A 53-year-old female, submitted to surgical correction of endomyocardial fibrosis (EMF) 12years before, sought medical care with hypotension and bradycardia.She complained of palpitations since the age of 29 years. Her symptoms aggravated 5 yearslater, with the appearance of dyspnea on moderate exertion. After 5 more years, the dyspneaintensified, being triggered on mild exertion and in the dorsal decubitus position. Thepatient was then referred to a hospital.In 1994, the physical examination revealed irregular pulse, heart rate of 88 bpm, bloodpressure of 104/80 mm Hg, and increased jugular venous pressure. The pulmonary exam wasnormal, and the heart auscultation showed arrhythmic heart sounds and mitral systolicmurmur (+/4). The exam of the abdomen and limbs was within the normal range.In February 1994, the electrocardiogram (ECG) showed atrial fibrillation, leftbundle-branch block and left ventricular hypertrophy .In 1996, on echocardiogram, the dimensions of the cardiac chambers were: left atrium, 57mm; left ventricle, 51 mm (diastole) and 33 mm (systole). Obliteration of the apical regionof both ventricles was observed, with suggestive signs of calcification. The morphologicalaspect was considered suggestive of EMF.In 1996, a ventriculography showed obliteration of the apical region of left and rightventricles, in addition to mild mitral regurgitation. On coronary cineangiography, thecircumflex branch of the left coronary artery originated from the right coronary artery. Noobstruction of the coronary arteries was identified. The ventriculography findings weresuggestive of EMF.Surgical treatment was indicated.In September 1996 the surgery was performed with incision in the apical region of the leftventricle and resection of a fibrous and calcified mass. Then, through the interatrialseptum, annuloplasty with bovine pericardium was performed in the posterior portion of themitral ring and in the anterior portion of the tricuspid ring.The control ventriculography one month after surgery showed mild left ventricularhypokinesia and competent valves.According to the patient, the dyspnea improved, but the palpitations remained.She reported a transient episode of speech difficulty and right hemiparesis in 2002. Thedyspnea reappeared, initially on moderate exertion and then on mild exertion.A new echocardiographic assessment detected marked tricuspid regurgitation.The medication was adjusted, with the prescription of the following drugs: warfarin, 5 mg;losartan, 50 mg; furosemide, 80 mg; digoxin, 0.25 mg; and diltiazem, 180 mg.The symptoms improved, although episodes of aggravation occurred.In 2005, a new hemodynamic study revealed hypertension of the right chambers. Leftventricular hypokinesia of moderate intensity in the inferior and apical walls, and of mildintensity in the anterior wall, was identified.The pharmacological treatment was maintained, with adjustments according to symptoms. Thepatient was brought to the hospital after 24 hours of vertigo, malaise and dyspnea.The physical examination on November 13, 2008, revealed pulse of 30 bpm, inaudible bloodpressure, crepitant rales in pulmonary bases, bradycardia, liver palpable 7 cm from thecostal margin, ascitis, and mild lower limb edema.The ECG revealed atrial fibrillation, high atrioventricular block and ventricular rate of30 bpm.Chest X-ray showed enlarged cardiac area (+++/4+) and no signs of pulmonary congestion.2); INR, 2.6; BNP, 250 pg/mL; hemoglobin, 12.6 g/dL; hematocrit,40%; leukocytes/mm3, 7900 ;platelets/mm3, 183000; arterial lactate, 11 mg/dL; and blood digoxin level,1.13 ng/mL.The laboratory findings on that occasion were as follows: potassium, 4.4 mEq/L; sodium, 134mEq/L; urea, 100 mg/dL; creatinine, 1.45 mg/L ;platelets, 99000/mm3.On December 4, 2008, the laboratory findings were as follows: creatinine, 2.4 mg/dL; urea,105 mg/dL; potassium, 5.3 mEq/L; sodium, 130 mEq/L; hemoglobin, 8.8 g/dL; hematocrit, 30%;leukocytes, 6200/mmThe patient had ventricular fibrillation and cardiac arrest, which did not respond to theresuscitation maneuvers, dying on December 5, 2008.At the age of 29 years, the patient developed palpitations, which, after 5 years,associated with dyspnea on exertion, which progressed slowly until the age of 39 years.In young patients, the major causes of heart failure (HF) are idiopathic dilatedcardiomyopathy, myocarditis, Chagas disease, alcoholic cardiomyopathy, and, more rarely,ischemic heart disease. In addition, rarer causes of HF in patients of tropical andsubtropical regions, such as EMF, are worthy of note.1. It is more commonin the eastern and central regions of Africa. Several cases have been reported in SouthAmerica and India, and sporadic ones have been reported worldwide. In some places, EMFhas an endemic distribution.When the patient first sought the hospital, she was diagnosed with EMF, which is anuncommon restrictive cardiomyopathy, accounting for 1.6% of the deaths due to cardiacdisease in Brazil4. That pathogenicprocess favors thrombosis, usually in the ventricular apex.Its etiology has not been completely clarified. Its pathogenesis is believed to involveseveral factors, such as environmental exposure, nutritional and immune abnormalities,in addition to genetic factors. One of the most accepted hypotheses is that of a moreadvanced spectrum of Loeffler's disease, caused by eosinophilic infiltration of theheart layers, with chronic inflammation and posterior fibrosis2. In addition, EMF usually affects theventricular inlet, the papillary muscles and the valvular apparatus, mainly the mitralvalve3.The disease is characterized by deposition of fibrous tissue in the endocardium and, toa lesser extent, in the myocardium, usually affecting the apical region of the right orleft ventricle, or both. A previous study has shown biventricular impairment in 50% ofthe cases, of the left ventricle in 30%, and of the right ventricle in 27%5. Ascitis can occur in 50% of thepatients, usually associated with important right ventricular fibrosis, worsening theprognosis6. Our patient hadascitis only in final stage of disease. Supraventricular arrhythmias can be observed in60% of the patients, atrial fibrillation, as seen in our patient, being the mostcommon7.In most patients, similarly to ours, the symptoms begin during adolescence, in thesecond or third decades of life. The initial symptoms relate to diastolic dysfunction,the systolic dysfunction being uncommon, except for the advanced stages of EMFThe diagnosis of EMF is established based on echocardiographic findings, which do notcorrelate with the severity of symptoms. The most common echocardiographic findings arechanges in relaxation and compliance of the affected chamber, but usually withoutenlargement of the ventricular volumes. The atria are often enlarged and dysfunctional.Regurgitation of the atrioventricular valves is common. Pericardial effusion is usuallypresent, and can be important.Our patient's echocardiogram was compatible with the diagnosis of EMF, with markedenlargement of the left atrium (57 mm) and preservation of the ventricular diameters.Biventricular impairment with suggestive signs of calcification was observed.9.In addition, our patient underwent ventriculography, which confirmed the biventricularinvolvement with mild mitral regurgitation. The hemodynamic study of patients with EMFusually reveals elevation of the end-diastolic pressure of the ventricle affected,restrictive pattern in the ventricular pressure recordings and obliteration of theventricular apex8, while less than 30% of those with FC IV survive twoyears10.The prognosis of EMF depends mainly on its clinical presentation. The following factorsare considered to worsen the prognosis: right ventricular impairment, ascitis, atrialfibrillation, mitral insufficiency, and increased atrial, end-diastolic ventricular andpulmonary pressures (> 40 mm Hg). The major factor determining the prognosis,however, is functional class (FC). A study has assessed survival according to the FC. Ofthe patients with FC I and II, 85% survive two years11, while that for more symptomatic ones [congestive HF (CHF) FC IIIand IV] is surgical treatment13. In the presence of worse prognosticfactors, some experts recommend surgery already for FC II.Thus, the treatment of EMF is based on symptoms. The recommendation for patients withfew symptoms (FC I and II) is clinical treatmentClinical treatment is extrapolated from the clinical treatment for diastolic HF, beingbased on the following: diuretics to control blood volume; beta-blockers or calciumchannel blockers to control heart rate in patients with AF or atrial tachycardia; andvitamin K antagonists for patients with intracardiac thrombi.Our