Myocardial Magnetic Resonance Imaging Research Articles

Germline HAVCR2/TIM-3 Checkpoint Inhibitor Receptor Deficiency in Recurrent Autoinflammatory Myocarditis

Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. To provide understanding on inflammatory myocarditis, we describe clinical, genetic, and immunological properties of a young male patient who suffered from recurrent myocarditis episodes since the age of four years. Electrocardiography, troponin I/T, echocardiography, myocardial magnetic resonance imaging and histological findings were consistent with recurrent myocarditis episodes. Homozygous c.245 A > G p.Tyr82Cys pathogenic variant in Hepatitis A Virus Cellular Receptor 2 (HAVCR2) gene encoding T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) receptor was found. Peripheral blood mononuclear cells were collected when the patient was asymptomatic; CD4+ and CD8+ T lymphoblasts, CD56+ natural killer cells and CD14+ monocytes were negative for surface TIM-3 expression. In vitro, TLR4 mediated interleukin-1β (IL-1β) response was high after LPS/ATP stimulation. Clinical symptoms responded to IL-1 receptor antagonist anakinra. TIM-3 p.Tyr82Cys CD4+ and CD8+ T cell proliferation in vitro was unrestrained. Findings on IL-2, interferon gamma, regulatory T cells, signal transducer and activator of transcription (STAT) 1, 3 and 4 phosphorylation, and PD-1 and LAG-3 checkpoint inhibitor receptor analyses were comparable to controls. We conclude that TIM-3 deficiency due to homozygous HAVCR2 c.245 A > G p.Tyr82Cys pathogenic variant in the patient described here is associated with autoinflammatory symptoms limited to early onset recurrent febrile myocarditis. Excessive IL-1β production and defective regulation of T cell proliferation may contribute to this clinical condition responsive to anakinra treatment.

Single-source dual energy CT to assess myocardial extracellular volume fraction in aortic stenosis before transcatheter aortic valve implantation (TAVI)

PurposeTo assess myocardial extracellular volume fraction (ECV) measurement provided by a single-source dual-energy computed tomography (SSDE-CT) acquisition added at the end of a routine CT examination before transcatether aortic valve implantation (TAVI) compared to cardiac magnetic resonance imaging (MRI). Materials and methodsTwenty-one patients (10 men, 11 women; mean age, 86±4.9 years [SD]; age range: 71–92 years) with severe aortic stenosis underwent standard pre-TAVI CT with additional cardiac SSDE-CT acquisition 7minutes after intravenous administration of iodinated contrast material and myocardial MRI including pre- and post-contrast T1-maps. Myocardial ECV and standard deviation (σECV) were calculated in the 16-segments model. ECV provided by SSDE-CT was compared to ECV provided by MRI, which served as the reference. Analyses were performed on a per-segment basis and on a per-patient involving the mean value of the 16-segments. ResultsECV was slightly overestimated by SSDE-CT (29.9±4.6 [SD] %; range: 20.9%–48.3%) compared to MRI (29.1±3.9 [SD] %; range: 22.0%–50.7%) (P<0.0001) with a bias and limits of agreement of +2.3% (95%CI: −16.1%–+20.6%) and +2.5% (95%CI: −2.1%–+7.1%) for per-segment and per-patient-analyses, respectively. Good (r=0.81 for per-segment-analysis) to excellent (r=0.97 for per-patient-analysis) linear relationships (both P<0.0001) were obtained. The σECV was significantly higher at SSDE-CT (P<0.0001). Additional radiation dose from CT was 1.89±0.38 (SD) mSv (range: 1.48–2.47 mSv). ConclusionA single additional SSDE-CT acquisition added at the end of a standard pre-TAVI CT protocol can provide ECV measurement with good to excellent linear relationship with MRI.

Т1 mapping in the evaluation of the risk factors for diffuse myocardial fibrosis in essential arterial hypertension

Background : The assessment of diffuse myocardial fibrosis is necessary to plan the management of patients with various cardiovascular disorders, including hypertensive heart disease. The development of imaging techniques has enabled a non-invasive detection of left ventricular myocardial fibrosis by magnetic resonance imaging (MRI) with T1 mapping. Aim: By cardiac MRI, to identify risk factors for diffuse left ventricular myocardial fibrosis in patients with hypertensive heart disease. Materials and methods : This was a cross-sectional observational study in 50 outpatients with hypertensive heart disease, aged 46 to 82 years (median, 68 [64; 72] years) and bodyweight of 52 to 120 kg (median, 91 [80; 98] kg). Standard cardiac MRI with delayed contrast enhancement was performed with Optima MR450w GEM 1.5T (General Electric, USA). For assessment of diffuse myocardial fibrosis MRI mapping by 2D MOLLI (3-3-5) technique was used. The results were analyzed with Cvi42 software (Circle Cardiovascular Imaging Inc., USA). The potential risk factors included patients’ age, gender, bodyweight, and diastolic heart failure. Results: The mean time of T1 relaxation without contrast enhancement was 1122.64 ±63.67 ms, indicating the presence of myocardial fibrosis in 100% of the patients. Female patients had more advanced diffuse myocardial abnormalities (p &lt; 0.001). In the elderly patients, there was a direct correlation between their age and degree of fibrosis (p = 0.006). There was an inverse correlation between higher bodyweight and increased extracellular volume. Heart rhythm disorders and diastolic heart failure had no impact on the changes in the mapping parameters of the left ventricular myocardium and MRI-assessed cardiac output values. No correlation between the myocardial fibrosis and dyslipidemia/hyperlipidemia was found. There was a direct correlation between the native T1 mapping values and extracellular volume fraction (p = 0.004) and an inverse correlation between low values of post-contrast T1 mapping and increased extracellular volume fraction (p = 0.05). Conclusion: Т1 mapping in patients with essential arterial hypertension allows for detection of diffuse myocardial fibrosis of the left ventricle, which is recognised as a major indicator of myocardial remodeling. Female gender, older age, and bodyweight were the factors associated with more advanced myocardial fibrosis.

Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial

Introduction: BELIEVE is an ongoing phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in adults with β-thalassemia requiring regular RBC transfusions (ClinicalTrials.gov identifier: NCT02604433). Treatment with luspatercept significantly reduced RBC transfusion burden and was associated with a favorable safety profile in this patient (pt) population (Piga A, et al. Blood. 2019;133:1279-89). Here we report iron-related efficacy endpoints of the BELIEVE study, including change from baseline in serum ferritin, liver iron concentration (LIC), and myocardial iron, as determined by T2*-weighted magnetic resonance imaging (MRI), and the effect of baseline iron levels on response to luspatercept. Methods: Adults with β-thalassemia or hemoglobin (Hb) E/β-thalassemia who required regular transfusions of 6-20 RBC units in the 24 weeks (wks) prior to randomization (with no transfusion-free period ≥ 35 days during that period) were randomized 2:1 to luspatercept (starting dose level 1.0 mg/kg; titration up to 1.25 mg/kg) or placebo, administered subcutaneously every 3 wks for ≥ 48 wks. Pts in both arms could receive RBC transfusions and iron chelation therapy (ICT) throughout the study to maintain their baseline Hb levels. Results: 332/336 randomized pts received treatment with luspatercept or placebo; 209/223 (93.7%) and 104/109 (95.4%) pts in the luspatercept and placebo arms had history of iron overload, defined as serum ferritin &gt; 1,000 µg/L or LIC &gt; 7 mg/g dry weight. 97.3% of luspatercept-treated and 97.2% of placebo-treated pts received ICT at baseline; 62.3%, 41.3%, and 37.2% received deferasirox, deferiprone, and deferoxamine, respectively, in the luspatercept arm, vs 57.8%, 36.7%, and 35.8% in the placebo arm. Fewer pts received ICT as combination therapy vs monotherapy (luspatercept arm: 28.6% vs 68.8%; placebo arm: 24.1% vs 72.3%, respectively). Mean baseline serum ferritin, LIC, and myocardial iron (by T2* MRI) for luspatercept vs placebo arms were 2,096.91 vs 1,845.05 μg/L, 12.04 vs 10.09 mg/g, and 33.52 vs 34.76 ms, respectively. As of Jan 7, 2019, 157 (70.4%) continue to receive luspatercept and 92 (84.4%) crossed over from the placebo arm. During the last 12 wks of the 48-wk randomized treatment period, mean change from baseline in serum ferritin was −248.02 μg/L vs +106.62 μg/L for pts in the luspatercept and placebo arms, respectively (least squares mean [LSM] difference: −347.80; P &lt; 0.0001). 158/224 (70.5%) and 33/112 (29.5%) pts in the luspatercept and placebo treatment arms achieved a ≥ 33% reduction in RBC transfusion burden of ≥ 2 RBC units during any 12-wk interval. Among the responders, mean change from baseline in serum ferritin was −343.22 μg/L and +47.30 μg/L for pts receiving luspatercept and placebo, respectively (LSM difference: −389.50; P = 0.0047). Of 140 luspatercept-treated pts with baseline ferritin ≥ 1,000 μg/L, 29 (20.7%) achieved post baseline ferritin of &lt; 1,000 μg/L when assessed over the entire treatment period; results were similar in responders and non-responders. During the treatment phase, mean change in myocardial MRI iron signal (T2*) from baseline to Wk 48 was −1.83 ms for luspatercept and +0.02 ms for placebo (LSM difference: −2.39; P = 0.0391). Over 96 wks, 6 (20%) luspatercept-treated pts with baseline myocardial iron ≤ 20 ms had post-baseline results &gt; 20 ms; results were similar between responders and non-responders. Mean LIC changes from baseline to Wk 48 (mg/g dry weight) were +0.10 and +0.08 for luspatercept and placebo arms, respectively (LSM difference: +0.11; P = 0.8685). Over 96 wks, mean change in LIC among luspatercept-treated patients overall was −0.5 mg/g and −1.1 mg/g among responders. When assessing impact of baseline iron loading there was a general consistency in achievement of ≥ 33% reduction in RBC transfusion with luspatercept over any 12 wks, regardless of iron loading subgroup (baseline serum ferritin, LIC, and myocardial iron) (Table). Conclusions: Luspatercept treatment resulted in clinically meaningful reductions in serum ferritin levels. Baseline iron overload did not seem to affect response to luspatercept; treatment resulted in clinically meaningful reductions in RBC transfusion burden regardless of baseline serum ferritin level, LIC, or myocardial iron loading. Disclosures Porter: Celgene Corporation: Consultancy, Honoraria; Protagonist: Honoraria; Vifor: Honoraria; La Jolla: Honoraria; Agios: Consultancy, Honoraria; Silence Therapeutics: Honoraria; Bluebird Bio: Consultancy, Honoraria. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Coates:apo pharma: Consultancy, Honoraria, Speakers Bureau; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Research Funding. Viprakasit:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Ionis: Consultancy, Research Funding; La Jolla: Consultancy, Research Funding. Voskaridou:Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Perrotta:Acceleron Pharma: Research Funding; Novartis: Honoraria, Research Funding. Kattamis:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Shetty:Celgene Corporation: Employment, Equity Ownership. Kuo:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene International: Employment. Zinger:Celgene Corporation: Employment. Linde:Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Taher:Protagonist Therapeutics: Consultancy, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Celgene Corporation: Research Funding; Abfero: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

