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Abstract We numerically investigate the flow dynamics in a model of a dilated thoracic aorta, and compare the flow features with the case of a prosthetic replacement in its ascending part. The flow is characterized by an inlet jet which impacts the aortic walls and sweeps toward the aortic arch. Secondary flows generated by the transvalvular jet evolve downstream into a helical flow. The small curvature radius at the end of the aortic arch induces flow separation and vortex shedding in the initial part of the descending aorta, during the systole. The implantation of a prosthesis determines several modifications in the global and local flow patterns. An increase of the pulse wave velocity in the aorta leads to larger pressures inside the vessel, due to the geometrical and rigidity modifications. The sweeping jet is more aligned along the axial direction and propagates faster along the aortic arch. Consequently, a stronger separation of the flow downstream of the aortic arch is observed. By also exploiting manifold analysis, we identify regions characterized by near-wall disordered flows which may present intense accumulation and drop of concentration of biochemicals. These regions are localized downstream of the prosthetic replacement, in the aortic arch, and may be more prone to a new emergence of vessel dilation. Graphical Abstract

The implantation of aortic valve prostheses is often associated with the dilation of the ascending aorta. It is well known that the modification of the fluid dynamics induced by both the prosthetic valve and aortic dilation may, in turn, promote further vessel remodelling. Besides, when the prosthesis is mechanical, a major concern is the blood cell damage and platelet activation which requires a lifelong anticoagulant therapy, which in turn is an additional significant factor of comorbidity. We analysed in vitro the combined effect of the presence of a bileaflet mechanical aortic valve and the dilation of the aortic root in patient specific laboratory models. Three model aortas with increasing degree of dilation, hosted in a mock loop reproducing the heart flow pulsatility, were investigated. The measurement of the time-resolved velocity field allowed the analysis of the general structure of the flow and shear strain-rate distribution. Additionally, the Blood Damage Indexes (BDIs) for both haemolysis and platelet activation were computed along synthetic particle trajectories. Results suggest that a feedback process can be triggered since the aortic dilation tends to decrease the shear stresses at the walls and favour blood stasis: two factors that are known to promote vessel remodelling. Secondly, the analysis of BDIs shows that aortic dilation significantly increases the damage index for haemolysis, whereas a similar effect is not shown when focusing on platelet activation. Graphical abstract

Pseudoaneurysm of mitral-aortic intervalvular fibrosa (P-MAIVF) is a rare acquired malformation of the mitral-aortic intervalvular area. It appears as a pulsatile cavity in the mitral-aortic junction communicating with the left ventricular outflow tract. P-MAIVF has been reported as a complication of aortic and mitral valve surgery, infective endocarditis, and thoracic trauma. It is associated with life-threatening complications. The recommended treatment is surgery, however, conservative therapy is an alternative approach for high-risk patients or when surgical treatment is refused. We describe a successfully exclusion of a P-MAIVF by transapical transcatheter aortic valve implantation in a patient with concomitant severe aortic stenosis.

Background A large amount of information on genotypic and phenotypic expressions has become available since the first clinical observations of cardiac manifestations secondary to lamin A/C gene mutations. Aims We aim to describe one of the longest longitudinal follow-ups reported so far (>22 years), concerning a whole family affected by a missense lamin A/C mutation (Arg60Gly), which manifested as an overlapping phenotype with cardiac and extracardiac involvement over time. Methods Starting from the family history, two generations of that family were prospectively observed, from 1997 until 2020. At baseline, four individuals with dilated cardiomyopathy and cardiac conduction defects showed the same mutation. This was also found in three young individuals, phenotypically unaffected at baseline assessment. Results The prolonged clinical and laboratory evaluation has shown the evolution of an overlapping phenotype in which cardiac alterations have been associated with lipodystrophy and neurological manifestations. In the first observed generation, the prognosis was negatively affected by the progression of heart failure and lipodystrophy, whereas in the second generation the first phenotypic manifestations became evident after the 2nd decade. Cardiac magnetic resonance played a relevant role in the early detection of cardiac alteration. Right bundle branch block was another sign of initial phenotypical expression. Conclusion In lamin A/C gene mutation carriers, a strict, multidisciplinary follow-up allows the opportunity to monitor the progress of the disease and to intervene precociously with the best available treatments.