patient had indication for those drugs, including anticoagulation, because shealready had had a thromboembolic event in 2002.The surgical treatment consists in resecting the area of endocardial fibrosis and incorrecting mitral or tricuspid regurgitation, when present, with valvular replacement orrepair.The initial surgical technique consists in replacing the impaired valves withprostheses. Later studies have shown that valvoplasty with native valve preservationrelated to lower morbidity and mortality.13; thus, whenever possible, the native valve should bepreserved.The mortality related to classical surgery is extremely high, ranging from 20% to30%Surgery determines an important improvement in symptoms and survival in symptomaticpatients, and should always be performed in such patients.14 published astudy, assessing 83 patients submitted to surgery for EMF, 45% of whom had CHF, FC I andII, and found a 55% survival in 17 years.In 1999, Moraes et al14.Recurrence of valvular regurgitation after surgery is not rare, and many patients mightrequire a new surgery to fix the problem15, assessing 107 patientsundergoing surgery, have found a 4.5% incidence of fibrosis recurrence. The surgicalmortality related to reoperation in such cases was extremely high, reaching50%15.Moraes et al16.Considering the high mortality associated with reoperation, the best treatment for thatgroup remains uncertain. The heart transplantation team of the Instituto do Coração ofthe Hospital das Clínicas of FMUSP has reported the good outcome and survival of onepatient with EMF previously submitted to surgery, but with recurrence of disease andimportant symptoms of HF. The possibility that, for that group of patients, cardiactransplantation can be more beneficial than reoperation has been raisedIn 1996, our patient underwent surgery for the resection of the endomyocardial fibrosis,as well as mitral and tricuspid valvoplasty, because of important HF symptoms (FC III).Initially, her symptoms improved, which was confirmed on the ventriculography performedone month after surgery, showing competent valves and mild ventricular hypokinesia.A few years after surgery, the HF symptoms recurred and a new echocardiogram showedimportant tricuspid regurgitation. A new hemodynamic study was performed in 2005,showing hypertension of the right chambers and moderate left ventricular hypokinesia,raising the suspicion of disease relapse. On the occasion, clinical treatment waschosen, but performing some tests, such as cardiac magnetic resonance, could have helpedto establish the diagnosis of disease relapse.The presence of hypertension of the right chambers could be related to HF itself,pulmonary thromboembolism, chronic obstructive pulmonary disease or other causes,requiring further investigation.The patient's symptoms worsened and, on November 13, 2008, she sought the hospital withcardiogenic shock and important bradycardia, requiring transvenous pacemakerimplantation. That bradycardia could have been caused by the use of medications tocontrol heart rate, diltiazem and digoxin, because the fibrotic impairment of thecardiac conduction system is not common in EMF.Despite all hemodynamic support and initial improvement, the patient's renal functionworsened, raising the suspicion that her most likely cause of death was cardiogenicshock secondary to EMF relapse with valvular impairment.The retrospective analysis of this case raised doubt whether a new surgery or hearttransplantation in 2005, when the patient's CHF symptoms recurred, would have changedthe disease course.Further studies are required to help deciding on the best treatment for EMF relapse.Diagnostic hypothesis: Endomyocardial fibrosisThe heart weighed 652 g  and had multiple adherences between thevisceral and parietal pericardium. Its volume was enlarged, especially because of theatria, whose volume was proportionally greater than that of the ventricles . OpeningAnatomopathological diagnoses:1) Biventricular endomyocardial fibrosis, operated on; 2) Congestive heart failure; 3)Low cardiac output.17. The myocardialtrabeculae can be bound together due to endocardial thickening, which can involve thepapillary muscle, chordae tendineae and the cusps of the atrioventricular valves,causing valvular insufficiency. Although our patient had already undergone mitral andtricuspid valvoplasty, such valves still had morphological changes of insufficiency,such as valvular ring dilatation and retraction of the free margin of the cusps.Microscopically, EMF is represented by dense and collagen endocardial fibrosis, withfragmented and irregularly arranged elastic fibers, which affect the subjacentmyocardium, whose close regions have vascular neoformation and a variable amount oflymphoplasmacytic and mononuclear inflammatory infiltrate, with or withouteosinophils18. Although notalways present, eosinophils in endocardial lesions and peripheral eosinophilia, observedin different studies of individuals with EMF, have been reported as one of the probablecauses of that disease19, whoseetiopathogenesis remains to be clarified20. Several authors have proposed that the eosinophilic form, alsoknown as Loeffler's endocarditis, and EMF without eosinophils represent different stagesof the same disease, because the morphological endocardial changes in the chronic stagecannot be differentiated in the patients with and without eosinophilia22. This can be seen in our patient, who had eosinophils in neither theendocardial inflammatory infiltrate nor other organs. As EMF progresses, the formationand organization of endocardial thrombosis contribute to the obliteration and reductionof the ventricular cavity, and advanced cases frequently show calcification amid thefibrosis18. Usually, atrialdilatation results from the ventricular restriction caused by the endomyocardialfibrosis and the mitral and tricuspid valvular insufficiency, as well as from thepulmonary vascular changes secondary to passive pulmonary congestion, as reported in ourpatient. The healed renal infarctions were very likely caused by embolism from theprevious thrombosis in the left ventricle. It is worth noting the post-surgery 12-yearsurvival of our patient, considering the extension of the EMF lesions found on thepostmortem examination. The survival likelihood of patients with EMF submitted tosurgery is approximately 70% ten years after surgery24. Such lesions verylikely represent disease relapse, but the possibility that not all the tissue affectedby EMF had been removed in the previous surgery should be kept in mind.The cardiac lesions revealed on the postmortem examination describe the morphology ofbiventricular EMF. The major characteristic of EMF is the focal or diffuse thickendocardial fibrosis, which affects mainly the inlet and apical region of one or bothventriclesSection editor: Alfredo José Mansur(ajmansur@incor.usp.br)Associated editors: Desidério Favarato(dclfavarato@incor.usp.br)anpvera@incor.usp.br)Vera Demarchi Aiello (


Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients.Ninety-nine non-transfusion dependent thalassemia patients  years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined.The median NTBI value was 3.15  μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb.This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients. Thalassemia intermedia are mild forms of thalassemia and known as non-transfusion dependent thalassemia (NTDT) , 2. AnemIt has been shown that iron overload cardiomyopathy can be reversible only if early intensive chelation therapy has been initiated –13. OverFor decades, HRV has been used to evaluate cardiac autonomic function in patients with heart disease, including post-myocardial infarction –42, hearThe study protocol was approved by the Institutional Ethics Committee of the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. NTDT patients enrolled in this study were defined as having thalassemia and receiving no more than seven RBC transfusions per year in the last five years, with age ranged between 10–50 years, and did not have any infectious diseases or acute illnesses during the investigation. Exclusion criteria included patients with a contraindication to MRI, and clinical evidence of other secondary causes of pulmonary hypertension, including human immunodeficiency virus infection, hepatitis virus infection, collagen vascular diseases, cirrhosis, chronic obstructive airway diseases and acquired heart disease associated with pulmonary hypertension. All patients were treated at Chiang Mai University Hospital during September 2013 to May 2014. All patients and their parents in the case of minorities gave written informed consent.Patient charts were reviewed