CORRELATION BETWEEN CARDIAC AND HEPATIC T2* MRI AND SERUM FERRITIN LEVEL IN PATIENTS WITH TRANSFUSION DEPENDENT Β-THALASSEMIA MAJOR

Background: β-Thalassemia occurs in higher frequency in the Mediterranean area and the Middle East. Classically serum ferritin and liver biopsy have been needed to monitor patient's response to chelation therapy. Magnetic resonance imaging (MRI) has been proved effective in detecting and quantifying iron in the heart and liver. Objective:To assess the value of MRI T2* procedure in assessment of hepatic (LIC) serum ferritin level and MRI T2* of liver and myocardium in patients with BTM. Methods: A cross -sectional study was conducted at Al-Imamein Al-Kadhimein Medical City in Baghdad, from September 2016 to September 2017, 45 patients with BTM were collected from the Thalassemia center in Ibn AL-Baldy Hospital. Hepatic and myocardial T2* MRI results were taken from the file records of the patients from the same center.The results of hepatitis B and C and serum ferritin were taken from the file records. Results: The total number of patients was 60, 15 patients were excluded because of heart failure and hepatitis B and C, the mean age was (19.95±6.85 years), male: female ratio equal to 1:1. Fifty-one patients (85%) were on Deferasirox and 19 patients (31.76%) were splenectomized. Serum ferritin ranged between (1009-10600 ng/l). Liver T2* MRI ranged from (0.5-17 ms) with a mean of (3.66±3.13 ms). Mild-moderate severity found in the majority, 18 cases (40%), 13 cases (28.9%) respectively, with strong inverse correlation between liver MRI and serum ferritin level. Myocardial T2* MRI ranged from (1.88-33.2 ms) with a mean of (13.16±7.81 ms). Moderate-severe degree of severity in the majority, 12 cases (26.67%), 19 cases (42.22%) respectively, with significant inverse correlation between serum ferritin and myocardial MRI. There is no positive correlation between myocardial T2* MRI nor liver T2* MRI with mean age of the patients. Conclusion: The study shows that MRI is an accurate and non-invasive method to assess iron overload in liver and heart in β-thalassemia patients with regular transfusion. Keywords: β-Thalassemia major, blood transfusion, serum ferritin, cardiac MRI, hepatic MRI Citation: Yaseen AK, Abbas SS, Abdulhadi AMA. Correlation between cardiac and hepatic T2* MRI and serum ferritin level in patients with transfusion dependent β-thalassemia major. Iraqi JMS. 2019; 17(1): 66-73. doi: 10.22578/IJMS.17.1.10

A semiautomatic method for rapid segmentation of velocity-encoded myocardial magnetic resonance imaging data.

To develop a semiautomatic method for rapid segmentation of myocardial tissue phase mapping (TPM) data. Manual segmentation of the myocardium was performed at end-diastole and end-systole. The points in both user-defined masks were then automatically tracked over the entire cardiac cycle using temporal integration of the velocity field. Paths that failed to visit both masks at the expected times were excluded, after which masks for all time points were generated automatically from the accepted paths. Midventricular and basal phase contrast TPM slices from 12 rats were segmented using the proposed method and fully manual segmentation. The results were compared using Dice's metric and Bland-Altman analysis, and interobserver variability was assessed. The semiautomatic method reduced the average user input time from 21 min to 1 min per slice. The Dice metrics between the methods were 0.88 ± 0.03 (midventricular) and 0.83 ± 0.06 (basal), and Bland-Altman limits of agreement of peak systolic and diastolic regional velocities were: midventricular: 0.05 ± 0.65 cm/s, -0.02 ± 0.42 cm/s, and -0.03 ± 0.40 cm/s (radial, tangential, longitudinal); basal: -0.04 ± 0.73 cm/s, 0.03 ± 0.60 cm/s, and -0.04 ± 0.48 cm/s (radial, tangential, longitudinal). Interobserver variability following semiautomatic segmentation was lower than for manual segmentation. The proposed method reduced the segmentation time substantially and exhibited well-preserved data quality and excellent interobserver limits of agreement. Magn Reson Med 78:1199-1207, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Comparison of preexisting and ablation-induced late gadolinium enhancement on left atrial magnetic resonance imaging.

Postablation atrial fibrillation recurrence is positively associated with the extent of preexisting left atrial (LA) late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI), but negatively associated with the extent of postablation LGE regardless of proximity to the pulmonary vein antra. The characteristics of pre- vs postablation LA LGE may provide insight into this seeming paradox and inform future strategies for ablation. The purpose of this study was to define the characteristics of preexisting vs ablation-induced LA LGE. LGE-MRI was prospectively performed before and ≥3 months after initial ablation in 20 patients. The intracardiac locations of ablation points were coregistered with the corresponding sites on axial planes of postablation LGE-MRI. The image intensity ratio (IIR), defined as the LA myocardial MRI signal intensity divided by the mean LA blood pool intensity, and LA myocardial wall thickness were calculated on pre- and postablation images. Imaging data from 409 pairs of pre- and postablation axial LGE-MRI planes and 6961 pairs of pre- and postablation image sectors were analyzed. Ablation-induced LGE revealed a higher IIR, suggesting greater contrast uptake and denser fibrosis, than did preexisting LGE (1.25 ± 0.25 vs 1.14 ± 0.15; P < .001). In addition, ablation-induced LGE regions had thinner LA myocardium (2.10 ± 0.67 mm vs 2.37 ± 0.74 mm; P < .001). Regions with ablation-induced LGE exhibit increased contrast uptake, likely signifying higher scar density, and thinner myocardium as compared with regions with preexisting LGE. Future studies examining the association of postablation LGE intensity and nonuniformity with ablation success are warranted and may inform strategies to optimize ablation outcome.

