique (LAO) and 70° left lateral projection images wereobtained over 5 min at a frame rate of 16 per cardiac cycle. The left ventricular ejectionfraction (LVEF) was calculated on the basis of LAO projection images. Cine clips wereevaluated by a nuclear medicine physician or a radiologist to assess regional wall motionabnormalities. MRI Study participants underwent a nonsedated single breath-hold examination of the heart by asingle 1.5T MRI scanner (Siemens Magnetom Symphony, Siemens, Malvern, PA) within 30 Hankins et al.Page 3 Pediatr Blood Cancer  . Author manuscript; available in PMC 2011 September 1. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    days of the echocardiogram, EKG, and MUGA scan. A short axis mid-ventricular 8-mm-thick slice positioned halfway between the base and apex of the left ventricle was acquired at 12 separate short echo times (TEs) in a single breath-hold (TEs ranging from 2 to 21.1msec with equal echo spacings). To ensure best possible cardiac motion compensation, EKGgating was performed while scanning.Images were transferred to a computer workstation for postprocessing region of interest(ROI) T2* measurement. Quantitative T2* maps were calculated offline, using customwritten MATLAB software, and the signal intensity drop over the image series was fitted ona pixel-by-pixel basis to a monoexponential decay, using the least-squares fit method byLevenberg-Marquardt.[16;17] ROIs were drawn either on the source images or on T2*maps, in the left ventricular septum, distant from lungs and cardiac veins. Images wereconsidered inadequate if a sufficient amount of pixels in the ROI could not be fitted, either due to iron accumulation (lack of MR signal) or the presence of cardiac motion artifacts(bright signal across the image). The total MR table bedtime required for the T2*-MRIexamination of the heart was approximately 20 min. Statistical Analyses To avoid intrapatient association and thereby a confounded interpretation of results, each patient participated in the study only once. LVEF values (measured by the MUGA scan) below 60% and LVSF values (measured by echocardiogram) below 28% were considered abnormal. Echocardiogram measurements were categorized as normal or abnormal, usingnormative age-specific published data.[18] The association of echocardiogram and MUGAvariables (both as continuous and categorical variables) with T2*-MRI measurements wasinvestigated using Fisher's Exact test, the Wilcoxon-Mann-Whitney test, or Spearman'srank-order correlation with exact  p -values estimated by Monte Carlo simulation. If thecorrelation coefficient was significantly different from zero,  p -values were reported;  p -values were considered significant if < 0.05. RESULTS Patient Characteristics Thirty-two patients with SCA underwent both heart T2*-MRI and cardiac tests (MUGAscan, EKG, and echocardiography), however two patients were excluded from the analysis:one due to prior heart surgery, and one due to artifacts in the chest that precluded MRIinterpretation. Of the 30 patients included in the analysis, 15 were male and 15 were female,and their SCA genotypes were Hb SS (28) and Hb S β 0 -thalassemia (2); their median agewas 13 years (range, 8–18 years). Reasons for patients to receive chronic transfusions weresecondary stroke prevention (10), primary stroke prevention (12), and prophylaxis againstrecurrence of vasoocclusive events such as acute chest syndrome (8). None of these 30 patients had a history of heart disease or used any heart medication. Mean (± SD) Hbconcentration was 9.9 g/dL (± 1.5 g/dL), and was obtained within 7 days in all but one patient who had it done within two weeks of cardiac testing. The mean (± SD) HIC and serum ferritin values were 10.8 mg Fe/g of dry weight liver (±5.9 mg Fe/g) and 3089 ng/mL(±2167 ng/mL), respectively. These 30 patients had received erythrocyte transfusions for amedian of 45 months (range, 7–162 months) before study enrollment. One patient came toour program in her teenage years and her records reported only 7 erythrocyte transfusions;however, since her serum ferritin was more than 1000 ng/mL, the total number of erythrocyte transfusions she received may have been underestimated. Fourteen (47%) of these patients had history of chelation therapy at the time of study enrollment, and their median duration of chelation therapy was 7.5 months (range 1 – 65 months). Hankins et al.Page 4 Pediatr Blood Cancer  . Author manuscript; available in PMC 2011 September 1. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  
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