(Circulation. 1995;91:66-71.)
© 1995 American Heart Association, Inc.
Articles |
Myocarditis in ß-Thalassemia Major
A Cause of Heart Failure
From the Cardiology Departments of Athens General Hospital and Hippokration Hospital, University of Athens Medical School, Greece.
Correspondence to Dimitrios Th. Kremastinos, MD, 2, Hatziyianni Mexi str, 115 28th Athens, Greece.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Although acute pericarditis is a common complication of ß-thalassemia major, the prevalence and consequences of myocarditis in this disease have not been investigated.
Methods and Results A prospective 5-year follow-up study was carried out in all patients with ß-thalassemia major in whom the diagnosis of acute infectious myocarditis could be established between 1977 and 1986. A similar number of age- and sex-matched control subjects with ß-thalassemia and normal left ventricular function and no evidence of myocarditis were also followed for 5 years. Of 1048 patients with ß-thalassemia major, 47 patients (age, 15±2.5 years) with precordial chest pain were diagnosed as having acute infectious myocarditis. Myocardial biopsy was diagnostic in 26 patients, borderline in 14 patients, and nondiagnostic in 7 patients. Acute heart failure with left ventricular dysfunction (left ventricular ejection fraction, 25±11%) developed in 11 patients (23.4%) with myocarditis, and 8 of them died within 1 month to 1 year after diagnosis. Thirteen patients with myocarditis (27.6%) developed chronic heart failure (left ventricular ejection fraction, 26±13%) within 3±1.3 years, and 10 of them died within 8±3 months. Left ventricular systolic and diastolic functions of the control subjects did not change significantly during the 5-year period (left ventricular ejection fraction, 63±11% versus 65±7%; P=NS). However, left ventricular restrictive abnormalities (early diastole/late diastole, >2.2; deceleration time, <110 milliseconds) combined with right ventricular dilatation (>30 mm internal diameter) and right-sided heart failure developed in 3 patients with extremely high mean serum ferritin levels. No significant difference was found in mean levels of serum ferritin and pretransfusion hemoglobin between patients with and those without myocarditis.
Conclusions In patients with ß-thalassemia, myocarditis appears to be involved in the pathogenesis of left ventricular systolic dysfunction, being the main cause of death. Iron overload appears to provoke left ventricular restrictive abnormalities combined with right ventricular enlargement and dysfunction.
Key Words: myocarditis • heart failure • ß-thalassemia
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Congestive heart failure is the main cause of death in patients with ß-thalassemia major and is traditionally attributed to iron overload.1 2 Although approximately half of patients with ß-thalassemia major develop acute pericarditis during their lives,3 4 no study has examined the prevalence of myocarditis in this disease and its potential role in the development of congestive heart failure. Therefore, to assess the impact of myocarditis on the cardiac function of patients with ß-thalassemia, all patients with ß-thalassemia major who were treated in our hospitals between 1977 and 1986 and in whom the diagnosis of acute infectious myocarditis could be established were followed for 5 years. For comparison, a similar number of patients with ß-thalassemia major who had normal left ventricular function and no evidence of myocarditis were also followed for 5 years.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Study Population
During the period of 1977 through 1986, 1048 patients with ß-thalassemia major were treated in our hospitals or attended our outpatient clinic. Acute infectious myocarditis was diagnosed according to the following criteria: (1) clinical evidence of myocarditis with acute development of typical precordial chest pain, recent fever, and flulike symptoms such as headache, sore throat, malaise, myalgia, vomiting, or diarrhea; (2) ECG changes such as abnormal Q waves, R-wave diminution, ST-segment elevation, and T-wave inversion; (3) documentation of normal coronary arteries by coronary angiography; (4) elevation of serum creatinine kinase (CK)-MB levels; (5) positive virological studies; and (6) endomyocardial biopsy (Table 1
).
