WITHDRAWN: Cardiac Complications in Patients with Thalassemia Major in Iran: A Meta-Analysis Study

Accepted Manuscript Cardiac complications in patients with thalassemia major in Iran: A meta-analysis study

Kourosh Sayehmiri, Gholamreza Badfar, Masoumeh Shohani, Ali Soleymani, Milad Azami PII: DOI: Reference:

S1058-9813(17)30067-X doi:10.1016/j.ppedcard.2017.10.007 PPC 1027

To appear in:

Progress in Pediatric Cardiology

Received date: Revised date: Accepted date:

12 May 2017 22 September 2017 17 October 2017

Please cite this article as: Kourosh Sayehmiri, Gholamreza Badfar, Masoumeh Shohani, Ali Soleymani, Milad Azami , Cardiac complications in patients with thalassemia major in Iran: A meta-analysis study. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ppc(2017), doi:10.1016/ j.ppedcard.2017.10.007

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ACCEPTED MANUSCRIPT Cardiac Complications in Patients with Thalassemia Major in Iran: A Meta-Analysis Study

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Kourosh Sayehmiri(PhD)1, Gholamreza Badfar(MD)2 , Masoumeh Shohani(PhD)3, Ali Soleymani(Msc)4, Milad Azami(MD)5*

Author affiliations

Associate Professor, Department of Biostatistics, Research Center for Prevention of Psychosocial Impairment, Ilam University of Medical Sciences , Ilam, Iran

Assistant Professor, Department of Pediatrics, Behbahan School of Medicine, Ahvaz Jundishapour

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university of Medical science, Behbahan, Iran

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4. 5.

Department of Nursing, Faculty of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran Dezful University of Medical Sciences, Dezful, Iran Medical Student, Student Research Committee, Ilam University of Medical Sciences, Ilam, Iran

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3.

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1.

Corresponding Author:

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Mobile: +989380316334

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Email:[email protected]

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Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran

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Cardiac complications are the most common cause of death in patients with thalassemia major. This study aims to assess cardiac complications in patients with thalassemia major in Iran. This study was conducted based on PRISMA guidelines for systematic review and metaanalysis studies. To find the relevant literature, a comprehensive search was conducted in several databases including SID, Magiran, Iranmedex, IranDoc, Medlib, PubMed, Scopus, Science Direct, Cochrane, Web of Science, and Google Scholar search engine. Search was performed using MeSH English and Persian equivalent keywords without any time limited until 2017. Studies were examined according to the inclusion and exclusion criteria. To assess the heterogeneity of the studies, I2 statistic and Cochran's Q test were used. Data were analyzed using Stata Ver.11.1 software through random effects model. In 20 studies, 4,017 thalassemia major patients were surveyed. The mean age of the patients was 16.79 years. The prevalence of all types of cardiac complications in Iranian patients with thalassemia major was estimated 41.2% (95%CI: 25.3-57.2) and this prevalence for males and females patients was estimated to be 21.8% (95% CI: 9.3- 34.4) and 21.4% (CI 95%: 14.2-28.6), respectively. The most common echocardiographic abnormalities were diastolic dysfunction (40.2% [95%CI: 14.1-66.2]), systolic dysfunction 18.9% [95%CI: 9.4-28.5]), pulmonary hypertension (14% [95% CI: 14.2-28.6]), left ventricular hypertrophy (7.4% [95%CI: 2.5-12.3]), tricuspid regurgitation (30.2% [95%CI: 11.2-50.4]), mitral valve prolapse (16.4% [95%CI: 0-46.8]), mitral regurgitation (12.3% [95%CI: 8.3-16.2]) and aortic regurgitation (4.4% [95%CI: 0.2-8.9]). The Abnormal echocardiography and electrocardiography was estimated to be 56.1% (95%CI: 9.0-100) and 32.6% (95%CI: 7.158.0), respectively. The relationship between cardiac complications and serum ferritin in patients with thalassemia major was not significant.