Myocardial dynamic contrast-enhanced Mr: vascular diseases and beyond.

Contrast-enhanced cardiac magnetic resonance imaging allows the evaluation of both myocardial perfusion and myocardial tissue characteristics. This paper reviews different microvascular and non-vascular conditions that can cause abnormal findings on contrast-enhanced myocardial magnetic resonance imaging. Knowledge of their characteristics can avoid misinterpretation and avoid inappropriate referral for further invasive imaging in patients suspected of myocardial vascular disease.

5‐Fluorouracil—Induced Tako‐Tsubo—Like Syndrome

Tako-Tsubo cardiomyopathy (also known as apical ballooning syndrome) is a relatively new clinical entity characterized by reversible left ventricular dysfunction. Its clinical presentation and electrocardiographic findings are similar to acute myocardial infarction but without significant coronary artery disease. Cardiotoxicity is a major complication of various anticancer drugs; however, only a few cases of Tako-Tsubo cardiomyopathy associated with anticancer drugs, including 5-fluorouracil, have been reported. We describe a 48-year-old man who developed acute coronary syndrome, thought to be similar to Tako-Tsubo syndrome, after receiving a chemotherapy regimen consisting of 5-fluorouracil, oxaliplatin, and calcium folinate (FOLFOX protocol) for colic adenocarcinoma. Approximately 24 hours after receiving his first cycle of chemotherapy, the patient, who did not have a history of cardiovascular disease, developed chest pain, with abnormal electrocardiographic results and a mildly increased troponin T level. Coronary angiography did not show any significant coronary lesions. Echocardiography revealed marked left ventricular dysfunction (left ventricular ejection fraction [LVEF] 15%) with severe hypokinesia in all apical and median segments. The patient was stabilized with the introduction of an intraaortic balloon pump and pressor therapy. One month later, myocardial magnetic resonance imaging confirmed total recovery of left ventricular systolic function. Thus, the second chemotherapy cycle was administered at half the dose-intensity, along with ramipril and diltiazem. The chemotherapy regimen was well tolerated. Two weeks later, at the end of the third chemotherapy cycle, administered using the full-dose regimen, the patient experienced cardiac arrest, necessitating cardiopulmonary resuscitation. After transfer to the cardiology intensive care unit, acute heart failure recurred (LVEF 35%). Normal recovery of left ventricular function occurred a few days later. Chemotherapy was discontinued, and treatment with bisoprolol was started. Four months later, the patient remained completely asymptomatic of any cardiac manifestations. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 8) between the patient's development of acute coronary Tako-Tsubo-like syndrome and 5-fluorouracil. Clinicians should be aware of this potential adverse effect when monitoring patients receiving chemotherapy with 5-fluorouracil.

101 Cardiac sarcoidosis: therapeutic management and prognostic factors from a cohort of 130 patients

The diagnosis of cardiac sarcoidosis (CS) (56 female-74 male; 73 White- 36 Black; age at CS: 40.5 ± 11.7 years) was defined by clinical signs (20%) and/or evidence of at least two procedures abnormalities: ECG (64%), echocardiography (71%), Magnetic Resonance Imaging (MRI) (58%) and myocardial scintigraphy (72%). With a 54 month-median follow-up, 124 patients were evaluable. The first line therapy was steroids alone in 57% of cases, steroids with immunosuppressive (IS) drug in 43%. A relapse of the CS was noted in 35 patients, a median time of 27 months. The RR of relapsing at any time was 3.1 times higher in Black (P = 0.008) and 4 times more when baseline abnormal myocardial MRI (P = 0.008). A recovery was achieved by 91 patients (73%), a stabilisation in 23% and 3% worsened. The relative risk (RR) of not recovering at any time was 5.4 times higher in patients who had a steroids treatment duration of less than 24 months (P < 0.0001), 2.4 times higher in patients with a nervous system involvement (P = 0.018) and 3.7 times higher in those who received a first line therapy with weekly methotrexate (P = 0.009). It was 21 times lower in patients who received monthly bolus of cyclophosphamide (CY) (P = 0.004). Death occurred in 13 patients (10%), related to CS in two patients. The 5-year survival rate was 91%. CS had a good prognosis under steroids alone or associated with an IS drug with a global recovery rate of 73% and a 5-year Survival rate of 91%. The risk of not recovering was associated with a steroids treatment duration of less than 24 months, and the use of a methotrexate first line therapy whereas CY was associated with a better prognosis. The identified independent risk-factors for relapsing were Black origin and a baseline abnormal cardiac MRI. This cohort demonstrates the need of maintaining a careful clinical and paraclinical follow-up of patients with a cardiac sarcoidosis with a more than 24-month steroids therapy.

Cardiac T2* Magnetic Resonance Imaging (MRI) in Iron Overload and Ventricular Diastolic Function.