The diagnosis was further supported by the presence
of a loud S3 gallop.5 Patients with typical
acute pericarditis and pericardial effusion were not included in the
study. CK isoenzymes were assessed electrophoretically and quantified
by fluorometric scanning. The normal upper limit was 220 U/L for CK
activity and 7 U/L or <5% of the total CK for the CK-MB fraction. The
first of the enzyme determinations was made during the initial 2 days
of symptoms or ECG changes and mainly during the ST-segment elevation
stage.6 Virological studies included the determination of
coxsackie B1-5 by complement fixation test or neutralizing antibody
titers. A fourfold rise in serial examination of viral antibody titers
was considered positive.7 Left ventricular endomyocardial
tissue was obtained by an average of five biopsies per patient using
the percutaneous long sheath technique. Diagnostic criteria for acute
myocarditis included appreciable lymphocytic and inflammation cell
infiltrates and damaged (necrotic) myocytes (Figure)
according to the Dallas criteria.8 During the acute phase
of myocarditis, noninvasive investigations, including ECG and
echocardiographic examination (two-dimensional, M-mode, and, in some
patients, Doppler assessment as described below), were performed on a
daily basis.
|
|
During follow-up, these investigations were performed at 6-month intervals. The study of the control group, consisting of age- and sex-matched patients with ß-thalassemia major derived from a consecutive series of patients with ß-thalassemia major who had normal left ventricular function and no evidence of myocarditis, was carried out between 1985 and 1991 and used echocardiographic assessment at 6-month intervals. Two-dimensional and M-mode echocardiograms were obtained using instruments with a 3-MHz transducer. A two-dimensional study was first performed to identify the overall cardiac anatomy and motion.9 10 Four- and two-chamber apical views were used to estimate ventricular systolic and diastolic volumes, which were calculated using the discs method.11 Subsequently, indexes were derived by dividing volume by body surface area. Left ventricular ejection fraction was calculated as [(end-diastolic volume minus end-systolic volume) divided by end-diastolic volume] multiplied by 100. A complete pulsed wave and continuous wave Doppler examination was performed. The lowest filter settings were used to record flow velocities. Doppler signal, surface ECG, and phonocardiogram were recorded on videotape simultaneously with speeds of 25, 50, and 100 mm/s. To record left ventricular inflow velocities, the apical four-chamber view was used, and the pulsed wave Doppler sample volume was placed at the level of the leaflet tips of the mitral valve. All measurements were analyzed manually with the incorporated computer digitizing system. Mean values were obtained by averaging at least two beats during inspiration and two beats during expiration for five respiratory cycles. Peak flow velocities of the left ventricular inflow in early diastole (E) and late diastole with atrial contraction (A) were measured from the baseline to the maximum flow velocity. An E/A velocity ratio was calculated for each cardiac cycle. Deceleration time was measured as the distance (time) between the projection of the peak E velocity on the baseline and the point where the EF slope encounters the baseline. Isovolumic relaxation time (IVRT) was measured as the time from the onset of the aortic component of the second heart sound to the onset of diastolic flow velocity.12 Intraobserver and interobserver variabilities of Doppler echocardiographic measurements in this clinical setting have been previously reported.13 Arterial blood pressure was measured in all patients and control subjects at the time of echocardiographic examination.
Each patient was receiving a transfusion every month to maintain hemoglobin levels between 10 and 13 g/dL. In all patients, transfusion therapy had been started before the age of 5 years. The mean serum ferritin level in each patient was derived as the mean of 30 values obtained at 2-month intervals over the past 5-year period. The mean hemoglobin and hematocrit levels were derived in the same way. Clinical cardiac evaluation was performed 48 hours after the last transfusion, and hemoglobin and hematocrit levels were determined before and after transfusion in all patients. There were no alterations in blood transfusion management or chelation therapy of patients who had developed myocarditis.
In the present report, acute heart failure denotes heart failure presenting as the first manifestation of acute myocarditis. This condition either led to death or resolved within 3 months from presentation. Chronic heart failure refers to subsequent development and persistence of heart failure during follow-up.
Statistical Analysis
All tests were carried out with the
CSS statistical
software package. Multivariate analysis was used for comparisons
between the groups with and without myocarditis. Data are presented
as mean±1 SD values.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Prevalence of Myocarditis in Patients With ß-Thalassemia Major
Of 1048 patients with ß-thalassemia major, 47 patients (age, 15±2.5 years; range, 13 to 20 years) were diagnosed as having acute myocarditis according to the discussed criteria and were followed for a period of 5 years. Thus, the prevalence of acute myocarditis in our series was 4.5% in 9 years. Consequently, 47 age- and sex-matched patients with ß-thalassemia major and without evidence of myocarditis were also followed as control subjects for 5 years.