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The prevalence of cardiac complications in Iranian thalassemia major patients is very high and screening the patients for early diagnosis seems essential. Keywords: Prevalence, Cardiac Complications, Thalassemia Major, Ferritin, Meta-Analysis, Iran

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ACCEPTED MANUSCRIPT 1. Introduction:

Thalassemia major is a hereditary hemoglobinopathy that is transferred through mutation in chain production of β-globin genes (1). The onset of disease is associated with anemia, oral manifestation, bone lesions, weakness and delayed growth (2-3). These patients are treated by receiving regular monthly blood that decreases the acute symptoms of the disease. On the other hand, regular blood transfusions may cause

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hemosiderosis and tissue dysfunction, including hepatic, cardiac and endocrine failures and growth disorders (4-10).

In the past years, these patients would die within the second decade of their life. But

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nowadays, with developments in medical treatment, particularly after initiation of chelation

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therapy, a breakthrough has been achieved in the treatment of these patients and they can expect a relatively long lifetime with a proper treatment (11).

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Despite improved treatment methods for iron overload, cardiac complications in these patients still have a high incidence and 71% of the causes of death in thalassemia major patients is cardiac involvement (12).

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In Iran, several studies have been reported on cardiac complications in patients with thalassemia major (13-32) and now a meta-analysis seems necessary to unify the results and

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provide a total estimate of these problems. Thus, this study was conducted to assess cardiac

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complications in patients with thalassemia major using a meta-analysis method in Iran.

2. Materials & Methods: 2.2. Study protocol

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Meta-analysis is a method that collects and analyzes various research data with an integrated goal to provide a reliable estimate of the effect of some medical interventions or observations

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in the medical sciences (33-34). Obviously, in meta-analysis methods, after data collection, the samples size is higher and therefore, the ranges of confidence interval decreases and the importance of statistical findings increases (34-36). This study was conducted based on PRISMA guidelines for systematic review and metaanalysis (36). To avoid bias, the search, data extraction and quality assessment was conducted by two researchers independently and the agreement on the results was reached by a third researcher. 2.3. Data Sources:

The results are based on studies published in national and international journals. To find the relevant literatures, a comprehensive search was conducted in Persian and English databases 3

ACCEPTED MANUSCRIPT such as Iranian Journal Database (Magiran), Iranian Biomedical Journals (IranMedex), Scientific Information Databases (SID), Global Medical Article Limberly (Medlib), Scopus, PubMed, Science Direct, Cochrane, Web of Science (ISI), and the Google Scholar search engine using Persian and English keywords without any time limited until 2017. The Persian terms and the English MeSH keywords include: “Prevalence”, “Cardiovascular Diseases”, “Heart Disease”, “Echocardiography”, “Electrocardiography”, “Pulmonary Hypertension”, “Arrhythmias”, “Heart Valve Diseases”, “Heart Failure”, “Pericardial

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Effusions”, “Hypertrophy”, “Ischemic Heart Diseases”, “Angina”, “Myocardial Infarction”, “Ferritin”, “Chelation Therapy”, “Cardiomegaly”, “Hemosiderosis”, “Thalassemia” and

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“Iran”. Combened search was performed using a combination of AND/OR operators.

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Moreover, the references of the identified papers were reviewed to find further papers. 2.4. Inclusion and Exclusion Criteria:

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The inclusion criteria included cardiac diseases in a population of patients with thalassemia major in Iran. Exclusion criteria were: non-relevant to the topic, non-random sample size, patients without thalassemia major, non-Iranian patients, not investigating cardiac

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complications, review articles, letters to the editor and case reports. The full text of papers was asked from the authors via e-mail if they were not available. 2.5. Quality Assessment of Studies:

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Selected papers were evaluated by researchers using STROBE checklist (Strengthening the

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Reporting of Observational Studies in Epidemiology) (37). This checklist contains 22 different sections and varied aspects of methodology including sampling methods, parameters measurement, statistical analysis, adjustment for confounding factors. The mentioned

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specifications evaluated the reliability and validity of the tools used in the list and the objectives of the study. Studies with a score of at least 16 entered the meta-analysis.