Background and aim Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in chronic heart failure symptomatic patients with broad QRS who are already undergoing optimal medical treatment. However, approximately one-third of implanted patients do not show any benefit from this treatment. Right ventricle (RV) dysfunction leads to a worse outcome in patients with heart failure, but its role in predicting the response to CRT has shown conflicting results. The purpose of our study was to investigate how the RV function, assessed by cardiac magnetic resonance (CMR), could influence the outcome of heart failure patients treated with CRT. Methods and results We retrospectively enrolled 72 heart failure patients, 38 affected by dilated cardiomyopathy (DCM) and 34 by ischemic dysfunction, with left bundle branch block, QRS greater than 120 ms and standard indications to CRT. We defined the response to CRT as an improvement of at least 10% of the left ventricular ejection fraction (LVEF) or at least one of the NYHA functional classes. We stratified the population into two groups based on the right ventricle ejection fraction (RVEF) at CMR: group 1 RVEF at least 55% (n = 32), group 2 RVEF less than 55% (n = 40). After a mean follow-up of 38 ± 12 months, 44 patients (61%) were considered responders whereas 28 (39%) did not show any benefit. Patients in group 1 had a higher rate of response to CRT (75 vs. 50%, P = 0.03). At the univariate analysis RVEF [54 vs. 43%; confidence interval (CI) = 0.907-0.980; hazard ratio = 0.943; P = 0.003], RV end-systolic volume (56 vs. 84 ml; CI = 1.005-1.034; hazard ratio = 1.019; P = 0.008) and tricuspid annular plane systolic excursion (TAPSE) (16.4 vs. 14 mm; CI 0.745-0.976; heart rate = 0.853; P = 0.021) were the parameters most strongly associated with the response to CRT. Male sex, atrial fibrillation, and older age also negatively influenced the outcome. At a multivariate model, RVEF and older age remained significant. Conclusion In our experience, patients with RV dysfunction less likely benefited from CRT. RV assessment, studied with CMR, appears to be a good predictor of the response to biventricular stimulation.

Superficial siderosis (SS) of the central nervous system is a rare and heterogeneous condition due to deposition of hemosiderin on the surface of the brain and spinal cord. The usually progressive clinical course is characterized by a combination of hearing loss, cerebellar ataxia, and myelopathy. There is no known treatment for SS, but the iron chelator deferiprone (DFP) has been proposed as a potentially useful treatment.We present a long-term (average 3.7 years) evaluation of four cases of SS treated with DFP (15 mg/kg po bid).Treatment with DFP proved safe and well tolerated. Two out of the four subjects were unchanged while the other two presented a clinical improvement with reduction of postural instability and cerebellar signs. Blinded evaluation of magnetic resonance imaging (performed every 6 months during follow-up) showed a reduction of the abnormal iron deposition for all patients.This long-term observational study suggests that DFP may be effective in the management of the neurological manifestations associated with iron accumulation in SS. CLINICALTRIALS.NTC00907283.

Background— The clinical course of patients with hypertrophic cardiomyopathy and advanced heart failure (HF) subtended by progressive left ventricular dysfunction has received limited attention. Our aim was to assess the outcome of HF and impact of treatment options including the implantable cardioverter-defibrillator and heart transplantation (HT) in patients with hypertrophic cardiomyopathy evaluated at 2 Italian referral centers >3 decades. Methods and Results— All-cause mortality and a combined end point including death, HT, or appropriate implantable cardioverter-defibrillator shock were assessed in 71 consecutive patients with HF not related to outflow obstruction (7% of the entire hypertrophic cardiomyopathy cohort) followed up for 6.1±6.9 years after development of New York Heart Association class III to IV symptoms. At enrollment, left ventricular ejection fraction was 50% in 16; all had restrictive left ventricular filling. During follow-up, 35 patients died (49%%; 5-year rate, 49%) and 53 met the combined end point (75%; 5-year rate, 62%). Most events occurred in the 3 years after HF onset (17% per year compared with only 3% per year subsequently). Appropriate implantable cardioverter-defibrillator shocks occurred in 11 of 34 implanted patients. Of 37 patients evaluated for HT, 14 were transplanted, 10 listed, and 13 excluded; 2 early post-HT deaths occurred in patients with elevated pulmonary vascular resistance. Eleven of the 14 HT patients were alive at 10±8 years. Conclusions— In hypertrophic cardiomyopathy, advanced HF not associated with outflow obstruction portends a severely unfavorable prognosis, particularly in the first 3 years after onset of symptoms, despite frequently preserved systolic function in about one quarter of the patients. Outcome of HT is favorable but requires early consideration, as the window of opportunity may be short.