Clinical Characteristics and Other Findings at Diagnosis of
Myocarditis
The diagnosis of acute infectious myocarditis in 47
patients with
ß-thalassemia major was made as shown in Table 1
.
Myocardial biopsy
was diagnostic for acute myocarditis in 26 patients (ie, 55% of the
total population with myocarditis), borderline in 14 patients (ie, 30%
of the total population with myocarditis), and nondiagnostic in 7
patients (ie, 15%). The most common symptom other than precordial
chest pain was dyspnea, either at rest or on mild exercise, followed by
palpitations and an abnormal third heart sound. Eleven patients
(23.4%) presented with acute left-sided heart failure (New York
Heart Association functional class III or IV) as the first
manifestation of acute myocarditis.
The most common ECG abnormality at
diagnosis was T-wave inversion
followed by ST-segment elevation (Table 1). Pathological Q
waves or
decreased R waves were found in all patients who presented with
left-sided heart failure during the acute phase. All patients had
normal echocardiographic studies with no regional wall abnormalities
(two-dimensional left ventricular ejection fraction, 65±9%) and ECG
without specific findings during the last examination before the acute
episode.
Follow-up of Patients with Myocarditis
Follow-up results are
presented in Table 2. Of
11 patients with acute heart failure (mean left ventricular
end-diastolic volume index, 127±22 mL/m2; left
ventricular end-systolic volume index, 95±18; ejection fraction,
25±11%), 3 patients had complete recovery with normal left
ventricular dimensions and function within 3 months after the acute
episode. The remaining 8 died: 6 patients within 1 month, 1 at 11
months after diagnosis, and 1 at 13 months after diagnosis. Of 36
patients who recovered after the acute episode of myocarditis, 13
patients developed chronic left-sided heart failure within the
following 3±1.3 years (mean left ventricular end-diastolic
volume index, 131±12 mL/m2; left ventricular end-systolic
volume index, 97±19; ejection fraction, 26±13%).
|
Patients Without Myocarditis
All patients had ECGs without
specific findings and, with the
exemption of 2 patients who had a deceleration time of <110
milliseconds, unremarkable echocardiographic studies at the time of
inclusion in the study (Table 3). The echocardiographic
characteristics of the patients without myocarditis did not change
significantly during this follow-up study. However, 3 patients of this
group (17, 17, and 18 years old) progressively developed right
ventricular enlargement (>30 mm internal diameter) with clinical signs
of right-sided heart failure combined with left ventricular restrictive
abnormalities (E/A, >2.2; deceleration time, <110 milliseconds).
Their mean serum ferritin level was extremely high: 6070, 5910, and
6170 ng/mL, respectively. No significant wall motion abnormalities or
ECG changes were encountered in the remainder of the patients.
|
Adjustment for age, sex, number of blood units transfused, and hemoglobin, hematocrit, and ferritin levels through discriminant analysis of the results showed no difference between patients with ß-thalassemia major who did and those who did not have myocarditis. Arterial blood pressure remained within normal limits in all patients. No patient developed significant enzyme changes during the follow-up period.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Features and Prevalence of Myocarditis in Patients with ß-Thalassemia Major
Although acute pericarditis has been long accepted as a common complication of ß-thalassemia major,3 4 the prevalence, pathogenesis, and natural history of acute myocarditis have remained obscure. Our series suggests that myocarditis is an injury that involves the myocardium more than the pericardium and is probably the underlying cause of the ST-segment elevation or T-wave inversion that occurs within this condition. Furthermore, the occurrence of ventricular tachycardia is indicative of myocardial involvement. Subepicardial macroreentry, arising from viable subepicardial muscle fibers, can occur in as many as 20% of ventricular tachycardia episodes in ischemic patients,14 but it is a consequence of myocardial scarring rather than of pericardial involvement. Q waves do not frequently develop because of the possibly scattered nature of the myocardial damage, which may be reversible. The presence of ventricular tachycardia or permanent pathological Q waves combined with congestive heart failure proved to be the worst predictors for survival. All patients with ventricular tachycardia died suddenly. No patient of the chronic heart failure group made a full recovery, in contrast to those of the acute heart failure group. Acute myocarditis in patients with ß-thalassemia major resulted in almost complete recovery in
47% (22 of 47) of patients. The severity and clinical
course of myocarditis are rather unpredictable and do not appear to be
related to the total amount of iron transfused.