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2.6. Study Selection:

In the first systematic search, 300 papers possibly related to the subject of the study were found, and 150 studies were excluded due to duplication. After a title and abstract screening, 89 studies were excluded for irrelevant to the study. In the next stage, the full texts of the remaining 61 studies were examined and 41 studies were excluded for various reasons: Lacking epidemiological data (N=12); not about Iranian thalassemia major patients (N=17), non-random sample (N=5); reviews, letter to the editor, case report and qualitative studies (N=7). Finally, 20 eligible studies entered the meta-analysis process (Figure 1). 2.7. Data Extraction:

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ACCEPTED MANUSCRIPT The final articles included in research process were extracted using a pre-prepared checklist. The checklist includes the author's name, year of study, place, study type, sample size, cardiac complications in males/females, the prevalence of left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, mitral valve prolapse (MVP), tricuspid regurgitation (TR), mitral regurgitation (MR), aortic regurgitation (AR), pericardial effusion, cardiomegaly, pulmonary hypertension (PH), the prevalence of electrocardiogram (ECG) abnormalities, arrhythmia and inverted T.

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2.8. Statistical analysis:

The variance of each study was calculated according to the binomial distribution. The studies

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were combined according to the sample size and variance. To assess the heterogeneity of the

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studies, I2 statistic and Cochran's Q test were used. The heterogeneity was higher than 90%, classifying it among the studies with high heterogeneity (heterogeneity index I2 less than

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25%; low heterogeneity, 25-75%; moderate heterogeneity and more than 75%; high heterogeneity). Random effects model was used to combine data in the meta-analysis (38-39). To investigate the relationship between the prevalence of cardiac complications and the year

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of study, the meta-regression model was used. Data were analyzed using Stata Ver.11.1 software. P<0.05 was considered significant. 3. Results:

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3.2. Search results and study characteristics

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In a systematic review, 20 studies published from 1998 to 2017 entered the meta-analysis process (Figure 1). Overall, the sample size included 4,017 patients and the mean age of participants in the study was 16.79 years (95% CI [Confidence interval]: 12.71-20.88). Table

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1 shows the data summary for each study. 3.3. Total prevalence of cardiac complications

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The prevalence of various types of cardiac complications in patients with thalassemia major in Iran was estimated to be 41.2% (95% CI [Confidence interval]: 25.3-57.2). The lowest prevalence was related to a study in Kerman in 1998 (9.1%) and the highest prevalence was related to a study in Zabul in 2014 (93%) (Figure 2). 3.4. Total prevalence of cardiac complications by gender

In 4 studies, the prevalence of cardiac complications in men and women Iranian thalassemia major patients was estimated to be 21.8% (95% CI: 9.3- 34.4) and 21.4% (CI 95%: 14.228.6), respectively (Figure 3). 3.5. Echocardiographic and electrocardiographic findings

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ACCEPTED MANUSCRIPT The prevalence of echocardiographic and electrocardiographic findings in patients with thalassemia major is shown in Table 2. 3.6. Serum ferritin and cardiac complications

Investigating the relationship between serum ferritin and cardiac complications is shown in Table 3, but the relationship is not statistically significant (P>0.05). 3.7. Prevalence of pulmonary hypertension

The prevalence of PH in Iranian patients with thalassemia major was estimated to be 14%

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in Sanandaj in 2006 (0%) and a study in Ilam in 2014 (45%).

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(95% CI: 14.2-28.6). The minimum and maximum prevalence of PH were related to a study

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4. Discussion:

This systematic review and meta-analysis is the first study on the cardiac complications in patients with thalassemia major in Iran. The overall Prevalence of cardiac complications in

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these patients was estimated to be 41%. Due to the low number of studies, we could not make other analyses on the overall prevalence of cardiac complications based on subgroup analysis

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(for example geographic regions and provinces).