for thalassemia diagnosis and genotypes, transfusion history, history of splenectomy, details of drugs history, and comorbidities. The body weight, height and liver size were recorded in each patient. Laboratory profiles , maximum ferritin in the past 5 years, plasma NTBI, labile plasma iron (LPI)), echocardiography, 24-h Holter ECG recording for HRV analysis, CMR T2* were collected and analyzed at the time of entry. The correlation between HRV and NTBI, hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), CMR T2* were determined.2).The SEER Light Holter system  was used. An ECG was recorded continuously for 24 h. The computer software MARS software version 7, GE Healthcare, Milwaukee, WI, USA was used to scan for rhythm disturbance and to detect and label each QRS complex. Excessive noise and artifacts were noted, and ectopy was quantified. The time-domain analyses included average heart rate, average R-R intervals (NN), standard deviation of the R-R intervals over a 24-h period (SDNN), standard deviation of all 5-min mean R-R intervals (SDANN), average standard deviation of all 5-min R-R intervals (ASDNN), the percentage of R-R intervals with more than 50-ms variation (pNN50), and the square root of mean squared differences of successive R-R intervals (rMSSD). The frequency-domain analyses were done with the same analytical software using Fast-Fourier transform analysis. The obtained frequency-domain indices were the total power (0–0.4 Hz), high-frequency power  spectral density, low-frequency power  spectral density, and very-low-frequency power (0.003–0.04 Hz) spectral density. Total power expresses the magnitude of the entire HRV, whereas HF power reflects the parasympathetic tone, and LF power indicates the sympathovagal interactions. These pThe designated physician who operated and fitted the Holter monitor to the patients was blinded to the patients’ information. The subjects were fitted with the Holter monitor after blood sample collection at the Holter unit of the Faculty of Medicine, Chiang Mai University. In the present study, none of the included patients took medications such as beta-blockers, calcium channel blockers, statins, and ACE-inhibitors which could affect the HRV.Mean Hb and serum ferritin in the last 12 months, hematocrit (Hct), maximum ferritin in the past 5 years, plasma NTBI, labile plasma iron (LPI) were determined in each patient at the date of entry.C.T 5diff, Coulter Corp., Miami, FL, USA).Complete blood counts were performed using an automated hematological analyzer (Beckman Coulter AThe Roche Cobas E601 (Germany) Immunology Analyzer was used to determine serum ferritin using a sandwich principle. In the first incubation, a plasma sample of 10 μL, a biotinylated monoclonal ferritin-specific antibody, and a monoclonal ferritin-specific antibody labeled with a ruthenium complex formed a sandwich complex. In the second incubation, after addition of streptavidin-coated microparticles, the complex became bound to the solid phase via the interaction of biotin and streptavidin. The reaction mixture was aspirated into the measuring cell where the micro particles were magnetically captured onto the surface of the electrode. The unbound substance was then removed with ProCell/ProCell M. The application of a voltage to the electrode then induced chemiluminescent emission which was measured by a photomultiplier. Results were determined via a calibration curve which was specifically generated by a 2-point calibration and a master curve provided via the reagent barcode , 47.3+-(NTA)2. Then, the Fe3+-(NTA)2 was separated from plasma proteins by spinning plasma mixture through a membrane filter  at 12,000 g, 15°C for 45 min. The ultrafiltrate was injected into a non-metallic 50-μL loop and analyzed with the high performance liquid chromatography (HPLC) technique. HPLC requirements were composed of a glass analytical column  and a mobile-phase solvent (3 mM CP22 in 19% acetronitrile buffered with 5 mM MOPS pH 7.0). Having been isocratically eluted with the mobile-phase solvent at a flow rate of 1.0 mL/min, NTBI as Fe3+-(NTA)2 was fractionated on the column, then immediately on-column derivatized with CP22 to form a Fe3+-(CP22)3 complex. The resulting orange-colored Fe3+-(CP22)3 product was on-line detected at 450 nm with the SpecMonitor 2300 flow-cell detector . The NTBI peak height was integrated and recorded for further determination of NTBI concentration from the calibration curve. A calibration curve was produced by plotting the obtained peak height values on the y-axis against iron concentration on the x-axis. An equation of linear regression line was used to calculate the plasma NTBI concentration.Plasma NTBI was determined as described in the previous study . First, In principle, redox-active LPI converts dihydrorhodamine (DHR) to oxidized fluorescent rhodamine (R), leading to an increase in fluorescence intensity (FI) . A plasmThe standard two dimensional and Doppler trans-thoracic echocardiography was performed at rest in all enrolled patients with Philips iE33 . Left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) were measured, and left ventricular ejection fraction (LVEF), stroke volume, cardiac output, and fractional shortening (FS) were determined based on the calculation of LV volumes by the method of discs, following the recommendations by the American Society of Echocardiography (ASE), and using apical two- and four- chamber views to measure cardiac function , 51.Impaired systolic LV dysfunction (LVEF < 55% or LVFS < 35%) was also determined in NTDT patients. DiastolMagnetic resonance acquisition was performed using a 1.5T MR scanner , using an 8-channel body array. For the measurements of myocardial iron overload, we used a T2* gradient—echo multi-echo sequence . A single mid ventricular short-axis view of the left ventricle was acquired at eight echo times (TEs)  in a single end-expiratory breath-hold.Cardiac magnetic resonance (CMR) T2* analysis was performed on a workstation  using commercial analysis software . According to the previous study, the 95% confidence interval of normal CMR T2* value (>20ms) was assessed , 53. TheP value of less than 0.05 was considered statistically significant. Statistical analysis was performed with the use of SPSS version 13.0 for Windows . The receiver operative characteristic (ROC) curve was analyzed, and the binary logistic regression analysis, forward likelihood method, was also applied to determine the association between CMR T2* and HRV.Numerical data are presented as median  due to the skewed distribution of numerical data. Differences between splenectomized and non-splenectomized NTDT patients were performed using the parametric independent student T-test. CMR T2* was regarded as the gold standard diagnostic technique. The correlations between HRV and laboratory profiles, echocardiographic parameters, CMR T2* were determined using the Spearman's rank correlation. A One hundred patients were enrolled in this study. One patient was excluded since this patient refused the MRI investigation. Clinical and biochemical characteristics, echocardiographic parameters, CMR T2* values, and HRV of NTDT patients (n = 99) were summarized in P = 0.008 and 0.002, respectively). Moreover, the number of blood transfusions and serum ferritin in the last 12 months, maximum ferritin in the past 5 years, NTBI, and LPI were also significantly higher in the splenectomized group.In this study, the median CMR T2* was 43.95  ms which indicated that the NTDT patients have preserved CMR T2* values . The comparison of HRV between the splenectomized (n = 35) and non-splenectomized (n = 64) group was shown in the supplementary table . Time-doR = -0.227, P = 0.026).The correlations analysis between time and frequency domains of HRV and clinical and biochemical parameters was presented in NTBI, non-transferrin-bound iron; SDNN, standard deviation of all normal sinus R-R intervals in the entire 24-h recording; SDANN, standard deviation of all averaged normal sinus R-R intervals for all 5-min segment in the 24-h recordings; ASDNN, average of the standard deviations of all R-R intervals for all 5-min segments in the 24-h recordings; rMSSD, root mean square of the mean of the squared difference of two consecutive R-R intervals; LF, low frequency power; HF, high frequency power; LF/HF ratio, ratio of power in low/high frequency.P = 0.001), but not the mean Hb in the last 12 months significantly correlated with CMR T2*. Since there is only one NTDT patient in this study that had CMR T2* <20 ms, we could not use the same cut point to determine cardiac iron overload as shown previously in TDT patients [P = 0.08). However, the