|Year : 2020 | Volume
| Issue : 1 | Page : 11-16
Evaluation of cardiac complications in transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT) beta thalassemia patients
Marah Sudad Nameq1, Rawand P Shamoon2, Mariwan H Saka3
1 Department of Histopathology, Rizgary Teaching Hospital, Erbil, Iskan City, Iraq
2 Department of Pathology, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region, Iraq
3 Department of Internal Medicine, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region, Iraq
|Date of Submission||19-Jul-2019|
|Date of Acceptance||15-Sep-2019|
|Date of Web Publication||15-Apr-2020|
Dr. Marah Sudad Nameq
Department of Histopathology, Rizgary Teaching Hospital, Erbil, Iskan City
Source of Support: None, Conflict of Interest: None
BACKGROUND: Cardiac complications are still the primary cause of mortality and a major cause of morbidity in thalassemia patients.
OBJECTIVES: The aims of this study were to assess the prevalence of cardiac involvement in TDT and NTDT beta thalassemia patients and compare between the different forms and severity in both groups.
MATERIALS AND METHODS: In this prospective study, 70 TDT and 50 NTDT β-thalassemia patients were recruited; their cardiac status was evaluated by transthoracic echocardiography as per the standard recommendations. Patients' cardiac status was evaluated against the causal risk factors.
RESULTS: The mean serum ferritin level was significantly (P < 0.001) higher in the TDT patients (4940 ± 3643 ng/mL) compared to the NTDT patients (634 ± 520 ng/mL). The mean hemoglobin was significantly (P = 0.004) higher in the TDT group (9.2 ± 0.8 vs. 8.7 ± 1.0 g/dL). The prevalence of dilated cardiomyopathy and left cardiac dysfunction in TDT was 18.6%, whereas pulmonary hypertension (PHT) was found in 30% of NTDT patients.
CONCLUSION: Dilated cardiomyopathy was prevailing in the adult TDT patients, whereas PHT was the main cardiac complication in NTDT patients.
Keywords: Cardiac complications, echocardiography, β-thalassemia
|How to cite this article:|
Nameq MS, Shamoon RP, Saka MH. Evaluation of cardiac complications in transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT) beta thalassemia patients. Iraqi J Hematol 2020;9:11-6
|How to cite this URL:|
Nameq MS, Shamoon RP, Saka MH. Evaluation of cardiac complications in transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT) beta thalassemia patients. Iraqi J Hematol [serial online] 2020 [cited 2021 May 18];9:11-6. Available from: https://www.ijhonline.org/text.asp?2020/9/1/11/282514
| Introduction|| |
β-thalassemia is an inherited autosomal recessive disorder caused by reduction or absence of the hemoglobin (Hb) β-globin chain synthesis. It presents in one of the three clinical phenotypes: transfusion-dependent thalassemia (TDT) major (TM), nontransfusion-dependent thalassemia (NTDT), and thalassemia minor.
TDT is a subset of thalassemia that requires regular red blood cell (RBC) transfusions for survival. The only curative treatment for TDT is stem cell transplantation, which has limited availability due to a lack of donors. Therefore, the main stay of long-term management is RBC transfusion. NTDT includes thalassemia patients who do not require frequent blood transfusions for survival, but they may still require occasional or more frequent RBC transfusion therapy in certain circumstances including but not limited to significant infection, pregnancy, periods of rapid growth, or surgery.
Recently, with the improvement in the overall care provided to thalassemia patients and resultant increase in their survival rates, complications related to iron overload, including cardiac complications, have been increasing. Reducing iron load is associated with a reduced incidence of heart failure (HF) and increased survival. Cardiac function may stay normal for many years; however, when symptoms of heart appear, death usually occurs within a relatively short period of time.,
In TDT, the most leading cause of death is iron overload cardiomyopathy, which causes an end-stage dilated cardiomyopathy and left HF. In NTDT, pulmonary hypertension (PHT) with continuous increase in tricuspid regurgitation and right side cardiac dysfunction is the main manifestation. The pathophysiology of cardiac complications in TDT and NTDT is different where iron overload plays a significant role in the pathophysiology of HF in the former, whereas hypoxia and chronic hemolysis remain the main causative factors of heart disease in later.
