COVID-19 in a Patient with ß-Thalassemia Major and Severe Pulmonary Arterial Hypertension.

We here report the successful recovery from coronavirus disease-19 (COVID-19) pneumonia in a patient with ß-thalassemia major (ß-TM) and severe pulmonary arterial hypertension (PAH), focusing on the patient's comorbidities, therapeutic course and drug interaction.

Prevalence and risk factors for pulmonary arterial hypertension in a large group of ß-thalassemia patients using right heart catheterization: a Webthal study.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a concern in patients with ß-thalassemia major (TM) and intermedia (TI); however, studies evaluating its prevalence and risk factors using systematic confirmation on right heart catheterization are lacking. METHODS AND RESULTS: This was a multicenter cross-sectional study of 1309 Italian ß-thalassemia patients (mean age 36.4±9.3 years; 46% men; 74.6% TM, 25.4% TI). Patients with a tricuspid-valve regurgitant jet velocity ≥3.2 m/s (3.6%) on transthoracic echocardiography further underwent right heart catheterization to confirm the diagnosis of PAH (mean pulmonary arterial pressure ≥25 mm Hg and pulmonary capillary wedge pressure ≤15mm Hg). The confirmed PAH prevalence on right heart catheterization was 2.1% (95% confidence interval [CI], 1.4-3.0) and was higher in TI (4.8%; 95% CI, 3.0-7.7) than TM (1.1%; 95% CI, 0.6-2.0). The positive predictive value for the tricuspid-valve regurgitant jet velocity ≥3.2 m/s threshold for the diagnosis of pulmonary hypertension was 93.9%. Considerable functional limitation and decrease in the 6-minute walk distance were noted in patients with confirmed PAH. On multivariate logistic regression analysis, independent risk factors for confirmed PAH were age (odds ratio, 1.102 per 1-year increase; 95% CI, 1.06-1.15) and splenectomy (odds ratio, 9.31; 95% CI, 2.57-33.7). CONCLUSIONS: The prevalence of PAH in ß-thalassemia patients as confirmed on right heart catheterization was 2.1%, with an ≈5-fold higher prevalence in TI than TM. Advanced age and splenectomy are risk factors for PAH in this patient population. CLINICAL TRIAL REGISTRATION URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01496963.

Clinical management of cardiovascular complications in patients with thalassaemia major: a large observational multicenter study.

AIMS: To determine the clinical management of cardiovascular complications, and the extent of cardiac left ventricular (LV) involvement, in a large cohort of homogenously treated patients with thalassaemia major. METHODS AND RESULTS: Participants were ≥ 16 years of age and diagnosed with thalassaemia major requiring regular blood transfusions since the age of 2. Patient characteristics, clinical and echocardiography data for 524 patients were extracted from Webthal®, an Internet-shared database. Patients were considered to have evidence of cardiovascular disease if at least one cardiovascular drug was recorded in their file. The majority of patients (422 of 524; 80.5%) had not taken any cardiovascular drug. Among those who had angiotensin-converting enzyme-inhibitors were the most commonly used (81 patients) and these were used by significantly more males than females (P < 0.01). Patients in whom cardiovascular drugs were prescribed showed evidence of cardiac structural and/or functional abnormalities, inasmuch as fractional shortening and ejection fraction were significantly lower (31.3 vs. 35% and 54.4 vs. 60.6; both P < 0.001) and LV end-diastolic diameter index was significantly higher (32.9 vs. 31.8; P = 0.004). Interestingly, when compared with patients in whom cardiovascular drug therapy was not deemed necessary, transfusion period was longer in treated patients (26.2 vs. 24.5 years; P= 0.002). CONCLUSION: Approximately 19% of regularly transfused and chelated thalassaemia major patients need cardiovascular drug therapy. This subgroup is characterized by a dilated and mildly hypokinetic left ventricle when compared with the majority of thalassaemia major patients, who do not need any cardioactive drug. These data underscore the importance of careful evaluation of cardiac functional status in patients with thalassaemia major. Moreover, this database may serve as a clinically useful reference grid for echocardiograph values in this patient population.