predicted area under the ROC curve of LF/HF was 0.684±0.063   .The major findings in this study are that the time-domain and frequency-domain of HRV parameters showed a significant correlation with the NTBI, mean Hb, serum ferritin, number of blood transfusions, and CMR T2*.HRV assessment is a technique that measures the beat-to-beat variability in the R-R intervals, which can imply the cardiac autonomic regulation. The decreased time-domain parameters or increased LF/HF ratio indicates there is a cardiac sympathovagal imbalance which is generally known as “depressed HRV” , 54. DepGrowing evidence from studies on thalassemic mice suggests that they had high NTBI levels and also had depressed HRV compared to the wild-type mice , 57, 58.It has been proposed that HRV may be used to indicate cardiac iron accumulation. Available data in animal studies supported this possibility by demonstrating that HRV showed a correlation with iron accumulation in the heart , 58. DesIn splenectomized patients, it has been shown that they had significantly higher serum ferritin, transferrin saturation, and desferrioxamine-induced urinary iron excretion (DFU) when compared to the non-splenectomized patients . In the One limitation of this study was the lack of a healthy control group or an additional group with a disease associated with cardiac iron overload, such as hereditary hemochromatosis. Although the inclusion of this latter group would allow us to differentiate whether the effects on HRV are specifically from iron overload, or from a combination of iron overload and anemia, hereditary hemochromatosis is extremely rare in our population, therefore the addition of this group is not possible for this study.Since most of the severity of cardiac iron overload of NTDT patients in this study were out with the traditional MRI cut-off for significant cardiac iron overload (CMR T2* > 20), we could not divide NTDT patients by a CMR T2* severity assessment. This study performed a cross-sectional study and could not take into account the morbidity and mortality prediction in this group of patients. Moreover, there was a significant female sex bias and the population was predominantly young adults. Both sex and age can influence HRV substantially and may limit the generalizability of the findings. Future prospective studies with long-term follow-up and larger sample are needed for this purpose.Early detection of iron overload cardiomyopathy to initiate early chelation therapy in thalassemia patients is a strategy to prevent cardiac complications and decrease the mortality rate. The findings of this study regarding the correlation between HRV and NTBI levels, and CMR T2* indicate that HRV could be a potential marker in identifying body free iron status as well as cardiac iron status in NTDT patients.S1 Table(DOC)Click here for additional data file.


This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline.Obesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics  may manifest prior to global changes in cardiac function . LV mechanics were quantified under baseline (resting) and/or stress conditions (40 μg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons.C57BL/6J mice were randomized to a high-fat or control diet  for varying time intervals  evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits.Differences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction.The online version of this article (doi:10.1186/s12968-015-0180-7) contains supplementary material, which is available to authorized users. Obesity is a highly prevalent disease , 2 that et al. found that fractional shortening and maximum time rates of pressure development (dP/dt) were no different between control and obese mice under baseline conditions, but the contractile response in the obese subjects was reduced with pharmacologic stress  was defined as the maximal slope of a linear regression of instantaneous, spatially averaged myocardial twist angles as a function of the distance between the three short-axis slices.Strains were quantified with the 2-dimensional Lagrangian finite strain tensor. For radial and circumferential strains (defined with respect to the LV center of mass), the three short-axis images were partitioned based on the standardized American Heart Association 16 segment model and a strain vs. time curve was calculated for each segment. A mean curve was defined by averaging these segment curves; the peak of the mean curve represents the peak strain reported. Peak longitudinal strain was similarly defined from the long-axis images and a defined coordinate system; however, the apical segments covering the bottom one-third of the ventricle were excluded from the analysis. Peak strain rates were calculated by taking positive and negative peaks of the first temporal derivative of the mean strain curve. All strains are reported as positive magnitudes to facilitate visual comparisons. Peak torsion [° · cmTo quantify left ventricular volumes, mass, and ejection fraction, the DENSE magnitude images were segmented at end-diastole  and end-systole. These contours were inputted to a custom 3-dimensional surface fitting algorithm  to calcue.g., linear) for that trend. For the longitudinal measurements in experiment 1, random effects were included to account for correlations among repeated measurements on the same specimen. The groups’ temporal trends were tested for equality; if this null hypothesis was rejected, then post-hoc tests were performed to compare the groups at various time points using a Benjamini-Hochberg adjustment for multiple comparisons. Some models were also fit with explanatory variables other than group . Version 9.3 of SAS software  was employed for these data analyses. T-tests were used, as indicated, for select individual comparisons. Pearson correlation coefficients were computed to report associations between peak strain and other obesity co-morbidities. The significance level was set to 0.05.Blood pressure, glucose tolerance, and body composition results were interpolated to be defined at the same time points as the CMR-derived outcome variables. Linear mixed models were then fit to relate outcome variables to time and group, allowing each group to have its own temporal trend and not assuming a specific parametric form .Conscious systolic blood pressure measurements via tail cuff yielded a passing result for each mouse at each measurement week. The data Fig.  displayep < 0.0001 overall for both measures) throughout the study from the earliest evaluation. Separate experiments at week 3 .Measures of glucose regulation, both with respect to fasting glucose levels Fig.  and the Finally, three subjects from the obese group died during the study , compared to zero in the control group. The causes of mortality could not be determined.Figure There were no statistically significant differences in peak strain rates (systolic or diastolic) or peak torsion between groups over time , there was a statistically significant (p < 0.001) and progressive decline in circumferential strain rates for the obese mice at peak stress over time. Post-hoc analysis revealed that these differences were significant from 22 weeks onward, while there was a trend (p = 0.09) towards a separation as early as 16 weeks on diet. Similar trends were observed with respect to radial systolic strain rates at peak stress ; however, there was a significant difference in torsion at stress between groups over time  with DENSE CMR, we did see altered systolic function in the obese mice. At baseline, this dysfunction was characterized by decreased longitudinal strain after 42 weeks on diet; however, at peak stress, changes in strains, strain rates, and torsion were all apparent, with dysfunction present by several measures after 22 weeks on diet. So even though baseline ejection fraction was normal, systolic dysfunction was still present with obesity, which is consistent with what has been reported in humans . Since c2-adrenergic receptors may play a primary role in this blunted response [The use of dobutamine stress in this study produced several meaningful insights as compared to the knowledge gained solely from evaluations at baseline. First, cardiac dysfunction was exacerbated with stress. While temporal differences in peak strains were observed at baseline, stress scanning additionally uncovered differences/deficiencies in systolic strain rates and torsion. In both of those cases, these differences appear to be the result of a loss of contractile reserve function in the obese group over time, as they were no longer able to increase strain rate or torsion with stress to the elevated level of the controls. Inhibitory