Accumulation of iron in the heart leads to myocardial dysfunction and in severe cases heart failure. Myocardial hemosiderosis occurs in many hematological diseases treated with blood transfusions, including sickle cell anemia (SCA) and beta thalassemia (β-thal). MRI T2* can quantify myocardial iron non-invasively and can be compared to functional studies (e.g., echocardiography). Multiple MRI readers can introduce variation in the measurement. We investigated the relationship of myocardial MRI T2* with echo measurements of both systolic and diastolic function, and the variability introduced by different MRI reviewers. Patients were selected if they received ≥ 18 transfusions, or had a serum ferritin ≥ 1000 ng/mL. Study participants underwent 1.5 Tesla MRI T2* and echocardiography testing within 30 days. Echo measurements included left ventricular ejection fraction (LVEF), mitral annular tissue Doppler (TDV) e' velocity (a measure of LV diastolic function), left ventricular myocardial performance index (a measure of both systolic and diastolic function - LVMPI), and left ventricular mass index (LVMI). Regions of interest (ROI) were drawn in a homogeneous area of the intraventricular septum. Three independent reviewers, blinded to the patients' clinical status and the other 2 reviewers' results, performed the ROI analysis. Agreement among the 3 raters was assessed using interclass correlation coefficient (ICC). Echo findings were associated with heart T2* both as continuous and categorical (normal vs abnormal) variables. Forty-seven patients, median age 14 years (range 7 – 37), participated; 24 (51.1%) were female. Thirty-five (74.5%) had SCA, 8 (17%) had β-thal (major or intermedia), and 4 (8.5%) had bone marrow failure syndromes. Mean (±1SD) echo results were LVEF (±5.8) %, LVMI 86 (±20.4) g/m2, LVMPI 0.3 (±0.1), and TDV e' velocity 16.2 (±3.4) cm/sec. Only one patient had low LVEF, but 8 (17%) had high LVMPI and 20 (42%) had low TDV e' velocity. All patients had normal LVMI. The mean myocardium T2* ranged among the 3 reviewers from 27 to 33 (±6.9 to 8.7) msec. Agreement among the 3 raters had an ICC = 0.64. Median T2* values were significantly lower among patients with lower LVMI (32 versus 42 msec, p= 0.019). No other comparisons among echo and T2* results were significant. Median echo findings were compared with T2* values above and below 20 msec: lower LVMI (71 vs 89 g/m2, p=0.04), and higher LVMPI (0.48 versus 0.28, p=0.015) were found among patients with T2* < 20 msec. Mean serum ferritin was 2917 (±2239) ng/mL. Serum ferritin was significantly negatively associated with T2* values (ρ=−0.33, p=0.031). We conclude:1.Most patients had normal LV systolic function, but 42% had signs of diastolic dysfunction,2.LVMPI was associated with myocardial iron loading (T2*>20msec), suggesting diastolic dysfunction to be an early sign of myocardial dysfunction in cardiac hemosiderosis,3.Heart T2* was weakly associated with serum ferritin,4.The agreement among reviewers of the heart T2* technique was acceptable, but not high, likely reflecting technical difficulties of accurate myocardial ROI determination on “bright blood” T2* maps drawn on thin intraventricular septa.Dark blood techniques should therefore be investigated to reduce blood artifacts, potentially improving accuracy by eliminating artifacts from bright blood signals and thus reducing inter-rater variability in the ROI analysis of myocardial iron.

Four‐year evaluation of myocardial and liver iron assessed prospectively with serial MRI scans in young patients with β‐thalassaemia major: comparison between different chelation regimens

This study was conducted in order to assess myocardial and liver iron concentrations (LICs) using serial magnetic resonance imaging (MRI) scans in patients with beta-thalassaemia major, over a 4-yr period, and consequently to compare the effectiveness of different chelation regimens. Fifty children and young adults with beta-thalassaemia major (27 boys and 23 girls) were recruited (mean age: 14.74 +/- 3.67 yr). All patients underwent detailed clinical examination, electrocardiography, echocardiography, myocardial and liver MRI at the beginning of the study, 2 and 4 yr after. Additionally, serum ferritin levels were regularly measured and data regarding LICs assessed by percutaneous liver biopsy were available in 26 patients. Both myocardial and liver MRI values showed a moderate inverse correlation with age (r = -0.379, P < 0.001 and r = -0.376, P < 0.001, respectively). Liver MRI was better correlated with serum ferritin concentrations (r = -0.342, P < 0.001) than myocardial MRI (r = -0.186, P = 0.011). Liver MRI values were highly correlated with LICs derived from percutaneous liver biopsy (r = -0.863, P < 0.001), whereas myocardial MRI values did not correlate at all with measurements derived from echocardiography. Regarding iron chelation treatment, patients receiving combined therapy with deferiprone and deferoxamine (DFO) significantly reduced myocardial iron overload during the 4-yr study period, whilst patients in monotherapy with DFO showed a significant increase in LIC.

Abstracts for the British Congenital Cardiac Association Annual Meeting: The Barbican, London, 24–25 November 2005: Poster Presentations: Severe coronary ostial stenosis after arterial switch operation detected by transthoracic Doppler echocardiography

Background: Asymptomatic proximal coronary artery stenosis after arterial switch operation (ASO) is rare, but a potentially life-threatening condition, that is reported to appear in up to 7%. Angiography, although considered the state-of-the-art method of diagnosis, is an invasive method, but has limitations for diagnosing ostial stenosis. We report changes in Doppler flow profile and coronary flow reserve (CFR) in two asymptomatic patients (9- and 10-year old) with left main coronary artery (LMCA) ostial stenosis after ASO. Methods: Coronary flow was assessed by Transthoracic pulsed and colour-flow Doppler echocardiography (TTDE). CFR was measured in one patient using adenosine infusion (140 mcg/kg/min) over 4 minutes. CFR was calculated as the ratio of reactive hyperaemia to basal average peak velocity (APV). Both children were investigated with coronary angiography. They had myocardial Single-photon Emission Computed Tomography (SPECT), and magnetic resonance imaging (MRI) at rest and after reactive hyperaemia with adenosine infusion. Both patients had balloon dilatation and Cypher select (drug eluted) stent. Results: On echocardiogram a flame-like colour-flow diastolic signal was detected at the stenotic coronary ostia. The maximal spectral velocities during baseline conditions over the stenotic ostia were over 1.9 and 2.0 m/s (normal 30 ± 10 cm/s). The post-stenotic CFR was haemodynmically significant with value of 1.3, normal adult range 2.5–4. Coronary angiography showed a significant ostial stenosis 90% in both patients. Myocardial SPECT and MRI at rest/adenosine infusion were consistent with severe myocardial ischemia in the territory of the left coronary artery. Normal coronary angiography and coronary flow studies after stenting. Conclusion: We suggest that coronary artery flow assessment should be an integral part of the TTDE in the follow up of children with ASO. Serious coronary artery stenosis can be detected with TTDE. Assessment of CFR provides information of the physiological significance of the coronary stenosis.

