Background: Heart disease represents the main determinant of survival in [beta]-thalassemia, but its particular features in the two clinical forms of the disease, thalassemia major (TM) and thalassemia intermedia (TI), are not completely clarified.
Methods: We compared clinical and echocardiographic global parameters in 131 TM patients who received regular chelation transfusions and were highly compliant with treatment (mean age, 28 [+ or -] 6 years [[+ or -] SD]), and 74 age-matched, TI patients who did not receive chelation transfusions.
Results: Congestive heart failure was encountered in five patients with TM (3.8%; age range, 25 to 29 years) and in two patients with TI (2.7%; age range, 37 to 40 years). Systolic left ventricular (LV) dysfunction (ejection fraction < 55% or shortening fraction < 35%) was only encountered in patients with TM (8.4%). Considerable pulmonary hypertension (systolic tricuspid gradient > 35 mm Hg) was only present in TI (23.0%). In the remaining patients without evident heart disease, cardiac dimensions, LV mass, LV shortening and ejection fractions, and cardiac output were significantly higher in patients with TI. LV afterload was higher in patients with TM. LV diastolic early transmitral diastolic peak flow velocity (E)/late transmitral diastolic peak flow velocity (A) ratio was also higher in TM. Systolic and mean pulmonary artery pressures and total pulmonary resistance were higher in both young and old TI patients.
Conclusion: Regular lifelong transfusion and chelation therapy in TM prevented premature heart disease and pulmonary hypertension, although LV dysfunction still occurred and led to heart failure. The absence of regular therapy in TI, in contrast, preserved systolic LV function but allowed pulmonary hypertension development, which also led to heart failure, starting within the fourth decade of life, a decade later compared to TM.
Key words: deferoxamine; heart failure; iron chelation; pulmonary hypertension; thalassemia; transfusions
Abbreviations: A = late transmittal diastolic peak flow velocity; ASE = American Society of Echocardiography; DT = E-wave deceleration time; E = early transmitral diastolic peak flow velocity; 1VRT = isovolumic relaxation time; LV = left ventricular; MVa = duration of forward A-wave. PVa = duration of pulmonary vein reverse flow during atrial contraction; TI = thalassemia intermedia; TM = thalassemia major
[beta]-thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia. (1) Depending on clinical severity, two forms are distinguished: thalassemia major (TM) and thalassemia intermedia (TI). The former is characterized by severe anemia starting during the first year of life and requiring life-long transfusion therapy for survival, while the latter has a later clinical onset with a milder anemia, permitting survival without regular transfusions, and a longer life expectancy.
Heart complications represent the leading cause of mortality in both forms of the disease. (2) Cardiac involvement in TM is generally characterized by iron-induced ventricular dysfunction, leading to heart failure. (3-5) However, the gradual adoption of what is currently considered to be the standard therapy by the different patient populations and the highly variable compliance of patients with this therapy have led to conflicting data with respect to the frequency of left ventricular (LV) dysfunction and the development of pulmonary hypertension. (4-7) At the same time, the cardiac benefits of a lifetime compliance with the standard therapy are not yet clear. In TI, however, age-related pulmonary hypertension and high-output state with LV remodeling have been described. (8) Cardiac studies in TI, however, comprised older populations compared to those dealing with TM, because of the considerably shorter survival of TM patients. Thus, findings regarding heart status are not comparable between the two forms of the disease.
As modern therapy has significantly improved survival in TM, the parallel evaluation of age-matched TM and TI populations has become feasible. In the present study, we performed a comparative assessment of global cardiac condition and pulmonary circulation in age-matched TM and TI patients, using Doppler echocardiography. To evaluate the effect of therapy on cardiac disease and to avoid the confounding effect of treatment variability, all TM and TI patients enrolled in the study have followed the corresponding "standard" therapy since their early infancy.
MATERIALS AND METHODS
All consecutive TM and TI patients who were referred for cardiac examination to this clinic between January 2002 and June 2003 were initially screened for recruitment. Screening included medical history assessment, focusing on cardiovascular symptomatology and transfusion and chelation history, physical examination, and transthoracic resting echocardiography. Medical history assessment included both patient interview and review of the hematology records of the corresponding thalassemia unit.