Cardiac Failure in Patients with ß-Thalassemia Major
Congestive heart failure is the most common complication of
ß-thalassemia major occurring during the second decade of life with
acute pericarditis. In our series, chronic left-sided heart failure
developed years after the manifestation of acute myocarditis only in
the group with myocarditis, raising the possibility that congestive
heart failure in patients with ß-thalassemia major might be related
to a late autoimmune process. This might lead to the development of the
established syndrome of dilated cardiomyopathy seen years later in this
patient population.
Iron Overload and Ventricular Function
Chronic iron
deposition in the lungs and heart has been shown to
provoke pulmonary hypertension and right ventricular dilatation in
combination with left ventricular diastolic dysfunction
(restriction).15 Our 5-year follow-up study of patients
with ß-thalassemia major and without evidence of myocarditis showed
that none developed left ventricular systolic dysfunction and
dilatation. These observations are in agreement with our previous
studies suggesting that iron overload does not appear to be the main
cause of congestive heart failure in patients with ß-thalassemia
major.16 17 In particular, we have recently shown
that
iron appears to have little effect on the left ventricular diastolic
function of young patients.13 Pseudorestrictive
transmitral or pulmonary vein flow abnormalities seen in very young
patients are possibly age and body surface area dependent. True
restrictive left ventricular abnormalities were observed only in a
small minority of patients (<10%), all belonging to the oldest
ß-thalassemia major population with highly elevated mean serum
ferritin levels and, consequently, chronic iron
overload.13 The fact that in some studies with small
groups of patients preclinical left ventricular diastolic wall
abnormalities15 18 or left ventricular systolic
dysfunction has been detected19 does not necessarily prove
that iron deposition in the myocardium alone is responsible for acute
or congestive heart failure development. Systolic and diastolic left
ventricular functions may well be preserved until the final stages of
the disease.16 17 20 The wide range in
age (6 to 31 years)
and iron transfused (3 to 104 g) in patients who died of congestive
heart failure was first reported in 1964.4 Myocardial iron
deposition appears to be a late event, occurring after the accumulation
of iron in the spleen and liver.21 In patients with
ß-thalassemia major, iron overload and deposition into myocardium
appear to be mainly related to left ventricular diastolic restriction,
combined with right-sided heart failure possibly due to iron deposition
in the lungs, which results in elevated pulmonary arteriolar
resistance.
It should be stated that ß-thalassemia major, traditionally accepted as iron storage disease, is not a true hemochromatosis, being a combination of chronic hemolytic anemia, iron storage disease, and myocarditis. Infectious myocarditis, possibly related to a high prevalence of infections due to abnormalities of the immune system,22 23 can cause acute or chronic left ventricular systolic dysfunction and dilatation. Thus, it appears to be involved in the pathogenesis of congestive heart failure in young patients, being the main cause of death during the second decade of life. The clinical presentation of myocarditis in our population is very suggestive of infectious myocarditis, which can be associated with nondiagnostic myocardial biopsies or serological tests.24 25 26 27 Convalescent serial endomyocardial biopsies that might have yielded additional information about the nature of myocardial involvement in our population were not performed for ethical reasons. In any case, acute myocarditis may be initiated by viral infection, but subsequent myocardial damage appears to be mediated by predominantly immunological mechanisms rather than by viral infection and replication.28
Study Limitations
First, our data suggest that clinically
evident myocarditis with
precordial chest pain is seen in <5% of patients with ß-thalassemia
major in a 9-year period, but the prevalence of at least histological
evidence of significant myocardial involvement in patients with
ß-thalassemia major is unknown. The possibility of some patients
having subclinical myocarditis, and thus lacking striking
symptomatology such as myopericardial precordial pain, cannot be
excluded. Furthermore, as many as 15% of these patients may have
normal myocardial biopsies, whereas histological evidence of
myocarditis without clinical symptoms can be detected even in
apparently healthy, young individuals.29 Therefore,
although myocardial biopsy is an important investigation for diagnosis
of myocarditis, it is not an infallible test. Thus, patients with
positive biopsies and specific clinical symptoms and signs have a
convincing diagnosis, but the opposite may not be true.