Pelvic floor failure is a common disorder that can seriously jeopardize a woman's quality of life by causing urinary and fecal incontinence, difficult defecation, and pelvic pain. Multiple congenital and acquired risk factors are associated with pelvic floor failure, including altered collagen metabolism, female sex, vaginal delivery, menopause, and advanced age. A complex variety of fascial and muscular lesions that range from stretching, insertion detachment, denervation atrophy, and combinations of pelvic floor relaxation to pelvic organ prolapse may manifest in a single patient. Thorough preoperative assessment of pelvic floor failure is necessary to reduce the rate of relapse, which is reported to be as high as 30%. Magnetic resonance (MR) imaging of the pelvic floor is a two-step process that includes analysis of anatomic damage on axial fast spin-echo (FSE) T2-weighted images and functional evaluation using sagittal dynamic single-shot T2-weighted sequences during straining and defecation. This article presents high-resolution FSE T2-weighted MR images that permit detailed assessment of anatomic lesions and briefly describes pelvic floor pathophysiology, associated clinical symptoms, and patterns of dysfunction seen with dynamic MR imaging sequences. MR imaging is a powerful tool that enables radiologists to comprehensively evaluate pelvic anatomic and functional abnormalities, thus helping surgeons provide appropriate treatment and avoid repeat operations.

We reviewed cardiac T2* assessments from 77 thalassemia major patients between the ages of 2.5 and 18 years to study optimal timing of cardiac iron screening by magnetic resonance imaging. No patient under 9.5 years of age showed detectable cardiac iron in contrast to 36% of patients between the ages of 15-18 years old, corresponding to an odds-ratio of 1.28 (28%) per year. All patients with cardiac iron had received at least 35 grams of transfusional iron. Liver iron and ferritin failed to predict cardiac iron loading. Initiation of cardiac magnetic resonance imaging assessment should be determined according to age and transfusional burden rather than indices of iron overload. When appropriate chelation therapy has been administered since birth, cardiac magnetic resonance imaging can be postponed until 8 years of age when anesthesia is not required. Patients with suboptimal chelation, increased transfusional requirements, or who have initiated transfusions later in life should be tested sooner.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron.\ud \ud METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy.\ud \ud RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p

Despite usual iron chelating therapy based on desferrioxamine, patients affected by β-thalassemia major (β-TM) often develop progressive heart failure caused by myocardial iron overload, which is the leading cause of mortality within the third decade of life. Heart transplantation is a limited therapeutic option, as very often these patients have multi-organ iron deposits and infective complications (particularly hepatitis C), secondary to frequent blood transfusions. We report the case of a 26-year-old male affected by β-TM with end-stage heart failure, who showed a dramatic improvement in symptoms and myocardial function when a new oral iron chelating agent, deferiprone, was added to standard therapy with desferrioxamine.

Objective To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA. Methods 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence. Results After 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP. Conclusion The data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease. (Clinicaltrials.gov identifier: NTC00907283).

Summary This study aimed to verify the impact of heart magnetic resonance imaging on chelation choices and patient compliance in a single-institution cohort as well as its predictive value for heart failure and arrhythmias. Abnormal cardiac T2* values determined changes in treatment in most subjects. Heart T2* was confirmed to be highly predictive over 1 year for heart failure and arrhythmias. The choice of chelation regimens known to remove heart iron efficiently was not sufficient by itself to influence the risk. Compliance with treatment had a more remarkable role.