The prevalence of cardiac complications in patients with thalassemia major in other countries including Australia, Italy, and Greece was reported to be 48.6%, 13.3% and 12.9%,

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respectively. This difference in the prevalence can be due to genetic differences, condition of

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blood transfusion and deferral therapy (40-42). According to the study of Aessopos in Greece, factors that reduce the prevalence of cardiac complications in lifelong was mentioned to be blood transfusion, and regular iron chelation therapy (43). In addition, a systematic

overload (44).

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review and meta-analysis showed that iron chelation therapy significantly reduces iron

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A systematic review and meta-analysis have reported the prevalence of regular chelation therapy in patients with thalassemia major in Iran to be 54%, and a large number of patients receive irregular treatment (45). In this study, the mean serum ferritin level in patients with thalassemia major in cardiac patients and healthy subjects was estimated to be 3377 and 2455 ng/ml. However, the mean serum ferritin level was higher in the group of heart patients, but this difference was not statistically significant. Perhaps, the most obvious reason for the lack of relationship between serum ferritin levels and cardiac dysfunction in these patients is the small sample size of studies. The trends of serum ferritin level are useful to monitoring body iron overload, but may not calculate heart iron overload. 6

ACCEPTED MANUSCRIPT Long-term increase of ferritin is important in cardiac mortality. The studies propose the ferritin level above 2500 ng/ml as an increased risk of heart disease (46-47). But there is no threshold, since they are still at risk with low levels of ferritin even less than 1000 ng/ml. Low ferritin level does not ensure heart complications in patients with thalassemia major (48). In this study, the abnormal echocardiography was estimated to be 56.1%, while the most common echocardiography disorder was the diastolic dysfunction (40.2%). In Aessopos’s

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study in Greece (2001-2003), the prevalence of left ventricular diastolic dysfunction was observed to be 35% (49). In a cohort study, 11 patients with thalassemia major died due to diastolic dysfunction after 15 years (50). However, the prevalence of systolic dysfunction was

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estimated to be about 18.8% or lower. In Aessopos’s study in Greece (2004) investigating the

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systolic dysfunction in 131 patients with thalassemia major and 74 patients with Thalassemia Intermediate in the same age group, the disorder was only observed in thalassemia major

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Patients (8.4%) (51).

In the current study, valve disorders in Iranian major thalassemia patients were high, so that the most common valvular disorder is TR (30.8%). MVP (16.8%), is much higher compared

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to the general population. Azami et al. who studied 600 patients referred to the heart clinic of Ilam (2013-2014), reported the prevalence of TR and MVP to be 2% and 4.5%, respectively

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(52). Moreover, Mahmoudi et al. reported the prevalence of valvular disorders in 7-8 yearsold students to be 0.4% in Hamadan (1993) (53).

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In order to minimize hypoxia in patients with thalassemia major, one needs to keep pretransfusion hemoglobin concentrations at the level of 10 g/dl or more. This sort of therapeutic approach, however, has been consistently adopted only in recent years and is not

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always applied nowadays. According to these remarks, many patients with thalassemia,

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particularly older ones, have been suffering from multiple effects of chronic anemia (54). Iron loading in thalassemia major causes damage to myocardium as a susceptible tissue. High-output cardiac failure due to severe anemia and death is observed in the first years of life if no treatment is applied. Supportive blood transfusions lead to iron overload, which cannot be naturally excreted, and iron accumulation within myocardium (siderosis) evokes formation of hydroxyl radicals as a reactive oxygen species (ROS), which damage cells and eventually causes cardiac dysfunction (55). Cardiovascular magnetic resonance (CMR) is widely used for assessment of myocardial iron content for clinical management to help prevent and evaluate cardiac complications in

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ACCEPTED MANUSCRIPT thalassemia patients (55). The outcome is significantly getting better after using CMR in terms of treatment intensification and education (56, 57). Chelation therapy is the treatment of choice. There are many chelation protocols including deferoxamine, deferiprone, and deferasirox, while all of them can take away cardiac iron. Chelation therapy can also be received in combination with a synergistic effect, although the evidence base on this approach is quite little (55-57).