interactions of insulin with the cardiac βresponse . These cresponse . Additioresponse , 36, 44.response , taking response  and torsresponse , 46 comp2 adrenergic receptors in the heart has already been noted [Fasting glucose levels and peripheral glucose clearance (AUC) were significantly altered (higher) in the obese group, indicative of glucose intolerance. These changes occurred very acutely after introduction of the diet, as early as 3 weeks, and these differences persisted and expanded during the course of the study. Prior studies have similarly reported acute changes in glucose tolerance . The conen noted . Additioen noted . Here, wUsing tail cuff measurements, no significant differences in systolic blood pressure were observed, so we could not reliably evaluate the association of blood pressure and cardiac mechanics in these mice. Previous studies using more sensitive telemetry measures of blood pressure observed differences in male mice at 16 weeks of high-fat feeding , so it iMyocardial mass was significantly elevated in the obese group beginning at 16 weeks on the diet, which is temporally consistent with presence of elevated blood pressure via telemetry . This veFigure The inter-test and inter-observer variability characteristics for DENSE-derived measures of strain, torsion, and synchrony in mice have been previously reported . The DENThis study was conducted in mice, so the relevance of our findings with respect to changes in cardiac mechanics in obese humans, and particularly the relevant timing of the development of dysfunction, needs to be established. However, CMR can be acquired in both humans and mice, so there is a rare ability with this experimental protocol to make comparable measurements in human subjects and directly compare findings. Furthermore, elucidating the time course of dysfunction in a mouse model is important for future studies seeking to evaluate the effectiveness of clinically relevant treatment strategies for reversing this dysfunction in mice at meaningful time points.Some of the mice used for these experiments were purchased through Jackson Laboratory’s Diet-Induced Obesity preconditioning service, which created some discrepancies in age and low-fat control diets. Specifically, mouse ‘cohorts’ 3–5 were purchased through the preconditioning service and were thus started on the diet at 6 weeks of age and the control diet was not sucrose-matched to the high-fat diet. Conversely, ‘cohorts’ 1–2 were started on their respective diets at 3 weeks of age and the control diet was sucrose-matched to the high-fat diet. Despite this variation, little, if any, differences were observed in the results between experiment 1 and baseline data acquired in experiment 2 (prior to the infusion of dobutamine) for weeks 4–16. Furthermore, the primary study findings were all based on data collected at or after 22 weeks on diet, at which point the ages and low-fat diets were consistent between experiments. Therefore, these differences had minimal effect on the study conclusions.Finally, blood pressure data were collected using a tail cuff measurement, which has known limitations for detecting subtle differences in systolic pressure. Therefore, no quantitative comparison of pressure data to cardiac mechanics is presented here, even though increased afterload would be expected to affect cardiac function. Future studies should determine if pharmacologic treatment of hypertension in this model has beneficial effects with regard to altered cardiac mechanics as well.Diet-induced obesity in mice through one year of high-fat feeding results in increased left ventricular mass and altered left ventricular mechanics, but no significant change in left ventricular ejection fraction. These functional deficiencies in obesity were accentuated with pharmacologic stress, which revealed reduced peak strains, strain rates, and torsion of the left ventricle. Furthermore, these changes in mechanics were revealed at earlier stages of disease progression under stress conditions than at baseline. Along with quantification of ventricular mass, changes in mechanics may carry prognostic significance for adverse cardiovascular outcomes related to obesity—further study is needed to explore these links. Under both baseline and stress conditions, reduced peak longitudinal strain was a strong discriminator between obese and controls subjects. Therefore clinical evaluations of left ventricular function in obesity should quantify cardiac mechanics , particularly peak longitudinal strain, and may also benefit from stress imaging to better identify early signs of dysfunction.


Myocardial hyperintensity on T2-weighted short-tau inversion recovery (STIR) (HyT2) cardiac magnetic resonance (CMR) images has been demonstrated in patients with hypertrophic cardiomyopathy (HCM) and is considered a sign of acute damage. The aim of the current study was to evaluate the relationship between HyT2 and both a) markers of ventricular electrical instability and b) clinical and CMR parameters.Sixty-five patients underwent a thorough clinical examination, consisting of 24-h ECG recording and CMR examination including functional evaluation, T2-STIR images and late gadolinium enhancement (LGE).HyT2 was detected in 27 patients (42%), and subjects with HyT2 showed a greater left ventricle (LV) mass index (p<0.001), lower LV ejection fraction (p = 0.05) and greater extent of LGE (p<0.001) compared to those without HyT2. Twenty-two subjects (34%) presented non-sustained ventricular tachycardia (NSVT) on the 24-h ECG recording, 21 (95%) of whom exhibited HyT2. Based on the logistic regression analysis, HyT2  and LGE extent  served as independent predictors of NSVT, while the presence of LGE was not associated with NSVT occurrence (p = 0.49). The presence of HyT2 was associated with lower heart rate variability (p = 0.006) and a higher number of arrhythmic risk factors (p<0.001).In HCM patients, HyT2 upon CMR examination is associated with more advanced disease and increased arrhythmic burden. The prevention of sudden cardiac death is the most relevant challenge in patients with hypertrophic cardiomyopathy (HCM) Myocardial hyperintensity upon CMR T2-weighted short-tau inversion recovery (STIR) imaging (HyT2) is a sign of edema that is secondary to acute ischemic or inflammatory damage We enrolled 69 consecutive patients with HCM based on previously reported criteria undergoing a CMR examination. Three patients were excluded for low-quality images, and 1 was excluded for claustrophobia. Thus, the final population consisted of 65 patients . The study was approved by the Ethical Committee of Fondazione G.Monasterio-Pisa. All the patients received and signed informed consent.The presence of established risk factors for sudden death in patients with HCM were evaluated, including a family history of sudden death, extreme LV wall thickness (>30 mm), unexplained syncope, non-sustained ventricular tachycardia on an ambulatory Holter ECG recording (>3 ventricular beats at a heart rate >120 beats per min), and an abnormal or “flat” systolic arterial pressure during an exercise stress test Patients also underwent a 24-h ECG recording around the time of CMR examination. Conventional ECG analysis was performed, including the following heart rate variability measurements in the time-domain analysis: standard deviation (SD) of the RR intervals, SD of the average normal to normal QRS (NN) interval calculated over periods of 5 min (SDANN), the number of interval differences of successive NN intervals >50 msec divided by the total number of NN intervals (pNN50), and the square root of the mean squared differences of successive NN intervals (RMSSD) CMR was performed using two 1.5 Tesla systems: a Signa Hdx  and a 1.5 Tesla Magnetom Avanto  with cardiac phased array multichannel coils.Short axis cine images from the mitral plane valve to the LV apex were acquired using a steady-state free precession pulse sequence with the following parameters: 30 phases, slice thickness 8 mm, no gap, views per segment 8, NEX 1, FOV 40 cm, phase FOV 1, matrix 224×224, reconstruction matrix 256×256, 45° flip angle, and a TR/TE equal to 3.5/1.5.T2-STIR images were acquired using triple inversion recovery T2-weighted pulse sequence in short axis views and 2 long axis views  using the following parameters: TR = 2 RR, TE ≈ 70 msec, FOV 40 cm, phase FOV 1, matrix 256×256. LGE images were acquired 10 min after the administration of Gd-DTPA  with a dosage of 0.2 mmol/kg for the short axis views. An inversion recovery T1-weighted gradient- echo (GRE) sequence was used with the following parameters: field of view 40 mm, slice thickness 8 mm, no gap between