To be enrolled in the study, patients with TM should have followed a regular transfusion and chelation program, defined as follows: (1) onset of regular transfusions before the age of 2 years; (2) maintenance of a pretransfusional hemoglobin level > 9.0 g/dL; (3) onset of chelation therapy before the age of 5 years; (4) subcutaneously administration of deferoxamine at a dose of 40 to 50 mg/kg/d over 8 to 12 h daily for at least 5 days a week; (5) for older patients and prior to the establishment of subcutaneous deferoxamine, chelation therapy by IM deferoxamine injections, 4 times a week, for a period not exceeding 5 years; (6) high compliance with chelation therapy, defined as a [greater than or equal to] 90% adherence to the instructions given by the hematologists. Patients with TI, however, should have not been treated with regular blood transfusions; occasional blood transfusions, administered for episodes of anemia exacerbation, were allowed. Furthermore, the two groups should be matched for age and sex.
According to the above criteria, of a total of 559 patients with [beta]-thalassemia (418 patients [74.8%] with TM and 141 patients [25.2%] with TI) examined during the > 1.5-year period, 205 patient (131 patients with TM and 74 patients with TI) were finally enrolled. All recruited patients were classified into two subgroups with respect to the presence or absence of evident heart disease, defined by at least one of the following: congestive heart failure, systolic LV dysfunction (LV shortening fraction < 30% or LV ejection fraction < 55%), and considerable pulmonary hypertension (peak systolic tricuspid pressure gradient > 35 mm Hg). To adjust for the effect of advancing age on pulmonary hypertension development, patients were also classified into two subgroups according to age: < 25 years or > 25 years. The study was approved by the local ethics committee, and all patients gave informed consent.
Complete M-mode, two-dimensional, and Doppler (pulsed-wave, continuous-wave, and color) echocardiography was performed at rest (Aloca ProSound SSD 5500 Ultrasound System; Aloca; Tokyo, Japan). Patients with TM were examined in the midinterval between two scheduled transfusions. All echo-Doppler studies were carried out by the same observer (A.A.). The intraobserver variability regarding echocardiographic and Doppler measurements in this clinic has previously been reported to be < 4%. All measurements represent the average values of at least three cardiac cycles. During the echocardiographic study, heart rate and BP were also measured; BP was measured in the right arm, using the same cuff sphygmomanometer for all patients.
Cardiac chamber dimensions were measured according to the recommendations of the American Society of Echocardiography (ASE) by M-mode echocardiography, while two-dimensional echo was used wherever M-mode measurements were considered unreliable. (9,10) Dilatation of left ventricle was defined by a LV end-diastolic diameter > 5.6 cm, dilatation of left atrium by a left atrial diameter > 4.0 era, and dilatation of right ventricle by a right ventricular diameter > 2.3 era. (11) LV mass was calculated using the ASE cube formula as corrected by Devereux et al. (12) The pattern of LV remodeling was also evaluated by the relative wall thickness, which estimates the adaptation of LV wall thickness to LV cavity size changes. (13)
Impaired LV contractility was defined by an ejection fraction < 55% or a shortening fraction < 30%. Stroke volume, ejection fraction, and cardiac output estimation were based on the calculation of LV volumes by the method of discs, following the ASE recommendations and using apical two- and four-chamber Views. (10) Cardiac diameters and volumes, LV mass, and cardiac output were indexed to body surface area to correct for differences in body constitution between TM and TI patients. The ratio of mean arterial BP to stroke volume was used as a rough means to estimate LV afterload (14); in addition, total peripheral resistance and end-systolic wall stress were calculated according to the literature. (15)
LV diastolic function was assessed by the pulsed-Doppler recording of mitral inflow. Standard diastolic Doppler indexes were recorded, including early transmitral diastolic peak flow velocity (E) and late transmitral peak flow velocitiy (A), E-wave deceleration time (DT), and LV isovolumic relaxation time (IVRT). Deceleration time and IVRT were divided by the square root of RR interval to correct for differences in heart rate. Moreover, the duration of pulmonary vein reverse flow during atrial contraction (PVa) was obtained from the pulsed-Doppler tracing of the right upper paraseptal pulmonary vein and divided by the duration of forward A-wave (MVa) to calculate the PVa/MVa ratio. The pattern of LV filling was evaluated according to the literature: restrictive filling was defined as DT < 160 ms plus E/A > 1.5 or PVa/MVa > 1, impaired relaxation as DT > 240 ms or E/A < 1, and pseudonormalized filling as DT > 240 plus E/A 1 to 1.5. (16) The possibility of pericardial constriction, defined by a respiratory variation of E wave > 12%, was also assessed. (11)