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Improved survival was proved to be better in patients receiving deferiprone in comparison with deferoxamine. At a dose of 92 mg/kg/day, deferiprone removed cardiac iron with the

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clearance rate of 2.2% per month and enhanced left ventricular ejection fraction (LVEF), compared to no significant changes in deferoxamine (58). Hence, monotherapy with oral

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deferiprone is suggested for cardiac iron overload with or without systolic dysfunction. Deferasirox is another oral chelation therapy that was recently examined for this purpose.

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This agent can eliminate cardiac iron, ranging from 1.3% to 1.5% per month. However, experiments have shown no improvement in LVEF (59). Therefore, deferasirox can be

ventricular systolic dysfunction (60).

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prescribed only for iron-overload treatment, in the absence of any accompanying left

The synergistic effects of combined administration of continuous deferiprone and

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deferoxamine improved iron removal and LVEF (61).

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This synergistic effect has also been shown to dramatically improve iron loads thalassemia patients when T2* values are between 8 ms and 20 ms at baseline (62). According to these results, the combined use of the two chelators (deferiprone and deferoxamine) is extensively

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used and recommended in patients with profound iron overload and systolic dysfunction (60). In addition, oral chelators such as deferiprone and deferasirox have also been proposed (63-

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65).

PH is a progressive disease caused by Heart, Pulmonary or Systemic Diseases that is associated with patient’s increased morbidity and mortality regardless of etiology (66-67). PH is a common complication in thalassemia patients (68). The pathogenesis of these complications is unknown. However, the secondary dilated cardiomyopathy has been suggested to the Iron deposition in the heart and myocarditis (69-70). Various studies have noted the prevalence of PH in patients with thalassemia major to be 10-79% (70-74). In our research, PH was estimated to be 14% in 5 studies and this is consistent with the results of other countries. PH was almost never observed in patients with thalassemia major, depending on lifelong regular blood transfusions and iron chelation therapy (59-60). 8

ACCEPTED MANUSCRIPT Animal models showed that Iron toxicity primarily occurs in the electrical and arrhythmia changes (75). Iron overload in Myocytes causes abnormal action potential by reducing overshoot and reducing the duration of action potential compared to natural myocytes (76). In our study, the frequency of abnormal ECG was estimated to be 32.6%, which is a lower percentage than echocardiography that indicates insufficient ECG to detect heart problems in patients with thalassemia major. Due to limitations in reporting studies except for arrhythmia

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and Inverted T, we could not report any statistics from the findings of the ECG. Arrhythmia is a major cardiac cause of mortality in patients with thalassemia major estimated with the prevalence of 3.2% in our study. In a study by Borgna et al. in Turkey, the prevalence of

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arrhythmias was estimated to be 5.7%, which was consistent with our estimates (77).

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Limitations of the Study include: 1) Low sensitivity of Iranian databases to search for a combination of words. 2) Failure to investigate the relationship between heart complications

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and desferal consumption, intervals and transfusion levels in many studies. 3) Due to the limited number of studies, we could not report any statistics about the prevalence of other

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cardiovascular complications.

5. Conclusion:

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The prevalence of complications in patients with thalassemia major is very high in Iran, which shows a lack of attention and follow-up from Policymakers about the cardiac

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complications of patients with thalassemia major. Moreover, screening these patients for early diagnosis of heart disorders is essential. It is recommended that patients with thalassemia major in Iran undergo echocardiography and electrocardiography every six

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months for heart diseases. The mean ferritin in patients with thalassemia major (both cardiac patients and healthy subjects) was high. On the other hand, many patients use iron chelation

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Therapy on a non-regular basis. It is recommended that measures such as training and awareness in this area are necessary in this regard.