Background— Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited. Methods and Results— Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean±SD global myocardial iron causing severe heart failure in 10 patients was 5.98±2.42 mg/g dry weight (range, 3.19 to 9.50 mg/g), but in 1 outlier case of heart failure was 25.9 mg/g dry weight. Myocardial ln[R2*] was strongly linearly correlated with ln[Fe] ( R 2 =0.910, P −1.22 for the clinical calibration equation with [Fe] in milligrams per gram dry weight and T2* in milliseconds. Midventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron. Conclusions— These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration. The iron values are of considerable interest in terms of the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in vivo by cardiovascular magnetic resonance of the midseptum.

Deferiprone was shown to reverse iron deposition in Friedreich’s ataxia. This multi-center, unblinded, single-arm pilot study evaluated safety and efficacy of deferiprone for reducing cerebral iron accumulation in neurodegeneration with brain iron accumulation. Four patients with genetically-confirmed pantothenate kinase-associated neurodegeneration, and 2 with parkinsonism and focal dystonia, but inconclusive genetic tests, received 15 mg/kg deferiprone bid. Magnetic resonance imaging and neurological examinations were conducted at baseline, six and 12 months. Chelation treatment caused no apparent hematologic or neurological side effects. Magnetic resonance imaging revealed decreased iron accumulation in the globus pallidus of 2 patients (one with pantothenate kinase-associated neurodegeneration). Clinical rating scales and blinded video rating evaluations documented mild-to-moderate motor improvement in 3 patients (2 with pantothenate kinase-associated neurodegeneration). These results underline the safety and tolerability of deferiprone, and suggest that chelating treatment might be effective in improving neurological manifestations associated with iron accumulation.

Purpose: To examine the reproducibility of the single breathhold T2* technique fromdifferent scanners, after installation of standardmethodology in five international centers. Materials and Methods: Up to 10 patients from each center were scanned twice locally for local interstudy reproducibility of heart and liver T2*, and then flown to a central MR facility to be rescanned on a reference scanner for intercenter reproducibility. Interobserver reproducibility for all scans was also assessed. Results: Of the 49 patients scanned, the intercenter reproducibility for T2* was 5.9% for the heart and 5.8% for the liver. Local interstudy reproducibility for T2* was 7.4% for the heart and 4.6% for the liver. Interobserver reproducibility for T2* was 5.4% for the heart and 4.4% for the liver. Conclusion: These data indicate that T2* MR may be developed into a widespread test for tissue siderosis providing that well-defined and approved imaging and analysis techniques are used. © 2010 Wiley-Liss, Inc., link_to_subscribed_fulltext

Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value

Pathologies that involve the ascending aorta are described in case reports of patients after complete repair of tetralogy of Fallot. Here, we present a case report. Preoperative tests showed an aortic ratio of1.5. The patient was operated on replacement of the ascending aorta according to the Bentall technique. At present, the guidelines for replacement of the ascending aorta recommend an aortic ratio of1.5 and in case of Marfan syndrome of1.3. In these patient subsets, cystic medial necrosis and an increased risk of aortic dissection have been described. Therefore, as for Marfan syndrome, why an aortic ratio of1.3 should not be considered a proper surgical indication also for these patients?

Despite usual iron chelating therapy based on desferrioxamine, patients affected by beta-thalassemia major (beta-TM) often develop progressive heart failure caused by myocardial iron overload, which is the leading cause of mortality within the third decade of life. Heart transplantation is a limited therapeutic option, as very often these patients have multi-organ iron deposits and infective complications (particularly hepatitis C), secondary to frequent blood transfusions. We report the case of a 26-year-old male affected by beta-TM with end-stage heart failure, who showed a dramatic improvement in symptoms and myocardial function when a new oral iron chelating agent, deferiprone, was added to standard therapy with desferrioxamine.