Right ventricular afterload was assessed by estimating systolic and mean pulmonary artery pressures and total pulmonary vascular resistance. Systolic pulmonary artery pressure was evaluated by the peak systolic right ventricular to the right atrial (tricuspid) pressure gradient, derived by continuous-Doppler tracing of the tricuspid valve flow in the presence of tricuspid regurgitation (17); the apical four-chamber, the parasternal short-axis, and the parasternal long-axis views were used while the subject suspended breathing at the end of a normal expiration. According to Aessopos et al, (18) increased systolic pulmonary artery pressure is defined by a tricuspid gradient > 30.0 mm Hg. Mean pulmonary artery pressure and total pulmonary vascular resistance were estimated by the pulsed-Doppler recording of systolic pulmonary valve flow and measurement of pulmonary acceleration time, according to the corresponding literature. (19)
Statistical analysis was performed using software (SPSS 10.0; SPSS; Chicago, IL). Continuous variables are expressed as mean [+ or -] SD. Mean values were compared among patient groups using Student t test or Mann-Whitney U test, according to whether the corresponding variables followed a normal distribution or not, as tested by the Kohnogorov-Smirnov test. Categorical variables were compared using the [chi square] test. Linear regression analysis was used to investigate potential relationships between variables. A p < 0.05 was considered statistically significant.
Hematologic Profile and Clinical Findings
Hematologic profile and clinical findings in TM and TI patients are presented in Table 1. Mean hemoglobin, serum ferritin, and peak serum ferritin levels were significantly higher in TM patients. History of splenectomy was significantly more frequent in patients with TI. Heart rate and mean systolic BP were significantly higher in TI patients, while diastolic BP did not differ between the two groups. Recent history or signs of congestive heart failure, including neck vein distention and/or hepatojugular reflux along with ankle edema, hepatomegaly, and gallop rhythm, were encountered in five TM patients (3.8%) aged 25 to 29 years, and two TI patients (2.7%, p > 0.05 vs TM) aged 37 and 40 years.
History of deep vein thrombosis was present in six patients with TI (8.1%) and none with TM. No history of pulmonary embolism was present in any of the patients. Moreover, history of alcohol abuse, IV drug use, or familial cardiomyopathy was not present in any of the eases. Regarding the smoking habits of the patients, 10% of them reported mild smoking, but smoking was not correlated with the observed cardiac abnormalities, such as LV dysfunction or pulmonary hypertension. According to the defined clinical and echocardiographic criteria, evident heart disease was present in 28 of 205 patients (13.7%), including 11 of 131 TM patients (8.4%, all with reduced LV contractility, 5 of whom also had congestive heart failure) and 17 of 74 TI patients (23.0%, all with considerable pulmonary hypertension, 2 of whom also had congestive heart failure).
Age-subgroup analysis (Table 2) showed that right ventricular afterload, expressed by peak systolic tricuspid gradient, mean pulmonary artery pressure, and total pulmonary vascular resistance, was significantly higher in TI cases, both in young patients (age [less than or equal to] 25 years) and in older patients. Diastolic LV indexes were not correlated with tricuspid gradient, mean pulmonary artery pressure, or total pulmonary vascular resistance in patients with TI.
Patients Without Evident Heart Disease
In this subgroup, TM and TI patients had similar mean age (28.0 [+ or -] 6.0 years vs 26.9 [+ or -] 6.9 years, p > 0.05) and gender distribution (male gender, 54 of 120 patients [45.0%] vs 32 of 57 patients [56.1%]; p > 0.05) [Tables 3, 4]. Mean hemoglobin concentration did not differ either between TM and TI (9.7 [+ or -] 0.4 g/dL vs 9.5 [+ or -] 1.2 g/dL, p > 0.05, respectively), while mean serum ferritin was higher in TM patients, in accordance with the entire cohort (1,789 [+ or -] 798 ng/mL vs 1,342 [+ or -] 959 ng/mL, p < 0.01).