Acknowledgement The present study is the result of the accepted research proposal by Ilam University of Medical Sciences, thus, we appreciate the fund. Authors’ Contribution

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ACCEPTED MANUSCRIPT Milad Azami,: Data Collection; Kourosh Sayehmiri: Biostatistics analysis; Milad Azami and Sirus Norouzi: study designs; Wesam Kooti, Milad Azami, Sirus Norouzi: Quality evaluation; Milad Azami, Sirus Norouzi: final revision and grammar editing.

Funding/Support

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This research was done using financial support of student’s research committee of Ilam

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University of Medical Sciences.

2006 2003 2011 2005 2006 2001 1999 1999 1996 1998 2002 1998 2011 2001 2010 2002 2014 2013 2014 2014

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Gilan Khorramabad Birjand Shiraz Sanandaj Tehran Kashan Sari Tehran Kerman Shiraz Qazvin Yasouj Ahvaz Ahvaz Zahedan Zahedan Qom Ilam Zabul

All 58 100 35 806 26 1069 17 100 67 340 144 65 72 120 63 80 48 48 36 100

Sample size Men 32 55 18 406 113 487

Women 26 45 17 400 106 582

55 33 155

31 57

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Rahimi11 Mohsenzadeh12 Chahkand13 Ansari14 Company15 Ansari16 Malekirad17 Ghaemian18 Kamali19 Vahidi20 Barzegar21 Pourmohammad22 Rohani23 Farhangi24 Mousavi25 NoorMohammadi26 NoorMohammadi27 Arjmandi Nia 28 Azami29 Mahmoudi30

Year

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Place

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Author Name

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Table1. Detailed characteristics of 20 articles included in the systematic review on the prevalence of cardiac complications in Iranian major thalassemia Patients Age Mean±SD 3.59±15.4 4.33±9.06 6.8±15.34

Prevalence of cardiac complications (%) 32.8(Ma:40.6, Fb:23.7) 33(M:32.7, F:33.3) 77.1 15.9(M:14, F:17.8)

6±12.57

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45 34 185

18.6 3.7±12.3 7.6±14.72

24 9.1

41 63

6.2±15.7 6±16.6 5.1±23.7

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58.3 19 37

Male; bFemale

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17 63

7.8±19.94 5.6±26 7±15.37

21.8(M:6.3, F:16.7) 93

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Figure1: Flow diagram of systematic search.

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Study

% ES (95% CI)

Weight

Rodpyma (1996)

0.24 (0.14, 0.34)

9.05

Vahidi (1998)

0.09 (0.06, 0.12)

9.37

Ansari (2001)

0.10 (0.08, 0.12)

9.39

Mohsenzadeh (2003)

0.33 (0.24, 0.42)

9.11

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Ansari (2005)

9.38

0.33 (0.21, 0.45)

8.92

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Rahimi (2006)

0.16 (0.13, 0.18)

Chahkandi (2011)

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Rohani (2011) Noormohammad (2014) Azami (2014)

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Mahmoodi (2014) Overall (I-squared = 99.2%, p = 0.000)

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NOTE: Weights are from random effects analysis -.98

0

0.77 (0.63, 0.91)

8.77

0.81 (0.72, 0.90)

9.12

0.58 (0.44, 0.72)

8.77

0.22 (0.08, 0.35)

8.81

0.93 (0.88, 0.98)

9.31

0.41 (0.25, 0.57)

100.00

.98

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Figure 2: The prevalence of cardiac complications in Iranian major thalassemia patients. Random effects model in meta– analyses (squares represent effect estimates of individual studies with their 95% confidence intervals of the prevalence of cardiac complications with estimates of individual studies with their 95% confidence intervals the prevalence of cardiac complications with size of squares proportional to the weight assigned to the study in the meta–analysis. the diamond represents the overall)