Because cardiac complications are considered as the primary cause of mortality and a major cause of morbidity in all thalassemia patients, we deemed necessary to estimate the prevalence, assess the magnitude, and compare the type and severity of cardiac complications in both TDT and NTDT patient groups.
| Materials and Methods|| |
This cross-sectional comparative study was conducted on 120 β-thalassemia patients. In this cohort, we included 70 TDT and 50 NTDT. β-thalassemia patients who were age and gender matched. The patients were conveniently enrolled from an Erbil thalassemia day care center between August 2018 and March 2019. The clinical diagnosis and genetic confirmation of the NTDT patients has been done in a previous study.
Demographic data, including age at first transfusion, frequency of transfusion, and history of splenectomy, were retrieved from patients' files. History and clinical examination regarding the presence of any signs and symptoms of heart disease were estimated including shortness of breath, fatigue, palpitation, chest pain, syncope, ankle swelling, elevated jugular venous pressure (JVP), pulmonary crackles, and peripheral edema.
Venous blood was collected into ethylenediaminete traacetic acid and gel tubes; full blood count was performed using an automated analyzer. Serum ferritin levels were measured using an automated immune analyzer, Cobas E411, Roche, Germany.
All patients had transthoracic echocardiography by Vivid T8 (GE) echo systems. A special transducer was used for pediatrics. Complete M-mode, two-dimensional, and Doppler echocardiography was performed at rest. All echo-Doppler studies were carried out by one expert cardiologist.
Echocardiographic parameters were measured according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging for adults and pediatrics.,, Echo parameters were analyzed according to the aforementioned guidelines; for pediatric cases, the parameters were analyzed against the body surface area.
The following echo parameters were measured: left ventricular ejection fraction; left ventricular end-diastolic and end-systolic dimension; right ventricular dimension and its wall thickness; TAPSE (tricuspid annular plane systolic excursion); left atrial dimension, area and volume; right atrial area and volume; E/A ratio and tricuspid regurgitation jet velocity. Pulmonary artery systolic pressure was estimated by measuring the tricuspid regurgitation jet velocity (TRV), which is the retrograde blood flow across the tricuspid valve during systole. TRV estimates the RV systolic pressure and correlates it with pulmonary artery pressure. The TRV cutoff point was set at 2.5 m/s.
At the end, after taking full history and examination to all thalassemia patients regarding any signs and symptoms of HF and after doing echocardiography to them and depending on measurement of the LVEF as the main terminology used to describe HF, as mentioned by the 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic HF, a final conclusive remark about the patient's cardiac status was provided by the cardiologist: “normal cardiac state,” “mildly affected” when there is mildly dilated cardiomyopathy with preserved cardiac function, and “markedly affected” when there is HF.
The study had been approved by the Ethics Committee of Hawler Medical University, and informed consent was taken from the all patients or guardians.
Statistical analysis was performed using the SPSS 22 statistical software package. Continuous variables were expressed as mean ± standard deviation. P < 0.05 was considered statistically significant. Student's t- test and Chi-square test were used to compare variables between TM and thalassemia intermedia patient groups.
| Results|| |
In this study, 120 patients with β-thalassemia, 70 with TDT and 50 with NTDT, were studied. The two groups were age and gender matched. Children and adolescents constituted 36.6% (44/120), of whom 24 cases were TDT and 20 were NTDT. The age range for TDT patients was 7–46 years and for NTDT was 9–50 years. The demographic and clinical data of the two groups are summarized in [Table 1].
|Table 1: Demographic and clinical data of transfusion-dependent thalassemia and NTDT patients|
Click here to view
There was a statistically significant difference in the age at diagnosis, age at first transfusion, and serum ferritin level in the TDT and NTDT groups. The mean pretransfusion Hb of the TDT patients was higher (9.2 g/dL) than the random Hb level of the NTDT group (8.7 g/dL).