Cardiac diameters, LV mass, LV end-diastolic volume, as well as LV ejection and shortening fractions, stroke volume, and cardiac output were all significantly higher in TI patients. LV afterload indexes, including total peripheral resistance and mean BP/stroke volume ratio were, in contrast, significantly higher in TM, but the end-systolic LV wall stress did not differ between the two forms of the disease. Relative wall thickness did not differ either between TM and TI patients.
Regarding diastolic LV function, the rate of restrictive LV filling pattern, according to the defined criteria, was 44% in TM vs 37% in TI (p > 0.05); E/A ratio and IVRT were significantly higher in TM patients, while DT did not differ between TM and TI. Impaired LV relaxation was encountered only in three patients with TI. All right ventricular afterload indexes were significantly higher in TI patients. Similarly, the occurrence of increased tricuspid gradient (> 30.0 mm Hg) was significantly more frequent in TI patients.
Patients With Evident Heart Disease
Mean age and gender distribution did not differ between TM and TI patients either in this subgroup: mean age, 27.1 [+ or -] 5.4 years vs 32.4 [+ or -] 7.9 years (p > 0.05); male gender, 8 of 11 patients (72.7%) vs 9 of 17 patients (52.9%) [p > 0.05; Tables 5, 6]. Both mean hemoglobin and serum ferritin levels, however, were significantly higher in TM patients (9.8 [+ or -] 0.3 g/dL vs 8.5 [+ or -] 1.0 g/dL, p < 0.001 and 2,150 [+ or -] 862 ng/mL vs 1,027 [+ or -] 745 ng/mL, p [+ or -] 0.01, respectively).
All 11 unfit TM patients were characterized by impaired LV contractility, while considerable pulmonary hypertension was absent; 3 patients had slightly increased tricuspid gradient values, ranging < 35 mm Hg. However, all 17 TI patients in the unfit subgroup had considerable pulmonary hypertension, with tricuspid gradient values ranging from 35.2 to 97.2 mm Hg, while none of them had reduced LV contractility.
In contrast to what was observed in fit patients, cardiac dimensions, LV mass, and LV end-diastolic volume did not differ between the two forms of the disease. The differences regarding LV ejection and shortening fractions, stroke volume, cardiac output, and left and right afterload indexes were in line to those encountered in patients without evident heart disease; however, these differences were more profound in this subgroup. Relative wall thickness was significantly higher in TI patients.
TM and TI share a common basic molecular mechanism: the reduced synthesis of the [beta]-globin chains. (1) The consequences of the resulting chronic anemia are also common and include growth retardation, bone marrow expansion, extramedular hematopoiesis, splenomegaly, increased intestinal iron absorption, susceptibility to infections, and hypercoagulability. (1,20) What differentiates the two forms is the severity of the clinical phenotype, which depends on a particularly heterogeneous molecular background and is mainly determined by the balance between [alpha]- and [beta]-globin chains and the quantity of [gamma]-globin chains. (1) The diverse clinical severity has led, in turn, to totally different therapeutic approaches, whose effects we try to factor out in the present work.
Structural and Functional Cardiac Abnormalities
In the present study, TM patients have universally been on an intensive transfusion regimen that has maintained their hemoglobin level close to normal, hence allowing an adequate tissue oxygen delivery. Patients with TI, in contrast, remained without transfusions due to their less severe molecular defect, a fact that lead to a lower overall hemoglobin level. The resulting chronic hemolysis and ineffective erythropoiesis led to chronic tissue hypoxia, followed by the previously described consequences, a part of which is cardiac adaptation. Indeed, TI patients without evident heart disease had significantly higher cardiac output and cardiac diameters and volumes with respect to TM patients. These findings are in line with those previously reported in TI. (8,21) Interestingly, these differences existed in fit patients even in the absence of significant hemoglobin level differences. It seems that the peripheral shunts within the bone marrow and the persistence of hemoglobin F, which is characterized by reduced tissue oxygen delivery, play an important role for the development of high-output state in TI. In accordance to the differences concerning cardiac output, LV afterload indexes (total peripheral resistance and mean BP/stroke volume ratio) were significantly lower in TI patients without evident heart disease. At the same time, end-systolic LV wall stress and relative wall thickness did not differ between TM and TI in the fit-patient subgroup, probably because they represent cardiac adaptation in a well-compensated state.