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Study

%

ES (95% CI)

Weight

Mohsenzadeh (2003)

0.33 (0.20, 0.45)

24.03

Ansari (2005)

0.14 (0.11, 0.17)

30.70

0.41 (0.24, 0.58)

19.91

0.06 (-0.05, 0.17)

25.36

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ID

Rahimi (2006)

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Azami (2014)

0.22 (0.09, 0.34)

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Overall (I-squared = 84.4%, p = 0.000)

NOTE: Weights are from random effects analysis 0

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-.576

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Study

ID

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Mohsenzadeh (2003)

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Ansari (2005)

Rahimi (2006)

Azami (2014)

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Overall (I-squared = 38.1%, p = 0.184)

100.00

%

ES (95% CI)

Weight

0.33 (0.20, 0.47)

18.95

0.18 (0.14, 0.22)

53.08

0.23 (0.07, 0.39)

14.97

0.17 (-0.01, 0.34)

13.01

0.21 (0.14, 0.29)

100.00

NOTE: Weights are from random effects analysis 0

.471

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Figure 3: The prevalence of cardiac complications in patients with thalassemia major of Iran in males (A) and females (B). Random effects model in meta–analysis

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ACCEPTED MANUSCRIPT Table 2: The prevalence of some of the echocardiography and electrocardiography findings in patients with thalassemia major in Iran Abnormal echocardiography Left ventricular hypertrophy Systolic dysfunction Diastolic dysfunction Mitral valve prolapse Tricuspid regurgitation Mitral regurgitation Aortic regurgitation Pericardial effusion Cardiomegaly Pulmonary hypertension Abnormal electrocardiography Arrhythmia T inversion

95% CIb 9.0-100 2.5-12.3 9.4-28.5 14.1-66.2 0-46.8 11.2-50.4 8.3-16.2 0.2-8.9 0-1.1 12-36.9 4-24 7.1-58 0-6.4 0-37.6

Prevalence (%) 56.1 7.4 18.9 40.2 16.4 30.8 12.3 4.4 0.6 19 14 32.6 3.2 18

Number; b confidence interval.

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I2 (%) 99.2 78.8 93 98.3 91.2 98.8 97.1 83.3 63 94.2 94.4 97.7 80.8 95.7

Sample size (Na) 1224 392 702 496 1095 1428 1500 263 1522 219 346 457 1371 225

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Studies (Na) 4 6 10 7 2 6 7 4 8 4 5 5 4 3

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Variable

Table 3: association between cardiac complications and serum ferritin I2

Cardiac complications(+)

Studies (Na) 3

Sample size (Na) 73

92.5

Cardiac complications(-)

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356

94.4

Number; bconfidence interval.

2455(95%CI: 1681.1-3229.2)

P-Value P>0.05

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The mean and 95% CIb for serum ferritin(ng/ml) 3377(95%CI: 2189.5-4564)

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Variable

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patients with thalassemia major. Am Heart J. 1999;138(2 Pt 1):384. 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(2):124-9. Wu KH, Chang JS, Su BH, Peng CT. Tricuspid regurgitation in patients with beta-thalassemia major. Ann Hematol 2004; 83: 779–83. Schwartz KA, Li Z, Schwartz DE, Cooper TG, Braselton WE. Earliest cardiac toxicity induced by iron overload selectively inhibits electrical conduction. J Appl Physiol. 2002; 93: 746–751. Kuryshev YA, Brittenham GM, Fujioka H, Kannan P, Shieh CC, Cohen SA, Brown AM. Decreased sodium and increased transient outward potassium currents in iron loaded cardiac myocytes: implications for the arrhythmogenesis of human siderotic heart disease. Circulation. 1999; 100: 675–683. 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(10): 1157-9.

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Highlight  The prevalence of complications in patients with thalassemia major is very high in Iran, indicating lack of attention and follow-up from policy makers in regard with the cardiac complications in patients with thalassemia major.

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