In the pediatric age group, very small proportion of patients showed abnormal echocardiographic parameters with no difference between TDT and NTDT patients [Table 2]. In adults, impaired echo parameters were encountered at higher rates; the LV parameters were remarkably more aberrant in the TDT patients as illustrated in [Table 3]. In the NTDT group, PHT was encountered at a significantly higher rate comparing to the TDT patients.
|Table 2: Impaired echo parameters in the pediatric TDT and NTDT patients|
Click here to view
The effect of risk factors of gender, age, Hb, serum ferritin level, and splenectomy on the overall cardiac state in the TDT and NTDT patients are illustrated in [Table 4] and [Table 5], respectively. The prevalence of remarkable cardiac impairment among the TDT group was 18.6% (13 patients), whereas only 2 (4%) patients of the NTDT group had cardiac impairment. Patient's age and splenectomy showed significant effect on the overall cardiac status in both TDT and NTDT groups.
|Table 4: Effect of risk factors on the cardiac status in the transfusion-dependent thalassemia patients|
Click here to view
|Table 5: Effect of risk factors on the cardiac status in the NTDT patients|
Click here to view
| Discussion|| |
Despite the advances in therapeutic management of thalassemia and resulting substantial improvement of patients' survival, heart disease always represented and still remains the primary reason of mortality and a major cause of morbidity in all thalassemic patients. Little is known about the prevalence and extent of cardiac involvement in our registered thalassemia patients, mainly among the NTDT group. In this study, we assessed the cardiac status of a cohort of 70 TDT and 50 NTDT patients using transthoracic echocardiography. Both groups were matched for age and gender.
In the current cohort, the mean pretransfusion Hb of the TDT patients was significantly higher than the mean Hb of the NTDT patients. Within the latter group, 14 (28%) patients never received blood and 22 (44%) others occasionally received blood transfusion (once every ≥2 years). In reverse, patients of the former group are on regular transfusion and chelation therapy. Similar results had been reported by Ferrara et al. in 2004; however, Karimi et al. from Iran reported higher Hb levels among NTDT patients who were treated by hydroxyurea.
The β-thalassemia cardiac disease is mainly characterized by two distinct phenotypes: a dilated phenotype with LV dilatation and impaired contractility, which is mainly seen in the TDT, and a restrictive phenotype with restrictive LV filling and PHT, which is mostly encountered in patients with NTDT.
It is well known that cardiac complications in thalassemia are related mainly to two factors, the iron overload resulted from repeated transfusions in the TDT and administration of effective and regular chelation therapy. Based on this, and comparable to the results of previous studies which reported minimum cardiac complications in the pediatric thalassemia patients, echocardiographic assessment of our children and adolescent patients revealed that majority had normal echo. In adults, there was increased end-diastolic volume, resting tachycardia, and high cardiac output in both TDT and NTDT patients because of the cardiovascular adaptation to chronic anemia resulting in increased left and right cardiac chambers' dimensions and volumes. Similar findings were reported by other articles., LV dysfunction was found to be related to long exposure to iron; our results showed a significant relationship between increasing serum ferritin and LV dysfunction. Similar correlations have been repeatedly reported.,,,, The rate of cardiac complications among the TDT patients was significantly higher some 30 years ago comparing to the recent studies including the current study;,, this is probably related to the improved medical care, provision of effective iron chelation, and early identification and treatment of patients at risk for cardiac complications.
Increased pulmonary vascular resistance leading to PHT and right side heart disease is the principal form of cardiac complication among the NTDT patients. PHT was encountered in 30% and 4.3% of only adults NTDT and TDT patients, respectively; none of the pediatric thalassemia patients had increase in the pulmonary pressure. The rate of occurrence of PHT in NTDT seems to be variable as the disease itself; a wide range of prevalence figures of PHT ranging from 18.5% to 60% have been previously reported.,,, This diverse range in the incidence of PHT among the NTDT is possibly multifactorial; patients' characteristics, especially their ages, the level of care services, and chelation therapy, are among the important variables. However, the clinical diversity of NTDT, reflected by the disease's genetic diversity, remains the principal factor which determines disease severity and hence its complications. It is worth to mention here that the use of different methods for measuring and detecting pulmonary arterial pressure with different sensitivity and specificity could also affect the results. Some researchers consider right heart catheterization as the definitive method of determining PHT, but we chose to use echocardiography as it is noninvasive and recommended as a screening tool by other authors.