So far, the most striking difference between the two forms of [beta]-thalassemia was thought to be the severity of cardiac impairment. Before the introduction of regular treatment in TM, most of the patients died of high-output heart failure, usually by the end of the first decade of life, while TI patients had a much longer survival. (22) The regular therapy, which was gradually applied thereafter, modified the form and the severity of thalassemia heart disease. At the same time, the heterogeneous cardiac outcome reflected the treatment variability with respect to frequency of transfusions and intensity of iron chelation. The reported incidence of heart failure in 1964, in the absence of regular therapy, was 63% at the age of 16 years (22); 3 decades later, following the introduction of regular transfusions and iron chelation, this rate fell to 33% and 37% in two different cohorts (mean ages, 20 years and 23 years, respectively) (23,24); a 9% incidence was more recently reported in young, not-well-treated patients with a mean age of 12 years. (7)
In the current series, the rigorous compliance of patients with what is currently considered to be the optimal therapy has provided the hitherto most encouraging cardiac outcome. Heart failure was encountered in < 4% of TM patients at a mean age of 28 years. Moreover, premature heart disease was avoided, as heart failure was not encountered before the age of 26 years. LV dysfunction was the only notable abnormality in TM and, in accordance with the existing knowledge, it was the cause of congestive heart failure in these patients. In TM patients with evident heart disease, end-systolic stress and relative wall thickness were affected following LV dysfunction. Systolic LV dysfunction, however, was not observed in patients < 23 years old.
In TI patients, despite the absence of transfusional iron overload, which is considered to be the main cause of heart disease in [beta]-thalassemia, cardiac involvement was not avoided either. Although systolic LV function was preserved, increased pulmonary pressure was observed with a high frequency (47% in fit patients, 100% in unfit patients), representing the typical finding in TI patients. This abnormality, although less serious in comparison with the early echo signs of systolic LV dysfunction observed in TM, affected right-heart afterload indexes and, in some of the eases, led to right-heart failure and development of congestive heart failure. However, heart failure was still less frequent in TI patients (2.7% vs 3.8%), although this difference was not significant, and it developed a decade later with respect to TM.
Restrictive LV filling is known to be associated with iron-induced cardiomyopathy. However, LV preload and cardiac output levels also affect echocardiographic diastolic indexes. Thus, the prognostic significance of diastolic echo findings has been questioned even in TM. (6) In the present study, using the current Doppler criteria, (16) a high occurrence of restrictive LV filling was noted in both forms of the disease. The E/A ratio, however, one of the most widely used criterion for restrictive LV filling, was significantly increased in TM, both in fit patients and in those with evident heart disease, representing probably the effect of iron overload. In TI patients, however, diastolic LV function indexes were not correlated with pulmonary vascular resistance or pulmonary artery pressure. This finding is in accordance to right-heart catheterization data reported earlier in TI. (8)
According to a previous study (7) concerning an inadequately treated and young TM population (mean age, 12 [+ or -] 6 years), puhnonary hypertension was encountered in the striking incidence of 66%. Age-related pulmonary hypertension was reported with a similarly high incidence in TI. (8) These findings suggest that pulmonary hypertension represents a part of the clinical spectrum of both forms of the disease. Moreover, the accumulated body of evidence shows that most forms of chronic hemolytic anemia, including sickle-cell disease, hereditary spherocytosis, and paroxysmal nocturnal hemoglobinurea, may develop pulmonary hypertension, suggesting that there is a syndrome