Second, our suggestions regarding the role of iron should be interpreted with caution. The number of blood units transfused has not been proved to be an accurate index of iron overload, since iron turnover and iron absorption are increased and iron chelation therapy decreases the amount of deposited iron.30 In contrast, serum ferritin is highly correlated with the amount of iron deposited in tissues and is considered a high-sensitivity index. However, potential mechanisms of iron toxicity (eg, interference with mitochondrial oxidative metabolic processes) might not alter function until a critical threshold is reached. Thus, the possible role of iron accumulation in the development of an acute inflammatory myocardial process is not known. Certainly, the precise role of iron in this setting cannot be derived from clinical studies.
In conclusion, infectious myocarditis is a clinical entity in ß-thalassemia major and results in acute or chronic congestive heart failure development with echocardiographic findings similar to those of left ventricular dilated cardiomyopathy. It occurs relatively early in life and often is fatal. Myocarditis does not appear to be associated with iron myocardial deposition as assessed by serum ferritin levels. The role of iron cannot be determined from our findings, but it appears that iron overload and deposition in the myocardium may be related to left ventricular diastolic restriction and right-sided heart failure.
|
|
Acknowledgments |
|---|
The authors thank Eleni Binou for her excellent secretarial assistance and Dr A. Tsonou for her comments on statistical analysis.
Received April 19, 1994; accepted August 8, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Sapoznikov D, Lewis N, Rachmilewitz EA, et al. Left ventricular filling and emptying patterns in anemia due to beta-thalassemia: a computer-assisted echocardiographic study. Cardiology. 1982;69:276-282. [Medline] [Order article via Infotrieve]
2.
Lau KC, Li AMC, Hui PW, Yeung CY. Left ventricular function
in ß-thalassemia major. Arch Dis Child. 1989;64:1046-1051.
3. Ehlers KH, Levin AR, Markenson AL, Marcus JR, Klein AA, Hilgartner MW, Engle MA. Longitudinal study of cardiac function in ß-thalassemia major. Ann N Y Acad Sci. 1980;344:397-404. [Medline] [Order article via Infotrieve]
4.
Engle MA, Erlandson M, Smith CH. Late cardiac complications
of chronic, severe refractory anemia with hemochromatosis.
Circulation. 1964;30:698-705.
5.
Meikkila J, Karjalainen J. Evaluation of mild acute
infectious myocarditis. Br Heart J. 1982;47:381-391.
6. Miklozek LC, Crumpacker SC, Royal DH, Come CP, Sullivan LJ, Abelman HW. Myocarditis presenting as acute myocardial infarction. Am Heart J.. 1988;76:115-118.
7. Menle W, Henle G, Horowitz CA. Infectious mononucleosis and Epstein Barr virus associated malignancies. In: Lennette EH, Schmidt NJ, eds. Diagnostic Procedures for Viral Rickettsial and Chlamydial Infections. Washington, DC: American Public Health Association; 1979:441-449.
8. Fenoglio JJ, Ursell PC, Kelogg CF, Drusin RE, Weiss MB. Diagnosis and classification of myocarditis by endomyocardial biopsy. N Engl J Med. 1983;308:12-18. [Abstract]
9. Armstrong WF, O'Donnell J, Dillon JC, McHenry PL, Morris SN, Feigenbaum H. Complementary value of two-dimensional exercise echocardiography to routine treadmill exercise testing. Ann Intern Med. 1986;105:829-835.
10. Armstrong WF, O'Donnell J, Ryan T, Feigenbaum H. Effect of prior myocardial infarction and extent and location of coronary disease on accuracy of exercise echocardiography. J Am Coll Cardiol. 1987;10:531-538. [Abstract]
11. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reicheh N, Sahn D, Schnittger I, Silverman NH, Tajih AJ. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiography. J Am Soc Echocardiogr. 1989;2:358-367. [Medline] [Order article via Infotrieve]
12. Spirito P, Maron BJ, Bellotti P, Chiarella F, Vecchio C. Noninvasive assessment of left ventricular diastolic function: comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Coll Cardiol. 1986;7:518-526. [Abstract]
13.
Kremastinos DT, Tsiapras D, Tsetsos G, Rentoukas E, Vretou H,
Toutouzas P. Left ventricular diastolic Doppler characteristics in
ß-thalassemia major. Circulation. 1993;88:1127-1135.