In the current cohort, depending on the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic HF, cardiac dysfunction was encountered in 13 (18.6%) TDT and 2 (4%) NTDT patients. There was mild echocardiographic aberrations in the form of dilated one or more than one chamber, but with otherwise normal cardiac function encountered in 18 (25.7%) and 16 (32%) TDT and NTDT patients, respectively [Table 4] and [Table 5]. When we analyzed the possible risk factors of cardiac complications, we found that increasing age, higher serum ferritin levels, and splenectomy are significantly associated impaired cardiac status in the TDT group. However, ferritin level did not show significant association in the NTDT group. Cardiac dysfunction mainly occurs after the age of 10 years, and advancing age means more iron absorption and more iron deposition; however, it may occasionally occur before that age, especially when access to chelation is limited., In both groups, patients' gender and Hb level were of no effect on the cardiac status. Splenectomy plays a significant role, mainly in the NTDT, in removing hematologic debris (phosphatidylserine-positive platelets, platelet fragments, and red cell fragments) from the cardiovascular system and suppresses intravascular hemolysis. Therefore, splenectomy is a strong risk factor for intravascular thrombosis and PHT.,
| Conclusion|| |
Cardiac complications in the pediatric TDT and NTDT were of little significance. The LV dimensions and function parameters were found defected more among the TDT patients (28%); however, impaired cardiac function was noted in 18.6% of them. PHT, on the other hand, was seen more in the NTDT group, of whom only 2 (4%) patients had impaired cardiac function. Age and splenectomy found to have significant correlation with impaired cardiac function in both groups. Echocardiography remains a useful screening tool for assessing cardiac siderosis and monitoring cardiac function in thalassemia patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Al-Allawi NA, Jalal SD, Mohammad AM, Omer SQ, Markous RS. B -thalassemia intermedia in Northern Iraq: A single center experience. Biomed Res Int 2014;2014:262853.
Silvilairat S, Charoenkwan P, Saekho S, Tantiworawit A, Phrommintikul A, Srichairatanakool S, et al.
Heart rate variability for early detection of cardiac iron deposition in patients with transfusion-dependent thalassemia. PLoS One 2016;11:e0164300.
Sleiman J, Tarhini A, Bou-Fakhredin R, Saliba AN, Cappellini MD, Taher AT. Non-transfusion-dependent thalassemia: An update on complications and management. Int J Mol Sci 2018;19. pii: E182.
Wonke B. Clinical management of beta-thalassemia major. Semin Hematol 2001;38:350-9.
Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, et al.
Survival in medically treated patients with homozygous beta-thalassemia. N
Engl J Med 1994;331:574-8.
Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol 2000;110:971-7.
Barbero U, Destefanis P, Pozzi R, Longo F, Piga A. Exercise stress echocardiography with Tissue Doppler Imaging (TDI) detects early systolic dysfunction in beta-thalassemia major patients without cardiac iron overload. Mediterr J Hematol Infect Dis 2012;4:e2012037.
Aessopos A, Farmakis D, Karagiorga M, Voskaridou E, Loutradi A, Hatziliami A, et al.
Cardiac involvement in thalassemia intermedia: A multicenter study. Blood 2001;97:3411-6.
Nouri N, Naderi M, Rajaie S, Dorgalaleh A, Tabibian Sh. Evaluation of cardiac function in patients with thalassemia intermedia. Iran J Ped Hematol Oncol 2013;3:193-9.
Shamoon RP, Al-Allawi NA, Cappellini MD, Di Pierro E, Brancaleoni V, Granata F. Molecular basis of β-thalassemia intermedia in Erbil province of Iraqi Kurdistan. Hemoglobin 2015;39:178-83.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al.
Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79-108.
Cantinotti M, Scalese M, Murzi B, Assanta N, Spadoni I, De Lucia V, et al.
Echocardiographic nomograms for chamber diameters and areas in Caucasian children. J Am Soc Echocardiogr 2014;27:1279-9200.
Dallaire F, Slorach C, Hui W, Sarkola T, Friedberg MK, Bradley TJ, et al.