Correlative Study of Iron Accumulation in Liver, Myocardium, and Pituitary Assessed With MRI in Young Thalassemic Patients

Clinical complications resulting from unevenly iron accumulation in individual organs of patients with beta-thalassemia major can affect both expectancy and quality of life. Magnetic resonance imaging (MRI) offers a quantitative, noninvasive, accurate method for estimating iron levels in various tissues, not easily accessible with other techniques. The aim of this study was to evaluate and correlate the level of iron accumulation in different organs (anterior pituitary, myocardium, and liver) assessed with MRI, in children and young adults with beta-thalassemia major. Thirty children and young adults (13 female and 17 male patients) with homozygous beta-thalassemia, treated conventionally, were studied with hepatic, myocardial, and hypophyseal MRI. For liver and myocardium, we calculated the natural logarithm of the signal-to-air ratio in flash 2-dimensional sequences with electrocardiogram gating, whereas for anterior pituitary, the signal intensity was measured in sagittal T2 sequences. All scans were performed within 3 months. In 13 patients, data regarding liver iron concentrations (LIC) assessed by percutaneous liver biopsy were available. The mean of serum ferritin concentrations for 1 year before scans was calculated for each patient. MRI values in myocardium and liver showed a significant negative correlation to age (r=-0.73 and -0.69, respectively). For pituitary MRI, a linear regression with age was recorded in patients over 14 years of age (r=-0.67), whereas a relatively increased signal intensity reduction was recorded in pubertal subjects. Mean serum ferritin concentrations ranged from 252 to 5872 mug/L with an average of 1525+/-1047 mug/L. No statistical significant correlation was noted between mean ferritin levels versus liver, pituitary, and cardiac MRI values (r=-0.49, -0.28, and -0.1, respectively). Mean LIC values assessed by percutaneous biopsy were 13.76+/-11.6 mg/g of dry tissue. A statistically significant negative correlation was observed between liver MRI readings and LIC determined by biopsy (r=-0.89). None of the 3 organs studied with MRI were significantly correlated to each other. Pituitary to liver MRI values and liver to myocardial MRI values were moderately correlated (r=0.34 and 0.42, respectively). Pituitary MRI was not correlated at all to myocardial MRI (r=-0.001). In conclusion, iron accumulation in thalassemic patients is a procedure progressing with age, which seems to act independently in different organs. MRI represents a reliable, noninvasive method for assessing iron overload in various tissues, non-easily accessible with other techniques. Regular scanning, to recognize preclinically excessive iron deposits and intensified chelation therapy, can prevent serious and fatal complications.

[Long term follow-up on emergent intracoronary autologous bone marrow mononuclear cell transplantation for acute inferior-wall myocardial infarction].

To investigate the effects of emergent intracoronary autologous bone marrow mononuclear cell (BM-MNC) transplantation on left ventricular function and myocardium lesion area in patients with first acute inferior-wall myocardial infarction. Forty patients with first onset of acute inferior-wall myocardial infarction, 28 males and 12 females, aged < or = 75, treated with emergent percutaneous coronary intervention (PCI) were randomly divided into 2 equal groups: group undergoing intracoronary transplantation of autologous BM-MNC via a micro-catheter right after PCI (BM-MNC group), and control group receiving normal saline and heparin. Blood routine examination, myocardium zymogram, and serum high sensitive C reactive protein (hsCRP) were detected, and 24-hour dynamic electrocardiography, delayed-enhancement myocardial magnetic resonance imaging (CMR), and angiography of the coronary artery and left ventricle were conducted before the transplantation and immediately, 1 week, and 6 months after transplantation. CMR showed that 6 months later the left ventricular ejection fraction (LVEF) of the control group was 47.9% +/- 6.7%, significantly higher than that 1 week later (43.4% +/- 6.7%, P = 0.001), and the LVEF of the BM-MNC group 6 months later was 51.5% +/- 5.2%, significantly higher than that 1 week later (44.5% +/- 7.1%, P = 0.001; however, the absolute change of LVEF (DeltaLVEF) of the BM-MNC group was 6.95% +/- 3.33%, significantly higher than that of the control group (4.05% +/- 1.68%, P = 0.047). Six months later the myocardial lesion area of the BM-MNC group decreased more significantly in comparison with the control group. Nevertheless, there was no difference in change of left ventricular end diastolic volume (LVEDV) between these two groups. The serum hsCRP 48 h after transplantation of the BM-MNC group was 2.8 g/L +/- 0.8 g/L, significantly lower than that before transplantation (13.4 g/L +/- 3.6 g/L, P < 0.001). No severe clinical events, such death, recurrent cardiac infarction, malignant arrhythmia, occur in these 2 groups. Emergent intracoronary transplantation of autologous BM-MNC in patients with acute inferior-wall myocardial infarction improves the left ventricular function and myocardial infusion, minimizes the myocardial lesion area significantly.