14.
Littmann L, Svenson Rh, Gallagher J, Selle JG, Zimmern SH,
Fedor JM, Colavita PG. Functional role of the epicardium in
postinfarction ventricular tachycardia: observations derived from
computerized epicardial activation mapping entrainment and epicardial
laser photoablation. Circulation. 1991;83:1577-1591.
15.
Crisaru D, Rachmilewitz EA, Mosseri M, Gotsman M, Latair JS,
Okon E, Goldfard A, Hasin Y. Cardiopulmonary assessment in
ß-thalassemia major. Chest. 1990;98:1138-1142.
16. Kremastinos DT, Toutouzas PK, Vissoulis GP, Venetis CA, Avgoustakis DG. Iron overload and left ventricular performance in ß-thalassemia. Acta Cardiol. 1984;1:29-40.
17. Kremastinos DT, Toutouzas PK, Vissoulis GP, Venetis CA, Vretou HP, Avgoustakis DG. Global and segmental left ventricular function in ß-thalassemia. Cardiology. 1985;72:129-139. [Medline] [Order article via Infotrieve]
18. Valdes-Cruz L, Reincenke C, Rutkowski M, Dudell G, Goldberg S, Allen H, Sahn D, Piomelli S. Preclinical abnormal segmental cardiac and manifestations of ß-thalassemia major in children on transfusion-chelation therapy: echographic alteration of left ventricular posterior wall contraction and relaxation patterns. Am Heart J. 1982;103:505-511. [Medline] [Order article via Infotrieve]
19. Martin BI, Borer JS, Bacharach LS, Green VM, Benz JE, Griffith P, Nienhuis AW. Detection of cardiac dysfunction in patients with severe beta-thalassemia and chronic iron overload. N Engl J Med. 1979;301:1143-1148. [Abstract]
20.
Kremastinos DT, Rentoukas E, Mavrogeni S, Kyriakides Z,
Politis C, Toutouzas P. Left ventricular inflow pattern in
ß-thalassemia major: a Doppler echocardiographic study. Eur
Heart J. 1993;14:351-357.
21. Johnston DL, Rice L, Vick W, Hedrick TD, Rokey R. Assessment of tissue iron overload by nuclear magnetic resonance imaging. Am J Med. 1989;87:40-47. [Medline] [Order article via Infotrieve]
22.
Smith WG. Adult heart disease due to Coxsackie virus group B.
Br Heart J. 1966;28:204-220.
23. Dwyer J, Wood C, McNamara J, Williams A, Andiman W, Rink L, O'Connor T, Pearson H. Abnormalities in the immune system of children with beta-thalassaemia major. Clin Exp Immunol. 1987;68:621-629. [Medline] [Order article via Infotrieve]
24. Chow LH, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular biopsy in the diagnosis of myocarditis. J Am Coll Cardiol. 1989;14:915-920. [Abstract]
25. Hauck AJ, Kearney DL, Edwards WD. Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocarditis: implications for the role of sampling error. Mayo Clin Proc. 1989;64:1235-1245. [Medline] [Order article via Infotrieve]
26. Reyes MP, Lerner AM. Coxsackievirus myocarditis: with special reference to acute and chronic heart effects. Progr Cardiovasc Dis. 1985;27:373-395. [Medline] [Order article via Infotrieve]
27. Gauntt CJ, Godeny EK, Lutton CW. Host factor regulating viral clearance. Pathol Immunopathol Res. 1988;7:251-259. [Medline] [Order article via Infotrieve]
28.
Kishimoto C, Abelmank WH. In vivo significance of T
cells in the development of coxsackievirus B3 myocarditis in mice:
immature but antigen-specific T cells aggravate cardiac injury.
Circ Res. 1990;67:589-598.
29. Stevens PJ, Ground KEV. Occurrence and significance of myocarditis in trauma. Clin Aviat Aerospace Med. 1970;41:776-780.
30. Jacobs A, Miller F, Worwood M, Beamish R, Wardrop C. Ferritin in the serum of normal subjects with iron deficiency and iron overload. Br Med J. 1972;4:206-211.