Human immunodeficiency virus and beta-thalassemia major: A "competition of guilt" for pulmonary arterial hypertension. Report of a case and a review of the literature.

We report a case of a 43-year-old woman, affected by human immunodeficiency virus (HIV) and beta-thalassemia major (beta-TM), adequately treated with antiretroviral and transfusion-chelation therapy, that develops progressive right ventricular dysfunction due to severe pulmonary arterial hypertension (PAH), in absence of symptoms. The existence of both HIV and beta-TM cardiomiopathy has recently been reported, but how these two diseases have a "competition of guilt" for creating PAH is still to be understood. The main physiopathological principles regarding HIV and beta-TM associated PAH are reviewed. The possible interplay between these two different pathologies is discussed.

Risk factors for heart disease in transfusion-dependent thalassemia: serum ferritin revisited.

Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1 years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p < 0.001) were the only risk factors with significant association with heart disease. A serum ferritin threshold of ≥ 3000 ng/mL was the best predictor for the development of heart disease (86.4% sensitivity and 92.8% specificity, AUC: 0.912, 95% CI 0.852-0.971, p < 0.001). On multivariate analysis, only a serum ferritin level ≥ 3000 ng/mL remained significantly and independently associated with increased risk of heart disease (HR: 44.85, 95% CI 18.85-106.74), with a 5- and 10-year heart disease-free survival of 58 and 39%. The association between iron overload and heart disease in patients with TDT is confirmed, yet a new serum ferritin level of 3000 ng/mL to flag increased risk is suggested.

Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies.

BACKGROUND AND OBJECTIVES: During the last decade new approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequel of the hemoglobinopathies, thalassemia and sickle cell anemia, but the use of standard oral treatment options, such as calcium channel blockers, endothelin receptor antagonists, and long-term anticoagulation therapy, is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5) which promotes selective smooth muscle relaxation in lung vasculature and has been utilized successfully in the treatment of PH. The primary objective of this study was to evaluate the efficacy of sildenafil treatment in the control of PH in patients with hemoglobinopathies. DESIGN AND METHODS: In this study patients with hemoglobinopathies (thalassemia intermedia n=4; thalassemia major n=2; sickle thalassemia n=1) suffering from severe PH were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months. RESULTS: A significant decrease in pulmonary pressure and improvement in exercise capacity and functional class were observed in all patients. No significant adverse events were reported. INTERPRETATION AND CONCLUSIONS: These data, in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies that cannot be treated with alternative oral drugs and is well tolerated long-term at a daily dose of 100 mg, though studies including more patients may uncover toxicities and limitations of efficacy.

Therapeutic approaches to pulmonary hypertension in hemoglobinopathies: Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathy.

New approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequela of the hemoglobinopathies, but the use of standard oral treatment options is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5), which promotes selective smooth muscle relaxation in lung vasculature and has been used successfully in the treatment of PH. Hemoglobinopathic patients suffering from severe PH who were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months showed a significant decrease in pulmonary pressure and improvement in exercise capacity and functional class. No significant adverse events were reported. These data, described in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies and is well tolerated long-term at a daily dose of 100 mg.

Iron overload-related heart failure in a patient with transfusion-dependent myelodysplastic syndrome reversed by intensive combined chelation therapy.

Patients with transfusion-dependent myelodysplastic syndromes (MDS) have an increased risk of cardiac events, due to both chronic anemia and iron overload. Here, we report the recovery of cardiac function after an intensive iron chelation therapy in a MDS patient who had developed heart failure due to iron overload.

Guideline recommendations for heart complications in thalassemia major.