Deferiprone: New Insight

Recent results from independent studies suggest that deferiprone is more cardioprotective than deferoxamine. Patients on long-term treatment with deferiprone have a better myocardial magnetic resonance imaging pattern and less chance to develop a new cardiac disease or worsen an existing one. Most of these observations are retrospective and require confirmation from randomized controlled trials. Other new observations regard the effects of combining the two chelators. Most results indicate an additional effect on iron excretion and a significant reduction of the time required to mitigate severe iron overload and to reverse clinical heart disease. Again, these data require confirmation, as they were mostly obtained on individual cases or small groups of patients treated with a wide range of combinations of the two chelators, but the univocity of results is impressive. After many years of controversy, deferiprone is emerging as a useful oral iron chelator that enhances the chances for the patient to have optimal treatment. Well-designed and -conducted studies will help in answering the questions still open.

Tricuspid regurgitation in patients with beta-thalassemia major.

Although cardiac complications remain the main causes of death in thalassemic patients, right heart dysfunction has been little studied and the mechanism is still unclear. Echocardiography was performed in 39 patients with beta-thalassemia major and 35 aged-matched controls. The gender, age, heart rate, blood pressure, left ventricular ejection fraction (LVEF), acceleration time (AcT) of right ventricular outflow and right ventricular ejection time (RVET), AcT/RVET, and the presence of tricuspid regurgitation (TR) were compared between the two groups. We also compared the gender, age, age at first blood transfusion, serum ferritin level, alanine aminotransferase (ALT), the presence of antibodies to hepatitis C virus, liver fibrosis, splenectomy, platelet counts, diabetes mellitus, arrhythmia, cardiomegaly, LVEF, AcT, RVET, AcT/RVET, and signal intensity ratio (SIR) of myocardial magnetic resonance imaging (MRI) between thalassemic patients with and without TR. The incidence of TR in thalassemic patients was significantly higher than that in the control group (30.8 vs 11.4%, p=0.03). The incidences of splenectomy (p=0.03), platelet counts (p=0.01), and SIR of myocardial MRI (p=0.03) in thalassemic patients with TR were significantly higher than in those without TR. The AcT was shorter and the AcT/RVET ratio was smaller, suggesting higher pulmonary pressure in the thalassemic patients with TR. Occurrence of TR in patients with beta-thalassemia major may be a consequence of cardiac iron deposit, thrombocytosis, splenectomy, or pulmonary hypertension.

Noninfarcted Myocardium: Correlation between Dynamic First-Pass Contrast-enhanced Myocardial MR Imaging and Quantitative Coronary Angiography

To determine the accuracy of first-pass contrast material-enhanced stress myocardial magnetic resonance (MR) imaging for depiction of myocardial ischemia in patients without myocardial infarction. First-pass contrast-enhanced MR images of the entire left ventricle were acquired in 104 patients at rest and during dipyridamole-induced stress by using an interleaved notched saturation technique. Coronary angiography was performed in all patients, and stress perfusion single photon emission computed tomography (SPECT) was performed in 69 patients. Receiver operating characteristic curve analysis was performed to compare the diagnostic accuracies of first-pass contrast-enhanced stress MR imaging and stress SPECT, with coronary angiography as the reference standard. The overall sensitivity of MR imaging for depicting at least one coronary artery with significant stenosis was 90% (69 of 77 patients). The sensitivities of MR imaging for depiction of single-, double-, and triple-vessel stenoses were 85% (33 of 39 patients), 96% (22 of 23 patients), and 100% (15 of 15 patients), respectively. The specificity of MR imaging for identification of patients with significant coronary artery stenoses was 85% (23 of 27 patients). The areas under the receiver operating characteristic curve for detection of significant stenosis in individual coronary arteries were 0.888 (observer 1) and 0.911 (observer 2) for MR imaging and 0.707 (observer 1, P <.001) and 0.750 (observer 2, P <.001) for SPECT. In patients without myocardial infarction, stress enhancement at dynamic MR imaging correlates more closely with quantitative coronary angiography results than does stress enhancement at SPECT.

Susceptibility-sensitive magnetic resonance imaging detects human myocardium supplied by a stenotic coronary artery without a contrast agent

ObjectivesEvaluation of the severity of a coronary artery stenosis is of paramount importance for therapy. A relevant stenosis provokes post-stenotic microvascular dilation with capillary recruitment. This autoregulatory response was investigated in the present study by use of susceptibility-sensitive magnetic resonance imaging (MRI) without contrast agents. BackgroundFunctional alterations of the microvascular system may be studied noninvasively and without a contrast agent by susceptibility-sensitive MRI, which is based on the paramagnetic property of deoxyhemoglobin. This effect, also referred to as the “blood oxygenation level-dependent (BOLD) effect,” is investigated by phase relaxation (T2*) measurements. MethodsIn patients (n = 16) with single-vessel coronary artery disease, no history of myocardial infarction, normal left ventricular function at rest, and a positive stress echocardiogram, the susceptibility-sensitive parameter T2* was assessed in the myocardium. ResultsIn regions associated with the stenotic artery, T2* was significantly lower than in residual myocardium (p < 0.01). This difference in T2* increased after application of the vasodilator dipyridamole (p < 0.001). In patients being re-investigated after therapeutic interventions, the microvascular dilation was partly removed. ConclusionsFor the first time, we could show that myocardial BOLD MRI detects post-stenotic capillary recruitment dependent on coronary artery stenosis.