Background The results of our previous one-year-treatment study (Clinicaltrials.gov Identifier: NCT00907283) suggested that deferiprone might be effective in reverse iron deposition and improve neurological manifestations in patients with NBIA. We report the clinical and neuroradiological findings of 3 of 9 pts involved in that study (all with PKAN) that completed 3 year’s treatment. Patients and methods Three patients with genetically confirmed PKAN (2 F; 1 M; age ranging 27–32; disease duration 4–14) received deferiprone solution at 15 mg/kg po bid. All patients underwent brain MRI at baseline and at 12 and 36 months’ follow up. The quantitative assessment of brain iron was performed with T2∗ relaxometry, using a gradient multi-echo T2∗ sequence. UPDRS/III, ICARS, and UDRS were administered at baseline and during follow up. Results The 36-month MRI evaluations showed reduced hypointensity in the globus pallidus (GP) of all the patients; the quantitative assessment confirmed a significant increment in the T2∗ value, and hence a reduction of the iron content in the GP of these patients. Clinical rating scales indicated an improvement in motor symptoms in 2 patients. No evident changes were observed in the other patient, who was the most severely affected. Conclusions The data from our 3-year follow-up study confirm the safety of deferiprone as a chelator agent for iron accumulation. The improvement observed in 2 patients and the clinical stabilization of the third suggests that this drug may be useful in the treatment of those neurological manifestations linked with iron accumulation and neurodegeneration.

A 35-year-old asymptomatic woman was referred to our echocardiography laboratory for the evaluation of a grade 2/6 systolic murmur. Transthoracic echocardiography showed the presence of a muscle band presenting as a finger-like projection into the left ventricle, which delimited an accessory chamber ( Panels A …

Patients with thalassemia major develop life threatening cardiac complications in their teens and twenties from iron overload. Cardiac MRI allows us to diagnosis preclinical cardiac iron deposition, but it is not known at what age T2* screening should be initiated. Historical data and pilot MRI studies suggest that patients must reach a critical transfusional exposure prior to cardiac iron uptake. This study was a two-institution characterization of the prevalence of cardiac iron overload in 77 pediatric patients. Methods: Study was performed at the Ospedale Regionale Microcitemie in Cagliari and the Childrens Hospital Los Angeles (CHLA). Retrospective review of medical records was authorized by the IRB for pediatric patients undergoing cardiac MRI prior to July of 2007. Subjects at both institutions had assessment of cardiac T2* and cardiac function using validated techniques on a 1.5 T General Electric CVi scanner; patients at CHLA also underwent MRI-based liver iron measurements. Complete transfusional iron burden was measured in the Italian patients. Serial MRI data was recorded in 30 patients, but associations between cardiac T2* and age were determined using linear and logistic regression using only results from the first patient MRI scan. Results: Patient ages ranged from 8.0 to 18 years of age at Cagliari (n=36) and 2.5 to 17.9 years of age at CHLA (n=41), reflecting the use of MRI to monitor liver iron in patients < 8 years of age. Patients were moderately iron loaded with hepatic iron concentrations of 12.7 ± 9.8 (CHLA) and ferritin values of 2329 ± 1162 (Cagliari). Median cardiac T2* was 30.2 and ranged from 3.4 to 72.8. Cardiac T2* and its reciprocal were uncorrelated with liver iron (CHLA) and ferritin levels (Cagliari). Figure 1 demonstrates the decrease in cardiac T2* with increasing chronologic age. Serial data are connected by lines. Although linear regression was weakly positive (r2 = 0.06, p = 0.03), the relationship was fundamentally nonlinear. No patient below the age of 9.5 years of age demonstrated an abnormal cardiac T2* (< 20 ms) while 36% of patients between the ages of 15–18 years had detectable cardiac iron. Figure 2 demonstrates the logistic regression curve modeling the prevalence of detectable cardiac iron as a function of age (r2= 0.13, p< 0.002). Chronologic age was highly correlated (r2 = 0.88) with both transfusional iron burden and with duration of transfusion therapy, making it impossible to separate the relative importance of these three variables. Conclusion: Thalassemia major patients did not accumulate cardiac iron until early in their second decade of life. Consequently, cardiac iron monitoring can be safely deferred until children are able undergo MRI examination without sedation. Figure Figure Figure Figure