of hemolysis-associated puhnonary hypertension. (25) The importance of chronic hemolysis on the development of pulmonary hypertension through its negative effect on nitric oxide and arginine availability has recently been stressed in the literature. (26) In addition, hemolysis has been associated with a diffuse elastic tissue defect that resembles pseudoxanthoma elasticum and is more pronounced in patients with thalassemia, especially with TI. (27) Red cell membrane elements produced by hemolysis-induced oxidative damage have been discussed as a responsible mechanism for the elastic tissue injury. Degenerative elastic tissue lesions have been encountered in pulmonary autopsies in sickle-cell disease and may also be related to the development of pulmonary hypertension in hemoglobinopathies. (28)
Pulmonary hypertension represents the leading cause of heart failure in TI and the primary risk factor for death in sickle-cell disease. (8,26) It has been postulated that transfusion therapy may be helpful in preventing or treating pulmonary hypertension in patients with TI. (8) In the present study, pulmonary hypertension was frequent both in young and older TI patients, while it was practically absent in the aged-matched and well-treated TM patients. This finding makes clear that pulmonary hypertension is a typical feature of TI patients without transfusion and not a simple age-related effect due to the increased survival of these patients, providing at the same time some support to the above hypothesis. Besides the restriction of the hemolysis-induced mechanisms, regular therapy may have some additional beneficial effects. Chelation therapy reduces pulmonary and cardiac iron deposition and their contribution to the elevation of pulmonary vascular resistance,s Regular transfusion therapy, however, besides restricting the negative effects of hemolysis on nitric oxide and arginine availability, also prevents chronic tissue hypoxia and its consequences that have been implicated in the pathogenesis of pulmonary hypertension in TI. (8,26) Moreover, regular transfusions decrease drastically the native precoagulant erythrocytes and the rate of splenectomy, both responsible of the thalassemia-related hypercoagulability, a particular precipitating factor for pulmonary hypertension in these patients. (20,29) Accordingly, no history of deep vein thrombosis or other thromboembolic episodes was encountered in any of well-treated TM patients, findings that have been described both in TI patients without transfusion and poorly-treated TM patients. (30) A first indication of the potential effects of transfusion and chelation therapy was provided by a case reportal of one patient with hemoglobin E/[beta]-thalassemia and pulmonary hypertension. In this case, regular therapy was followed by normalization of plasma thrombin-antithrombin III complex levels and reduction of puhnonary vascular resistance and mean pulmonary artery pressure. (31)
Although molecular background predetermines therapeutie approach in [beta]-thalassemia, the particular features of applied treatment have a global effect on patient's clinical appearance, survival, and form of complications. The dramatic improvement of prognosis and survival observed in TM over the past decades represents a challenge for even better results. However, nontreated TI patients follow the natural history of the disease and have complications that might be prevented by the current therapeutic modalities. At this point, however, the time of therapeutic intervention in TI remains an open issue that requires investigation. The early treatment application may be proven unnecessary due to a cost-benefit imbalance, while the late application following the development of certain severe complications, which represents the current strategy, may prove unable to restore the established abnormalities.
* From the First Department of Internal Medicine (Drs. Farmakis, Deftereos Tsironi, Tassiopoulos, and Aessopos), University of Athens Medical School, "Laiko" General Hospital; Department of Cardiology (Dr. Moyssakis), "Laiko" Hospital; and Thalassemia Unit (Dr. Karagiorga), "Aghia Sophia" Children's Hospital, Athens, Greece.