each slice, repetition time 4.6 msec, echo time 1.3, a flip angle of 20°, matrix 224×224, reconstruction matrix 256×256, and an excitation number of 1. The appropriate inversion time was set to null for normal myocardium (range 250–300 msec).A commercially available research software package  was used to quantify the functional parameters using conventional methods T2-STIR images were evaluated using a qualitative visual assessment performed by three expert independent investigators who were blinded to each other’s results. The presence of signal abnormalities (HyT2) was established when there was agreement between at least two investigators. Agreement among the three investigators was reached when analyzing the images of 95% patients.The extent of LGE was measured using a previously validated method Categorical variables were compared using Pearson’s chi-squared test with the continuity correction or Fisher's exact test when appropriate. The Kolmogorov-Smirnov test was used to assess the normality of the data. Pearson’s (r) and Spearman’s (ρ) correlation coefficients were employed for Gaussian and skewed variables, respectively. One-way analysis of variance (ANOVA) and Kruskal-Wallis test, when appropriate, were employed to compare quantitative variables between groups. Logistic regression analysis was used to explore the impact of each variable in a model, with NSVT upon 24-h Holter ECG monitoring as the dependent variable and myocardial abnormalities on T2-STIR, LGE extent, LV mass index, maximal end-diastolic wall thickness, and number of arrhythmic risk factors (excluding NSVT) as independent variables.A p-value <0.05 was considered statistically significant. Data are presented as continuous variables and proportions (percentages). Continuous variables are expressed as the mean ± SD or the median and interquartile range (IQR), as indicated.The clinical characteristics of the HCM population are reported in Twenty-two subjects (34%) presented with non-sustained ventricular tachycardia on the 24-h ECG recording, 11 (17%) had a family history of sudden death, and 8 (12%) showed a maximal end-diastolic wall thickness ≥30 mm, while none had a significant blood pressure drop during exercise. Thirty-six patients (55%) had no risk factors for sudden death, 18 (28%) presented one risk factor, and 11 (17%) patients had an arrhythmic risk score ≥2.A summary of the CMR results is reported in LGE was present in 55 patients (84%). Patients with LGE had greater end-diastolic wall thickness (p = 0.05), and a linear relationship was found between the extent of LGE and the LV mass index .On T2-STIR images, HyT2 was detected in 27 patients (42%), with no sex (p = 0.62) or age (p = 0.10) differences . The relDuring the 24-h ECG, 22 patients (27%) had episodes of NSVT. As shown in Together, our findings led to the following conclusions: 1) HyT2 was associated with signs of advanced disease, i.e., higher LV mass index, lower ejection fraction and greater LGE extent; 2) HyT2 was associated with a higher arrhythmic risk score, markers of arrhythmic burden (NSVT) and autonomic impairment (decreased heart rate variability), as shown by 24-h ECG recordings; and 3) HyT2 was the best predictor of NSVT among all CMR-derived and clinical parameters. These results suggest that the presence of myocardial edema, which was identified by HyT2 in HCM patients, is linked to disease progression and arrhythmogenesis.HyT2 was detected in 95% of patients with NSVT during the 24-h ECG recording. Indeed, NSVT detection is considered a relevant arrhythmic risk marker in patients with HCM as well as ischemic and non-ischemic cardiomyopathies Although HyT2 is a sign of myocardial edema on CMR, this relationship remains incompletely understood In our HCM patients, HyT2 was located in the midwall of hypertrophic myocardial segments and was localized with or without LGE. Previously, Melacini et al. hypothesized that these T2 abnormalities in HCM could be attributed to ischemia caused by microvascular dysfunction, impaired diastolic relaxation, mismatch between capillary density, myocardial tissue interstitial fibrosis and/or myocardial bridging The hypothesis that microvascular disease and ischemia result in HyT2 is strongly supported by the observation that the area of HyT2 closely matched the region of hypoperfusion based on the first-pass gadolinium CMR technique The presence of LGE in patients with HCM may be considered relevant in terms of risk stratification, as recent reports have demonstrated that after a clinical follow-up of 3 years, patients with LGE had a worse prognoses than those without Some limitations of the current study should be mentioned. First, HyT2 may be detected in conditions other than ischemia and inflammation, and the results of the current study did not allow us to understand the nature and etiology of HyT2 in HCM. Additionally, the mechanism underlying the association between HyT2 and ventricular arrhythmias remains unclear. Second, we assumed that HyT2 in HCM is a sign of acute, transient myocardial damage, although this assumption was based only on the observation of HyT2 in other cardiac diseases. Thus, further studies with serial CMR examinations should be performed to confirm the reversibility of HyT2 and the prognostic role of HyT2 in larger HCM populations.In conclusion, in patients with HCM, the presence of HyT2 upon CMR examination is associated with more advanced disease, ventricular arrhythmias and signs of electrical instability. HyT2 was detected in 42% of patients with HCM, and it was the best predictor of NSVT during a 24-h Holter ECG recording. HyT2 was associated with decreased heart rate variability and a greater number of arrhythmic risk factors.


Measurement of mitral annulus (MA) dynamics is an important component of the evaluation of left ventricular (LV) diastolic function; MA velocities are commonly measured using tissue Doppler imaging (TDI). This study aimed to examine the clinical potential of a semi-automated cardiovascular magnetic resonance (CMR) technique for quantifying global LV diastolic function, using 3D volume tracking of the MA with conventional cine-CMR images.E) and atrial systole (PSRA), PSRE/PSRA ratio, deceleration time of sweep volume (DTSV), and 50% diastolic sweep volume recovery time (DSVRT50); these were compared with TTE diastolic measurements.124 consecutive patients with normal ejection fraction underwent both clinically indicated transthoracic echocardiography (TTE) and CMR within 2 months. Interpolated 3D reconstruction of the MA over time was performed with semi-automated atrioventricular junction (AVJ) tracking in long-axis cine-CMR images, producing an MA sweep volume over the cardiac cycle. CMR-based diastolic function was evaluated, using the following parameters: peak volume sweep rates in early diastole (PSRE (5.25 ± 1.38 s−1 vs. 7.72 ± 1.7 s−1), a higher PSRA (6.56 ± 1.99 s−1 vs. 4.67 ± 1.38 s−1), a lower PSRE/PSRA ratio (0.9 ± 0.44 vs. 1.82 ± 0.69), a longer DTSV (144 ± 55 ms vs. 96 ± 37 ms), and a longer DSVRT50 (25.0 ± 11.0% vs. 15.6 ± 4.0%) . CMR diastolic parameters were independent predictors of TTE-based diastolic dysfunction after adjusting for left ventricular hypertrophy, hypertension, and coronary artery disease. Good correlations were observed between CMR PSRE/PSRA and early-to-late diastolic annular velocity ratios (e′/a′) measured by TDI .Patients with TTE-based diastolic dysfunction (n = 62) showed significantly different normalized MA sweep volume profiles compared to those with TTE-based normal diastolic function (n = 62), including a lower PSR3D MA sweep volumes generated by semi-automated AVJ tracking in routinely acquired CMR images yielded diastolic parameters that were effective in identifying patients with diastolic dysfunction when correlated with TTE-based variables. Left ventricular (LV) diastolic dysfunction refers to mechanical abnormalities that impede effective volume filling during diastole. This is the main mechanism of heart failure with preserved ejection fraction (HFPEF), which accounts for up to 50% of overall cases of heart failure . DespiteTransthoracic echocardiography (TTE) is currently the standard method used in the noninvasive evaluation of diastolic function. Commonly, pulsed-wave Doppler of transmitral flow (TMF) is used, with pulmonary venous flow (PVF) and tissue Doppler imaging (TDI), to assess myocardial relaxation and filling pressures. However, TTE measurements have limitations, due to variability in sampling locations and ultrasound beam alignment . In partCardiovascular magnetic resonance (CMR) has emerged as a promising alternative modality for quantifying diastolic