Cardiac T2* Magnetic Resonance Imaging (MRI) has been recently used to evaluate myocardial iron deposition in patients with transfusion dependent beta-thalassemia major. No comparable studies have been published for patients with myelodysplastic syndromes receiving chronic red blood cell transfusion. Therefore we measured cardiac-MRI T2* in 16 patients (10 male, 6 female) with myelodysplastic syndromes (aged 54 – 82 years, median age 67). All of them were transfusion dependent having received a median number of 60 (range 16–225) packed red blood cell transfusion equivalent to 3.2 – 45 (median 12) grams of iron. Nine have been irregularly and sporadically chelated by deferoxamine, seven were unchelated. Serum ferritin levels ranged from 1163 to 6241 mg/dl (median value 2086). None of the patients presented signs or symptoms of cardiac dysfunction at the time of the study. Cardiac-MRI T2*values obtained ranged from 5.6 to 80 (median value 46.5) milliseconds (ms). Correlation between serum ferritin and cardiac T2* value was weak ( r= 0.43, r2 =0.18). According to D. Pennel we considered as significant of myocardial iron deposition a relaxation time ≤ 20ms. Cardiac T2* was < 20ms in 3 patients who had never used iron chelators (5.6, 12.4 and 8.5 ms, respectively). They had received 39, 101 and 200 units of red blood cell transfusion, corresponding to 7.8, 20 and 40 grams of iron, respectively. Of relevance 2 of them died within few months after the end of the study and one showed early signs of left ventricular dysfunction. None of the patients with a cardiac T2* value >20 ms showed instrumental nor clinical signs of cardiac deterioration in six months follow up. No patient who had received less than 39 transfusions presented cardiac T2* value ≤20 ms. Evaluation of myocardial iron deposition by T2* cardiac MRI could be recommendable in myelodyplasia patients who had received more than 30 packed red blood cells transfusisions.

Iron loading in patients with thalassemia intermedia occurs slowly and is mainly due to increased gastrointestinal iron absorption secondary to chronic anemia, while in patients with thalassemia major iron overload is faster and secondary to the chronic transfusion therapy. Moreover, iron accumulation in thalassemia intermedia is prevalent in parenchymal cells, while in thalassemia major iron derived from red cell breakdown firstly accumulates in the reticulo-endothelial cells and subsequently in the parenchymal cells. Although heart disease represents the main determinant of survival in beta thalassemias, the cardiac complications are different in the two clinical forms, that are thalassemia major and thalassemia intermedia. In this study we evaluated liver and iron overload in patients with thalassemia intermedia. We have studied 8 patients with thalassemia intermedia with a mean age of 36 ± 12 years. All these patients were homozygotes for the beta zero 39 non-sense mutation (C→T) and were never transfused or had received only sporadic transfusions (less than 10 blood units throughout their life). Myocardial iron (heart T2*, Anderson et al 2001), echocardiographic left ventricular ejection fraction, serum ferritin (mean of the last 5 years) and hemoglobin (mean of the last 2 years) have been evaluated in each patient. Hepatic iron content was determined in 5 patients with atomic absorption after liver biopsy. Six patients were on chelation therapy with subcutaneous desferrioxamine (mean 2 ± 1 grams/week). Mean ferritin was 637 ± 497 ng/ml and mean hemoglobin 8.0 ± 1.0 g/dl. Heart T2* was normal in all patients (mean 46 ± 11 msec, range 36 – 62 msec). The mean left ventricle ejection fraction was 61 ± 6 % (range 51 – 70 %). Echocardiogram showed in all the patients a mild enlargement of both ventricles. Three patients had pulmonary hypertension and two had an extrasystolic arrhythmia. To our knowledge this is the first study reporting the results of heart T2* in thalassemia intermedia. As a consequence of the mechanism and rate of accumulation patients with thalassemia intermedia do not have heart iron overload, while liver iron concentration is quite relevant. Cardiac complications in thalassemia intermedia are mainly due to the hyperdynamic circulation associated with chronic anemia and to pulmonary hypertension.