Neue Ansätze der Magnetresonanztomographie zur Beschreibung myokardialer Mikrozirkulationsparameter am Menschen

One crucial goal of magnetic resonance imaging (MRI) in patients with coronary artery disease (CAD) is the characterization of myocardial microcirculation that reflects tissue supply much better than detection and quantification of a stenosis itself. PERFUSION: Myocardial perfusion is one important parameter of microcirculation and it is commonly detected by first-pass techniques using contrast agents (CA). Despite the quantification of perfusion it is an indispensable component of a comprehensive diagnosis to determine the perfusion reserve, which is believed a good indicator for viability of myocardium. However, most MRI techniques for perfusion imaging are Ca based and this implies a restricted reproducibility in humans. Beyond it, most first-pass techniques are qualitative and not quantitative. REGIONAL BLOOD VOLUME: Another parameter of microcirculation is the regional intracapillary myocardial blood volume (RBV) that almost represents the whole intramyocardial blood volume due to its dominating volume fraction. The RBV reflects the autoregulatory adaptation of microvessels, e.g., a severe stenosis may lead to an increase of the RBV by capillary recruitment, and the RBV is reduced in scar areas. The RBV may be quantified by first-pass techniques; however, this demands a definite relation between signal intensity and concentration of the CA, which is difficult to find for the range of concentrations present during the first pass. Until recently, no techniques existed for the exact and noninvasive assessment of the RBV. CAPILLARY RECRUITMENT: The evaluation of the relevance of a coronary artery stenosis is of paramount interest for the therapeutic decision. A severe stenosis implies the activation of compensation mechanisms, which includes poststenotic dilation of the microvascular system. This lowering of the vascular resistance aims to maintain sufficient blood supply at least under resting conditions. However, many obstacles hamper the noninvasive assessment of this autoregulatory response so far. Our laboratory recently developed different techniques for the assessment of myocardial perfusion, regional myocardial blood volume, and capillary recruitment. These techniques are based on theoretical and physiologic considerations and work mainly without CA. In this article, feasibility and reproducibility of these approaches are shown in volunteers and patients. MR exams were performed on a 1.5-T whole body scanner (SIEMENS Vision) and a 2-T system (BRUKER Tomikon). Stress examinations were done repeatedly under pharmacologically induced stress (dipyridamole or adenosine, infusion rate: 0.56 mg/kg body weight over 4 min via an antecubital vein). Heart rate and blood pressure were continuously monitored during stress exams. T1 Spin labeling used in this work is based on T1 measurements after global and slice-selective spin preparation using a fast ECG-gated saturation recovery FLASH sequence. Due to the inflow of unsaturated proton spins, T1 in tissue is shortened after slice-selective preparation case compared to global saturation. We showed that, assuming a two compartment model with fast proton exchange between the compartments, the absolute perfusion P (in [ml/g/min]) can be calculated as P = lambda/T1(blood) ([T1(global)/T1(selective)] - 1), where the blood tissue partition coefficient lambda represents the quotient of water content of capillary blood and perfused tissue, which is approximately 0.9 ml/g in myocardial tissue. T1(blood) is the longitudinal relaxation time T1 of the arterial blood, measured in the left ventricle (LV). T1(global) and T1(selective) are the myocardial T1 calculated after the respective spin preparation. Perfusion reserve is evaluated as the quotient of perfusion under adenosine-induced stress and perfusion at rest. In volunteers quantitative perfusion was determined as 2.5 +/- 0.7 ml/g/min (rest), perfusion reserve was about 2.0. Absolute perfusion decreased to 1.6 +/- 0.6 ml/g/min under oxygen breathing. In patients with CAD, myocardial regions with decreased perfusion reserve could be identified. perfusion reserve could be identified. Performing the described spin-labeling technique with an intravascular CA facilitates the determination of the intra-extracapillary water proton exchange frequency and the RBV. In a patient study, the effect of the intravascular CA Feruglose (Amersham) on relaxation rate in myocardium (R1(myo)) in the steady state was investigated (Figure 1). The dependence of R1(myo) on R1(blood) was characterized and compared with a theoretical model which allowed determination of the intra-extracapillary water proton exchange frequency (f = 0.48 s(-1)) and the intracapillary blood volume (RBV = 12.9%). A linear response range of Delta R1(myo) on Delta R1(blood) was estimated which, in future studies, will allow the determination of RBV with intravascular CA (Figure 2). T2* We anticipated that poststenotic vasodilatation implies a capillary recruitment. Almost all (i.e., > 90%) of intramyocardial blood residues in that type of vessel. Due to their large arteriovenous oxygenation difference, myocardial capillaries contain considerable amounts of deoxyhemoglobin (Figure 3). Hence, in regions with autoregulatory capillary recruitment the tissue concentration of deoxyhemoglobin should be elevated when compared to myocardium supplied by a normal vessel (Figure 5b). Due to its paramagnetic property and its intravascular confinement, the natural CA deoxyhemoglobin may be assessed by susceptibility sensitive, or also called blood oxygenation level-dependent (BOLD) MRI. For T2* measurements, a segmented gradient echo pulse sequence was used, which acquired ten successive gradient echoes per rf excitation in a single breathhold. In volunteers, there was an increase in T2* of about 10% under dipyridamole-induced stress (Figure 4). This means a decrease of the intracapillary deoxyhemoglobin concentration, whereas the oxygen consumption under increased perfusion did not change. In myocardial regions of patients, associated with the stenotic artery T2* was significantly lower than in residual myocardium (p < 0.01; Figure 5a). This difference in T2* increased after application of the vasodilator dipyridamole (p < 0.001). In patients being reinvestigated after therapeutic interventions, the microvascular dilation was partly removed (Figure 5c). For the first time we could show that myocardial BOLD MRI detects poststenotic capillary recruitment dependent on a coronary artery stenosis.