Thalassemia major is an inherited hemoglobin disorder resulting in a chronic hemolytic anemia. Transfusion therapy together with elevated gastrointestinal absorption of iron determines iron overload, which causes most of the mortality and morbidity associated with the disease. Heart complications represent the leading cause of mortality in this disease, although, because of an improvement in chelation treatment, an important and progressive increase of life expectancy mainly as a result of a reduction in mortality due to cardiac dysfunction has been demonstrated in recent years. Clinical pictures of heart damage range from the involvement of the ventricles to pulmonary hypertension or symptomatic ventricular or supra-ventricular arrhythmias. For this reason, the possibility of having specific recommendations is noteworthy. These recommendations outline the definition, the follow-up and the treatment of the main heart complications in this group of patients. The identification of topics and the nomination of the committee were made on behalf of the Society for the Study of Thalassemia and Hemoglobinopathies (SoSTE). The document obtained the auspices of ANMCO, SIC, SIRM and the Cardiovascular Magnetic Resonance Working Groups of the ANMCO, SIC and SIRM. All recommendations provided in this document have been performed according to the American Cardiology College (ACC) and American Heart Association (AHA) guidelines. Moreover, the recommendations were reviewed by two external referees before the definitive approval.

Standardized T2* map of a normal human heart to correct T2* segmental artefacts; myocardial iron overload and fibrosis in thalassemia intermedia versus thalassemia major patients and electrocardiogram changes in thalassemia major patients.

Studies of the standardized, 3D, 16-segments map of the circumferential distribution of T2* values, of cardiovascular magnetic resonance (CMR) in thalassemia major (TM) and thalassemia intermedia (TI) patients and of electrocardiogram (ECG) changes associated with TM, have been carried out. Similarly, the segment-dependent correction map of the T2* values and the artifactual variations in normal subjects and the T2* correction map to correct segmental measurements in patients with different levels of myocardial iron burden have been evaluated. Cardiovascular magnetic resonance can be a suitable guide to cardiac management in TI, as well as in TM; TI patients show lower myocardial iron burden and more pronounced high cardiac output findings than TM patients. Moreover, it is proposed that, due to its good positive predictive value (PPV) and low cost, ECG can be a suitable guide to orient towards CMR examination in TM cases.

Lack of prognostic value of normalized integrated backscatter analysis of myocardium in patients with thalassemia major: a long-term follow-up study.

BACKGROUND: Patients with beta-thalassemia major often present with severe anemia and must undergo continuous transfusion therapy, consequently developing iron overload leading to hemochromatosis. Because of these the iron deposits and/or secondary structural changes, patients develop an increase in myocardial integrated backscatter (IB). AIM: To investigate the prognostic value of analyzing acoustic quantitative properties of the myocardium in patients with beta-thalassemia major. PATIENTS AND METHODS: Between 1989 and 1990, 38 patients (mean age: 18 years, range: 7-26, 21 males) with beta-thalassemia major and without clinical signs of cardiac failure were enrolled prospectively. All patients were on chelation therapy (desferroxiamine). To obtain quantitative operator-independent measurement of the IB signal of the left ventricular septum and posterior wall, the ultrasonic radiofrequency signal integrated values were normalized to the pericardial interface and expressed in percentage (IB%). RESULTS: Follow-up was 122 +/- 36 months, during which 15 events (7 cardiac deaths and 8 heart failures) occurred. The event-free survival was comparable in patients with normal and abnormal IB%. Septal IB% was 33 +/- 14 in the 15 patients with events, and 33 +/- 12 in the 25 patients without events (P = ns). The %IB had no prognostic value in this population. A prognostic value was found in multivariate analysis for patient refusal/noncompliance of chelation therapy (P = 0.02, OR: 4.37, 95% CI: 1.72-16.9) and also body mass index (P = 0.04, OR: 1.2, 95% CI: 1.0-1.4). CONCLUSION: Analysis of end-diastolic IB% of myocardium in patients with beta-thalassemia and iron overload was not predictive of adverse cardiac events during long-term follow-up in this study.