If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Corresponding author: Akinori Higaki, MD, PhD, Department of Intractable Disease and Aging Science, Ehime University Graduate School of Medicine, Toon, Japan, Address: 454 Shitsukawa, Toon, Ehime, Japan 791-0204, Tel: +81-89-960-5303.
Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, JapanDepartment of Intractable Disease and Aging Science, Ehime University Graduate School of Medicine, Toon, Japan
β-thalassemia is a well-known single-gene disorder that causes microcytic anemia but has also been reported as a predisposing factor for heart failure. In β-thalassemia major, iron overload due to life-long blood transfusions results in reduced ejection fraction (EF). In contrast, transfusion-independent thalassemia (intermedia and minor) rarely causes heart failure, and when it does, the EF is usually preserved
. In this report, we present a case of β-thalassemia intermedia without a history of transfusion, showing a phenotype of dilated cardiomyopathy. This case demonstrates that heart failure with reduced EF (HFrEF) can occur in thalassemia intermedia without iron deposition.
Case description
A 73-year-old man was admitted to the hospital with respiratory distress. The patient was diagnosed with heart failure and required four hospitalizations in a year for refractory symptoms. During his last hospitalization, he was diagnosed with pyothorax caused by Klebsiella pneumoniae and was treated with thoracic drainage. Nine months after the initial onset of symptoms, the patient was referred to our hospital for close examination and treatment of heart failure.
Upon admission, his blood pressure was 116/72 mmHg, and his heart rate at 82/min. Physical examination revealed a funneled chest. Laboratory data indicated microcytic anemia with a hemoglobin level of 8.4 g/dL, mean corpuscular volume of 51 fL (reference range: 80-95), and red blood cell count of 5.72 x 106 /μL. Iron and ferritin levels were 50 μg/dL (reference range: 120-140) and 1,929 ng/dL (reference range: 22-274), respectively. The Mentzer index was calculated as 8.92 (<13 suggesting thalassemia), percentage of HbA2 was increased (3.8%), and the patient was suspected of having β-thalassemia. Genetic testing identified a heterozygous mutation in the beta-globin gene (NM_000518.5), namely, c.1A>G at chr11:5227021; This mutation causes the loss of the primary start codon, leading to the abnormal hemoglobin production. Based on the clinical presentations and genetic screening, the patient was diagnosed with β-thalassemia intermedia.
The electrocardiogram showed a finding of left atrial load, counter-clockwise rotation, and negative T waves in the precordial leads (Fig. 1A). Transthoracic echocardiography revealed a dilated left ventricle (left ventricular end-diastolic diameter 55 mm) and decreased left ventricular systolic function with diffuse hypokinesis, with an EF of 35% (Fig. 1B, C). Cardiac magnetic resonance imaging (CMR) was performed on day 10. Late gadolinium enhancement was not observed, and T2-weighted images showed a normal signal intensity (Fig. 2A, B). The T2-star was not included in the imaging protocol.
Figure 1Electrocardiogram, transthoracic echocardiogram, and coronary angiograms (A) Electrocardiogram. (B) Parasternal long axis view of the echocardiogram. (C) Apical four-chamber view of the echocardiogram. (D) Left coronary artery angiogram. (E) Right coronary artery angiogram.
Figure 2Cardiac magnetic resonance imaging (MRI) and the histological analysis of the heart (A, B) Cardiac MRI shows no specific findings. (C) Hematoxylin and eosin staining. (D) Masson’s trichrome staining. (E) Immunohistochemistry for CD3-positive lymphocytes. (F) Tenesin C staining. (G) Negative for Berlin blue staining. (H) Electron microscopic histology is compatible with dilated cardiomyopathy.
Cardiac catheterization was performed on day 11. Coronary angiography showed no significant stenosis (Fig. 1D, E). Endomyocardial biopsy of the right ventricular septum was performed. Hematoxylin and eosin staining showed mild-to-moderate hypertrophy of the myocytes (Fig. 2C). The Masson’s trichrome staining revealed a relatively mild interstitial and perivascular fibrosis (Fig. 2D). Immunohistochemistry revealed mild infiltrates of CD3-positive lymphocytes (Fig. 2E), and tenesin C was partially positive in the endocardium and interstitium (Fig. 2F). Berlin blue staining revealed no iron deposition (Fig. 2G). Electron microscopic histology showed degeneration of myofibrils, autophagosomes, lipofuscin deposits, and proliferation of mitochondria in the myocytes. An increase in collagen fibers in the interstitium was also observed (Fig. 2E). There was no evidence of secondary cardiomyopathy, and all histological findings were consistent with dilated cardiomyopathy.
In parallel with the etiological examination of heart failure, we intensified medical therapy for HFrEF; sacubitril/valsartan 200 mg/day, bisoprolol 5 mg/day, and spironolactone 25 mg were administered. The sodium-glucose cotransporter 2 inhibitor was discontinued because of a suspected urinary tract infection. Unfortunately, the day after catheterization, the patient developed pneumonia and required several days of antibiotic therapy. Thereafter, his symptoms improved steadily, and he was discharged on day 23 of hospitalization. At the time of the out-patient clinic visit, 6 months after the initial admission to our hospital, echocardiography showed that the left ventricular end-diastolic diameter was 45 mm, and EF improved to 54%.
Discussion
β-thalassemia is a genetic hemoglobin disorder that results in anemia due to impaired hemoglobin production caused by an abnormal globin gene. While heart failure is a common complication of thalassemia major, it is rarely reported in thalassemia intermedia. A previous study reported that among 110 patients with beta-thalassemia intermedia, 5.4% developed congestive heart failure, but none had reduced left ventricular contractility
Therefore, we explored the etiology of reduced cardiac function in this patient with β-thalassemia intermedia using multimodal imaging. In transfusion-independent thalassemia, increased iron absorption from the intestinal tract causes iron deposition
. However, there was no evidence of iron deposition in the myocardial tissue, and CMR did not show a reduced signal intensity on T2-weighted images. In addition, no imaging or laboratory findings were suggestive of hemochromatosis in the other organs.
In addition to iron overload, inflammatory factors have been implicated in the dilated phenotype of thalassemia cardiomyopathy
. In this case, although the myocardial histology was consistent with dilated cardiomyopathy, the presence of inflammatory cell infiltration did not exclude the possibility of chronic myocarditis or healing of acute myocarditis.
It has been suggested that patients with thalassemia have an inadequate immune response and are more susceptible to infection. Chung et al. reported that Klebsiella infections are frequently observed in transfusion-dependent thalassemia (7.5%) and are associated with a high mortality rate
. Our patient was transfusion-independent but may have been prone to pneumonia because of his funnel chest. Therefore, we speculate that chronic inflammation due to recurrent K. pneumoniae may have triggered inflammatory cardiomyopathy in the present case. The discussion presented thus far does not eliminate the possibility that the occurrence of thalassemia and DCM are simply coincidental.
In summary, we reported a case of HFrEF in a patient with genetically confirmed β-thalassemia intermedia who was successfully treated with cardioprotective drugs.
Acknowledgements
We are grateful to Professor Hirofumi Ochi for his support and guidance. We would also like to thank Editage (www.editage.com) for English language editing.
Funding Sources
No funding was received for this work.
Disclosures
The authors have no conflicts of interest to disclose.
References
Kremastinos D. T
et al.
β-thalassemia cardiomyopathy: History, present considerations, and future perspectives.
00053-7&id=gr1.jpg){kind=link}
00053-7&id=gr2.jpg){kind=link}