Reference values for pulse wave Doppler and tissue Doppler imaging in pediatric echocardiography. Circ Cardiovasc Imaging 2015;8:e002167.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.
2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200.
Ferrara M, Matarese SM, Borrelli B, Perrotta A, Simeone G, Greco N, et al.
Cardiac involvement in beta-thalassemia major and beta-thalassemia intermedia. Hemoglobin 2004;28:123-9.
Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: Absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol 2009;82:213-8.
Mohammad AM. Echocardiographic evaluation of thalassemia intermedia patients in Duhok, Iraq. BMC Cardiovasc Disord 2014;14:183.
Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, et al.
Cardiovascular function and treatment in β-thalassemia major: A consensus statement from the American Heart Association. Circulation 2013;128:281-308.
Bosi G, Crepaz R, Gamberini MR, Fortini M, Scarcia S, Bonsante E, et al.
Left ventricular remodelling, and systolic and diastolic function in young adults with beta thalassaemia major: A Doppler echocardiographic assessment and correlation with haematological data. Heart 2003;89:762-6.
Derchi G, Formisano F, Balocco M, Galanello R, Bina P, Dessì C, et al.
Clinical management of cardiovascular complications in patients with thalassaemia major: A large observational multicenter study. Eur J Echocardiogr 2011;12:242-6.
Gharzuddine WS, Kazma HK, Nuwayhid IA, Bitar FF, Koussa SF, Moukarbel GV, et al.
Doppler characterization of left ventricular diastolic function in beta-thalassaemia major. Evidence for an early stage of impaired relaxation. Eur J Echocardiogr 2002;3:47-51.
Ocal B, Oguz D, Karademir S, Birgen D, Yüksek N, Ertem U, et al.
Myocardial performance index combining systolic and diastolic myocardial performance in doxorubicin-treated patients and its correlation to conventional echo/Doppler indices. Pediatr Cardiol 2002;23:522-7.
Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al.
Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89:1187-93.
Marsella M, Borgna-Pignatti C, Meloni A, Caldarelli V, Dell'Amico MC, Spasiano A, et al.
Cardiac iron and cardiac disease in males and females with transfusion-dependent thalassemia major: A T2* magnetic resonance imaging study. Haematologica 2011;96:515-20.
Pepe A, Meloni A, Rossi G, Midiri M, Missere M, Valeri G, et al.
Prediction of cardiac complications for thalassemia major in the widespread cardiac magnetic resonance era: A prospective multicentre study by a multi-parametric approach. Eur Heart J Cardiovasc Imaging 2018;19:299-309.
Aessopos A, Kati M, Farmakis D. Heart disease in thalassemia intermedia: A review of the underlying pathophysiology. Haematologica 2007;92:658-65.
Rafsanjani KA, Mafi N, Tafreshi RI. Complications of β-thalassemia intermedia in Iran during 1996-2010 (single-center study). Pediatr Hematol Oncol 2011;28:497-508.
Vlahos AP, Koutsouka FP, Papamichael ND, Makis A, Baltogiannis GG, Athanasiou E, et al.
Determinants of pulmonary hypertension in patients with beta-thalassemia major and normal ventricular function. Acta Haematol 2012;128:124-9.
Phrommintikul A, Sukonthasarn A, Kanjanavanit R, Nawarawong W. Splenectomy: A strong risk factor for pulmonary hypertension in patients with thalassaemia. Heart 2006;92:1467-72.
Moghaddam HM, Badiei Z, Eftekhari K, Shakeri R, Farhangi H. Prevalence of pulmonary hypertension in patients with thalassemia intermedia in 2009: A single center's experience. Electron Physician 2015;7:1102-7.
Fernandes JL, Fabron A Jr., Verissimo M. Early cardiac iron overload in children with transfusion-dependent anemias. Haematologica 2009;94:1776-7.
Musallam KM, Taher AT, Rachmilewitz EA. B-thalassemia intermedia: A clinical perspective. Cold Spring Harb Perspect Med 2012;2:a013482.
Aessopos A, Farmakis D. Pulmonary hypertension in beta-thalassemia. Ann N
Y Acad Sci 2005;1054:342-9.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]