dysfunction . CMR's gMitral annular (MA) dynamics has been previously studied with various methods -18; howeThe research protocol was approved by the local Institutional Review Board. Study subjects were identified from retrospectively reviewed clinical data of all consecutive patients who underwent both clinically indicated TTE and CMR at New York University Langone Medical Center between June 2011 and December 2013. Inclusion criteria were: (1) cine-CMR performed within 2 months of TTE, (2) TTE included assessment of diastolic function, and (3) normal LV systolic function on both CMR and TTE (EF > 50%). Patients were excluded for: (1) incomplete CMR images for MA reconstruction, (2) poor CMR image quality due to arrhythmias , or (3) sinus tachycardia that rendered interpretation of the cardiac phases difficult . Clinica2. Abnormal LA dilatation was defined as LA volume index ≥ 29 mL/m2 [Study subjects were divided into normal diastolic function and diastolic dysfunction groups, using TDI velocities as reference. According to echocardiography guidelines ,21, dias29 mL/m2 .TTE was performed using conventional equipment: Philips iE33 , General Electric Vivid 7 , or Siemens SC2000 . Standard apical and parasternal views were obtained. Function and dimensional measurements were performed according to accepted guidelines . TMF velConventional cine-CMR (2D steady state free precession pulse sequence) was performed using 1.5 or 3 T MRI systems  with a 6-element phased array anterior receiver coil, as part of routine clinical protocol. Cine images were acquired in multiplanar short-and long-axis views with retrospective electrocardiographic gating. Cine short-axis views were used for routine evaluation of global cardiac function. Typical imaging parameters were as follows: TR/TE = 2.4/1.4 ms, temporal resolution = 37–63 ms, in-plane spatial resolution = 1.4 mm × 1.4 mm - 1.8 mm × 1.8 mm, flip angle = 51°, slice thickness = 6 mm, receiver bandwidth = 930 Hz/pixel, and 25 reconstructed phases per cardiac cycle.The atrioventricular junction (AVJ), the septal and lateral junction between the left atrium and ventricle, was tracked in two-, three-, and four-chamber long-axis CMR views over the cardiac cycle . This waIn this calculated correlation map, the location of the maximum-intensity pixel indicates the best corresponding location of the initial template feature in the new ROI, which is thus taken as the AVJ location in phase 2 Figure C. This nn) was then generated for each cardiac phase tn, using the MA areas at tn-1 and tn, and the 3D distance (positive or negative) through which the MA traversed . Note that PSRE/PSRA is analogous to the e′/a′ ratio used in TDI.The resultant MA sweep volume curve was manually divided into its corresponding cardiac cycle intervals according to transitions in its slope: systole, early diastole (ED), mid-diastole (MD), and atrial systole (AS) Figure . In addiSV), measured from ED onset to the time of PSRE; (2) deceleration time (DTSV), measured by linear extrapolation of PSRE to baseline; and (3) 50% diastolic sweep volume recovery (DSVRT50), defined as the time required in diastole for the MA to recover 50% of its end systolic sweep volume ; this index had been introduced in a prior study to describe CMR LV volume filling [Three time-interval parameters were selected to characterize diastolic function from the sweep volumes: (1) acceleration time . Continuous variables were presented as mean ± SD, whereas categorical data were presented as frequencies with percentages. Differences between groups were evaluated using either the Student t-test for normally distributed data, or the Mann–Whitney U-test for asymmetrically distributed data; Shapiro-Wilk test was used to assess normality of distributions. Fisher's exact test was used to compare differences in categorical data. In addition, the association between CMR- and TTE-based parameters was assessed using the Spearman's rank correlation test. For classification performance, receiver operating characteristic (ROC) analyses were used to evaluate the ability of CMR parameters to identify patients with TTE-based diastolic dysfunction. Optimal cutoff values for these parameters were obtained, along with their associated sensitivity and specificity. Multivariate logistic regression was used to determine the predictive ability of CMR parameters with respect to TTE-based outcomes, after controlling for age, HTN, left ventricular hypertrophy (LVH), and CAD status. A two-tailed value of p < 0.05 was considered statistically significant.Intraobserver and interobserver variability were evaluated for 10 randomly selected subjects using intraclass correlation coefficients (ICC), Bland-Altman analyses, and Pearson's r correlation coefficients. For interobserver variability assessment, analyses were performed by two independent CMR readers who were blinded to TTE and each other's results. For intraobserver variability assessment, analyses were performed by one user who re-analyzed the same 10 subjects after a 3 week interval.A total of 124 consecutive subjects met the selection criteria and were included in the study. The time difference between the dates of CMR and TTE was 16 ± 16 days. Based on TTE findings, subjects were classified as either having normal diastolic function (n = 62) or diastolic dysfunction (n = 62).Table Our CMR method successfully generated MA sweep volume curves for all subjects in the study. The approximate processing time for each case was less than 3 minutes. The processing included the initial user delineation of AVJ points, review and possible correction of semi-automated tracking results, MA reconstruction in 3D, and the identification of cardiac intervals within the sweep volume curve. Manual corrections of AVJ locations were primarily necessary in images with blurring artifacts affecting the regions of interest. Approximately 30% of cine image series required at least one manual correction. Cases that did not require manual correction were analyzed in under 1 minute.50. Furthermore, the derivative curve provides a visual representation of the normalized MA sweep rate at each cardiac interval. In normal diastolic function, there was typically a higher MA sweep rate during early diastole that was accompanied by a relatively lower sweep rate during atrial systole; this was reversed in diastolic dysfunction. In these cases, peak MA sweep rates (PSRE and PSRA) on CMR were in qualitative relative agreement with the echocardiographically-derived early (e′) and late (a′) TDI annular velocity profiles . The diastolic dysfunction group also had a lower PSRE/PSRA ratio , due to their relatively higher peak sweep rate in atrial systole. During early diastole, the MA of hearts with diastolic dysfunction recovered a smaller proportion of their end systolic sweep volume , and their MA sweep volume constituted a smaller percentage of their stroke volume . Diastolic dysfunction was also differentiated by its longer DTSV  and longer DSVRT50 .Table E/PSRA and echo septal e′/a′ , the correlation between PSRE/PSRA and lateral e′/a′ was even stronger . The strongest correlation, however, was seen between PSRE/PSRA and the average e′/a′ of septal and lateral positions .Figure E and PSRE/PSRA ratio demonstrated excellent classification power (both AUC = 0.88), as did DTSV (AUC = 0.83) and DSVRT50 (AUC = 0.79). The optimal cutoff value for PSRE was 6.7 s−1, with a sensitivity of 89% and specificity of 74%; the optimal cutoff for PSRE/PSRA was 1.17, with a sensitivity of 84% and specificity of 81%. In comparison, DTSV and DSVRT50 exhibited slightly lower accuracies, with optimal cutoffs at 101 ms and 19.45%, respectively. A recovery threshold of 50% of end-systolic sweep volume was chosen for the parameter DSVRT50 because this generated the best classification performance compared to other recovery thresholds .Table E, PSRE/PSRA, and DSVRT50 were significant independent predictors of TTE-based diastolic dysfunction after controlling for age, HTN, LVH, and CAD status (Table SV was near significant as an independent predictor with an odds ratio of 1.12 per 10 ms increment (p = 0.077). In addition, PSRE/PSRA had an odds ratio of 0.86 per 0.1 increment (p = 0.016), whereas PSRE and DSVRT50 had odds ratios of 0.54 (p = 0.007) and 1.14 (p = 0.013), respectively.Multivariate logistic regression analysis demonstrated that PSRus Table . DTSV waE and PSRE/PSRA showed an improved AUC of 0.895 in predicting TTE-based diastolic dysfunction. When adding in DTSV and DSVRT50, the AUC improved slightly to 0.896. The latter model with all four parameters was used to demonstrate the prevalence of CMR-based diastolic