This article has been cited by other articles:
 |
|
 |
|
  A Pepe, V Positano, M Capra, A Maggio, C L Pinto, A Spasiano, G Forni, G Derchi, B Favilli, G Rossi, et al. Myocardial scarring by delayed enhancement cardiovascular magnetic resonance in thalassaemia major Heart, October 15, 2009; 95(20): 1688 - 1693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Roghi, S. Dellegrottaglie, P. Pedrotti, S. Pedretti, E. Cassinerio, and M. D. Cappellini Unexpected myocarditis in thalassaemia major patient screened for iron load cardiomyopathy BMJ Case Reports, February 16, 2009; 2009(feb04_1): bcr0820080811 - bcr0820080811. [Full Text]
|
|
|
|
 |
|
 D. Th. Kremastinos, D. P. Tsiapras, A. G. Kostopoulou, E. S. Hamodraka, A. S. Chaidaroglou, and E. D. Kapsali NT-proBNP levels and diastolic dysfunction in {beta}-Thalassaemia major patients Eur J Heart Fail, May 1, 2007; 9(5): 531 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Hamdy Use of strain and tissue velocity imaging for early detection of regional myocardial dysfunction in patients with beta thalassemia Eur J Echocardiogr, March 1, 2007; 8(2): 102 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Kramer, S. B. Murthi, R. M. Wise, I-T. Mak, and W. B. Weglicki Antioxidant and lysosomotropic properties of acute d-propranolol underlies its cardioprotection of postischemic hearts from moderate iron-overloaded rats. Experimental Biology and Medicine, April 1, 2006; 231(4): 473 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Farmakis, A. Polonifi, S. Deftereos, M. Tsironi, I. Papaioannou, and A. Aessopos Aortic Valve Replacement in a Patient With Thalassemia Intermedia Ann. Thorac. Surg., February 1, 2006; 81(2): 737 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y F Cheung, S Y Ha, and G C F Chan Ventriculo-vascular interactions in patients with {beta} thalassaemia major Heart, June 1, 2005; 91(6): 769 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Davis, C. O'Sullivan, P. H. Jarritt, and J. B. Porter Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major Blood, July 1, 2004; 104(1): 263 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.F. Cheung, G. C.F. Chan, and S.Y. Ha Arterial Stiffness and Endothelial Function in Patients With {beta}-Thalassemia Major Circulation, November 12, 2002; 106(20): 2561 - 2566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Walker The heart in thalassaemia Eur. Heart J., January 2, 2002; 23(2): 102 - 105. [Full Text] [PDF]
|
|
|
|
|
|
G. Hahalis, A.S. Manolis, D. Apostolopoulos, D. Alexopoulos, A.G. Vagenakis, and N.C. Zoumbos Right ventricular cardiomyopathy in {beta}-thalassaemia major Eur. Heart J., January 2, 2002; 23(2): 147 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.J. Anderson, S. Holden, B. Davis, E. Prescott, C.C. Charrier, N.H. Bunce, D.N. Firmin, B. Wonke, J. Porter, J.M. Walker, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload Eur. Heart J., December 1, 2001; 22(23): 2171 - 2179. [Abstract] [PDF]
|
|
|
|
 |
|
 J. P. Kushner, J. P. Porter, and N. F. Olivieri Secondary Iron Overload Hematology, January 1, 2001; 2001(1): 47 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Kremastinos, P. Flevari, M. Spyropoulou, H. Vrettou, D. Tsiapras, and C. G. Stavropoulos-Giokas Association of Heart Failure in Homozygous {beta}-Thalassemia With the Major Histocompatibility Complex Circulation, November 16, 1999; 100(20): 2074 - 2078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. F. Olivieri The {beta}-Thalassemias N. Engl. J. Med., July 8, 1999; 341(2): 99 - 109. [Full Text] [PDF]
|
|
|
|
|
|
E. Economou-Petersen, A. Aessopos, A. Kladi, P. Flevari, F. Karabatsos, C. Fragodimitri, P. Nicolaidis, H. Vrettou, D. Vassilopoulos, M. Karagiorga-Lagana, et al. Apolipoprotein E &b.epsi;4 Allele as a Genetic Risk Factor for Left Ventricular Failure in Homozygous beta -Thalassemia Blood, November 1, 1998; 92(9): 3455 - 3459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. F. Olivieri and G. M. Brittenham Iron-Chelating Therapy and the Treatment of Thalassemia Blood, February 1, 1997; 89(3): 739 - 761. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||