(1) Olivieri NF. The [beta]-thalassemias. N Engl J Med 1999; 341: 99-109
(2) Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and disease complications in thalassemia major. Ann N Y Acad Sci 1998; 850:227-231
(3) Ehlers KH, Levin AR, Markenson AL, et al. Longitudinal study of cardiac function in thalassemia major. Ann N Y Acad Sci 1980; 344:397-404
(4) Hahalis G, Manolis AS, Apostolopoulos D, et al. Right ventricular cardiomyopathy in [beta]-thalassaemia major. Eur Heart J 2002; 23:147-156
(5) Spirito P, Lupi G, Melevendi C, et al. Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major. Circulation 1990; 82:88-94
(6) Kremastinos DT, Tsiapras DP, Tsetsos GA, et al. Left ventricular diastolic Doppler characteristics in [beta]-thalassemia major. Circulation 1993; 88:1127-1135
(7) Du ZD, Roguin N, Milgram E, et al. Pulmonary hypertension in patients with thalassemia major. Am Heart J 1997; 134: 532-537
(8) Aessopos A, Farmakis D, Karagiorga M, et al. Cardiac involvement in thalassemia intermedia: a multicenter study. Blood 2001; 97:3411-3416
(9) Sahn DJ, De Maria A, Kisslo J, et al. The committee on M-mode standardization of the American Society of Echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58:1072-1083
(10) Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards Subcommittee. J Am Soc Echocardiogr 1989; 2:358-367
(11) Feigenbaum H. Echocardiographic evaluation of cardiac chambers. In: Feigenbaum H, ed. Echocardiography. 5th ed. Philadelphia, PA: Lea & Febiger, 1994; 134-173
(12) Devereux RB, Monso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57:450-458
(13) Peterson LR, Waggoner AD, Schechtman KB, et al. Alterations in left ventricular structure and function in young healthy obese women: assessment by echocardiography and tissue Doppler imaging. J Am Coll Cardiol 2004; 43:1399-1404
(14) Hahalis G, Manolis AS, Gerasimidou I, et al. Right ventricular diastolic function in [beta]-thalassemia major: echocardiographic and clinical correlates. Am Heart J 2001; 141:428-434
(15) Bahl VK, Malhotra OP, Kumar D, et al. Non-invasive assessment of systolic and diastolic left ventricular function in patients with chronic severe anemia: a combined M-mode, two-dimensional, and Doppler echocardiographic study. Am Heart J 1992; 124:1516-1523
(16) Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002; 105:595-601
(17) Chan KL, Currie PJ, Seward JB, et al. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery disease. J Am Coll Cardiol 1987; 9:549-554
(18) Aessopos A, Farmakis D, Taktikou H, et al. Doppler-determined peak systolic tricuspid pressure gradient in persons with normal pulmonary function and tricuspid regurgitation. J Am Soc Echocardiogr 2000; 13:645-649
(19) Dabestani A, Mahan G, Gardin J, et al. Evaluation of pulmonary artery pressure and resistance by pulsed Doppler echocardiography. Am J Cardiol 1987; 59:662-668
(20) Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood 2002; 99:36-43
(21) Vaccari M, Crepaz R, Fortini M, et al. Left ventricular remodeling, systolic function, and diastolic function in young adults with [beta]-thalassemia intermedia: a Doppler echocardiography study. Chest 2002; 121:506-512
(22) Engle MA, Erlandson M, Smith CH. Late cardiac complications of chronic, refractory anemia with hemochromatosis. Circulation 1964; 30:698-705
(23) Grisaru D, Raehmilewitz E, Mosseri M, et al. Cardiopulmonary assessment in [beta]-thalassemia major. Chest 1990; 98: 1138-1142
(24) Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous [beta]-thalassemia. N Engl J Med 1994; 331:574-578
(25) Vichinsky EP. Pulmonary hypertension in sickle cell disease. N Engl J Med 2004; 350:857-859
(26) Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004; 350:886-895
(27) Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in [beta] thalassemia and the sickling syndromes. Blood 2002; 99: 30-35
(28) O'Driscoll A, Mackie IJ, Porter JB, et al. Low plasma heparin cofactor II levels in thalassaemia syndromes are corrected by chronic blood transfusion. Br J Haematol 1995; 90:65-70
(29) Haque AK, Gokhale S, Rampy BA, et al. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002; 33:1037-1043
(30) Borgna Pignatti C, Carnelli V, Caruso V, et al. Thronaboernbolic event in [beta]-thalassemia major: an Italian multicenter study. Acta Haematol 1998; 99:76-79
(31) Atichartakarn V, Chuncharunee S, Chandanamattha P, et al. Correction of hypercoagulability and amelioration of pulmonary arterial hypertension by chronic blood transfusion in an asplenic hemoglobin E/[beta]-thalassemia patient. Blood 2004; 103:2844-2846
Manuscript received July 12, 2004; revision accepted November 1, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).
Correspondence to: Athanasios Aessopos, MD, PhD, First Department of Internal Medicine, "Laiko" General Hospital, 17 Aghiou Thoma St, Athens 115 27, Greece; e-mail: aaisopos@ cc.uoa.gr; email@example.com
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