Background Approximately 60,000 people are born with thalassaemia major every year. The average life expectancy of thalassaemia major patients is 35 years due to iron overload Cardiomyopathy. The cardiomyopathy is reversible when treated early, but once heart failure is established it is often rapidly progressive, and unresponsive to treatment. The single breath hold (SBH) T2* technique has been validated as the most robust and reproducible non-invasive measurement of myocardial and iron load. Our aim in this study was to validate the transferability and reproducibility of this technique in different scanners worldwide. Methods We aim to compare the reproducibility in six different sites worldwide as part of an NIH funded grant (R01-DK66084-01). So far, two of these sites have been validated: Singapore (Siemens Sonata, 1.5T scanner) and Cagliari, Italy (GE Signa, 1.5 T scanner). At both validation sites, 10 patients were scanned for heart and liver T2*, and scans were repeated for interstudy reproducibility. All patients then flew to London to be rescanned on our reference Siemens Sonata scanner. Results Of the 20 patients scanned, 70% had myocardial iron loading (T2* Liver iron loading was present in 65% of patients and in 30% this was severe. The coefficient of variation (COV) for the heart T2* measurements between the local sites and London was 5.9% and 4.9% yielding an average coefficient of variation across both sites of 5.4% (figure 1). The coefficient of variation (COV) for the liver T2* measurements between the local sites and London was 11.3% and 3.9% yielding an average coefficient of variation across both sites of 7.6% (figure 2). There was no significant correlation between liver and myocardial loading. Conclusion These are the first data demonstrating the transferability of the SBH T2* technique and the clinical validation from the 2 collaborating centers were excellent for both heart and liver measurements. Further MR sites confirmed for validation include Children’s Hospital of Philadelphia (USA); Ramathibodi Hospital, Bangkok (Thailand); and Chinese University Hong Kong. Figure 1 Figure 1. Figure 2 Figure 2.

Introduction: Beta thalassaemia major (TM) is a hereditary anaemia affecting 60 000 births worldwide each year. Survival is dependent upon lifelong blood transfusions resulting in iron overload. Cardiac siderosis can result in a cardiomyopathy which is the leading cause of death in TM. The validated cardiac magnetic resonance (CMR) T2* technique allows non-invasive and reproducible quantification of myocardial iron. Assessment of myocardial iron loading is essential in determining appropriate chelation therapy. This technique has the potential to become the new gold standard in the assessment of cardiac siderosis but is currently available at only a few sites worldwide. For maximal healthcare benefit its inter-scanner reproducibility must be demonstrated before being widely disseminated. Objective: To demonstrate that CMR T2* quantification of myocardial iron can be reproducibly transferred to MR scanners of different manufacturers in different centres. This project was sponsored by the Thalassemia International Federation. Methods: The previously described multi breath-hold gradient echo T2* technique was installed on MR scanners (all 1.5Tesla) at 6 different centres. Scanner details were as follows: Site 1, Phillips Intera (Turin, Italy), Site 2, Siemens Sonata (Philadelphia, USA), Site 3 GE Signa (Limassol, Cyprus) Site 4, Phillips Intera (Nicosia, Cyprus), Site 5, GE Signa (Cagliari, Sardinia) and Philips Intera (Genova, Italy). 34 patients (mean age 30+/− 5.7years) were scanned in total. All patients were subsequently re-scanned at the standardization centre in London, UK (Siemens Sonata, 1.5T) within 31 days of their original scan. Results: The T2* sequence was successfully installed on all 6 scanners. Myocardial T2* values ranged from 3.6ms to 51ms (14.2 +/− 11ms). The overall inter-scanner reproducibility (SD/mean) was 5.3% (figure 1). The mean difference between T2* values at the standardization centre and visited sites was 0.32ms. Conclusion: We have demonstrated that the multi breath-hold T2* technique for the quantification of myocardial iron can be reproducibly transferred to 1.5T MR scanners at different sites and of different manufacturers. There is therefore real potential to roll out this technique worldwide to facilitate maximal healthcare impact in the management of patients with iron overload conditions such as thalassaemia. Figure Figure