dysfunction in a number of important clinical conditions in our sample population  between two images, as a function of pixel position . AssuminE/PSRA ratios. Likewise, prior echocardiographic studies have reported the analogous phenomenon of TDI e′/a′ MA velocity reversal in diastolic dysfunction [E and PSRE/PSRA improved performance in identifying patients with TTE-based diastolic dysfunction. The ability to characterize atrial systole with our methods is an advantage compared to techniques such as MR tagging, which cannot reliably produce late diastolic strain rates because of fading signal intensities due to T1 relaxation [Our results showed that patients with TTE-based diastolic dysfunction had lower normalized peak and average MA sweep rates in early diastole, resulting in the reversal of PSRfunction ,29. The function . Based olaxation .MA sweep mechanics were reported here in terms of "percentage sweep volume recovery". This index showed that patients with normal diastolic function recovered nearly 70% of the end-systolic sweep volume by the end of early diastole, or 10.6 mL in absolute volume, but patients with diastolic dysfunction only recovered 54%, or 6.8 mL. These findings were in rough overall agreement with a prior study that reported an average MA excursion volume of 6 mL in nine healthy subjects . HoweverSV (144 ± 55 ms) compared to the normal diastolic function group (96 ± 37 ms). ATSV was slightly longer in the diastolic dysfunction group, but the difference was not significant. Both findings were consistent with a published TDI study that examined acceleration and deceleration times pertaining to MA velocities  [We also investigated the time intervals of the MA sweep volume. The results showed that patients with TTE-based diastolic dysfunction had significantly longer DT 168 ms) .50 was an additional CMR diastolic function parameter, which measured the time needed for the MA to recover 50% of its end systolic sweep volume, adjusted for R-R interval. On average, longer DSVRT50 times were observed in patients with TTE-based diastolic dysfunction. This parameter was analogous to an index used in a prior study named "diastolic volume recovery" [E, PSRE/PSRA, and DSVRT50 each independently predicted TTE-based diastolic dysfunction after controlling for age, LVH, HTN, and CAD.DSVRTecovery" , which aClinically, the study demonstrated that patients with HTN, LVH, and CAD had increased prevalence of CMR-based diastolic dysfunction. Among the LVH subgroup, a large percentage (20/23 patients) was also diagnosed with hypertrophic cardiomyopathy. Similar results regarding these clinical subgroups have been reported in the past . In geneE/PSRA correlated better with the average TDI e′/a′, compared to single-site measurements, thereby supporting the hypothesis that the proposed method inherently better characterizes global LV function. It is interesting to note that CMR PSRE/PSRA correlated better with lateral TDI e′/a′ than it did with septal e′/a′. This finding is consistent with studies showing that, among single site measurements, lateral TDI velocities have the best correlations with global LV filling pressures and invasive indices of LV compliance [The MA shape was reconstructed in 3D with six imaged AVJ points, derived from three standard LV long-axis planes situated approximately 60 degrees apart in space. By accounting for MA 3D motion in its entirety, in both transverse and longitudinal directions, the proposed method was hypothesized to be a better representation of global diastolic function than TDI, which only measures longitudinal motion. Typically in TDI, longitudinal velocities are measured regionally at the septal and lateral sides of the MA. However, prior studies have reported significant regional variability in LV myocardial velocities . Specifimpliance .The CMR-derived MA sweep volume was found here to effectively characterize global diastolic function. Prior echocardiography studies have demonstrated that MA excursion volume plays an important role in LV function ,38. In aThere were some limitations in our study design. First, this was a retrospective investigation and most patients did not have their imaging studies performed on the same day. Although the subjects were in stable clinical condition between studies, changes in cardiac function between studies were possible. This may explain some discrepancy in diastolic function as identified by CMR and TTE. Other potential reasons for discrepancy include differences in temporal resolution between the methods, as well as sampling location, where regional dysfunction identified by TDI may not correspond with global dysfunction as assessed by MA sweep volume , or viceThere are also several limitations of the proposed technique. First, the three long-axis images used to reconstruct the MA were acquired at similar, but different, points in time, e.g., with potential differences in respiratory excursion. Second, the accuracy of NCC feature-tracking can be affected by image scaling, rotation, and distortion ; as withFuture studies involving a larger cohort with assessment of the prognostic utility of the information may offer further evaluation of the potential clinical utility of CMR-derived 3D MA sweep volume as a technique for evaluation of diastolic dysfunction. A larger population could also allow stratification of the different diastolic dysfunction stages. In addition, there may be particular value in applying the technique in evaluating specific patient groups with potential ventricular dysfunction, such as athletes, patients with hypertrophic, dilated, or restrictive cardiomyopathies, or patients undergoing anthracycline therapy.3D MA sweep volumes generated by semi-automated AVJ tracking in routinely acquired CMR images demonstrated diastolic parameters that were effective in identifying patients with TTE-based diastolic dysfunction. These parameters also correlated well with TDI MA velocities, and may serve as a useful tool for characterizing patients with diastolic dysfunction.


T2 star (T2*)-weighted MR imaging can be utilized to semi-quantitatively analyze tissue iron content. Excessive cardiac iron may aggravate cardiac performance, however, little is known about the T2* signal intensity in myopathic heart. We analyzed T2* signal intensity in primary and secondary cardiomyopathy.We enrolled 11 non-cardiomyopathic and 93 cardiomyopathic patients with following diagnoses: hypertensive or hypertrophic cardiomyopathy (n=22), dilated cardiomyopathy (n=28), sarcoidosis (n=13), old myocardial infarction (n=7), and other form of cardiomyopathy (n=23). Using 3-Teslar cardiac MRI , T2* signal intensity in the cardiac ventricular septum and hepatic parenchyma were measured.Compared with the cardiac T2* values in non-cardiomyopathic group (25.7±5.7 msec), those in hypertrophic cardiomyopathy or hypertensive cardiomyopathy (24.6±7.9 msec) did not differ significantly, however, those in the dilated cardiomyopathy  and sarcoidosis  were significantly lower. On the other hand, liver T2* values, as well as serum ferritin and iron concentrations, in patients with dilated cardiomyopathy or those with sarcoidosis did not differ those in the non-cardiomyopathic group.Cardiac T2* signal intensity was lower in the heart of dilated cardiomyopathy and sarcoidosis. Whether excessive iron in these forms of cardiomyopathy aggravates cardiac performance through generating noxious reactive oxygen species needs further investigation.N/A.


Pre-contrast T1-mapping and Late Gadolinium Enhancement (LGE) imaging offer a detailed characterization of the infarcted myocardium and its severity after acute myocardial infarction (AMI). However, the influence of T2*-effects in infarcts with microvascular injury (MVI) on local T1-mapping values has not yet been elucidated. We evaluate the effect of T2*-decay on T1-relaxation times in the infarcted myocardium in patients after AMI.Forty-three patients after AMI, treated with successful primary percutaneous coronary intervention, underwent CMR at 4 (3-5) days, for cine imaging, pre-contrast T1-mapping and T2*-mapping, and LGE. MVI was defined as a contrast-devoid area in the core of the infarcted, hyperenhanced myocardium on the LGE images. T1- and T2*-mapping was performed in short-axis orientation at the level of the infarcted area. T1- and T2*- relaxation time values were determined in a region of interest (ROI) in [1] the core of the infarcted myocardium within the hyperenhanced region incorporating any area with MVI when present, [2] the border zone within the hyperenhanced myocardium but outside any areas of MVI, and [3] remote myocardium without hyperenhancement. Left ventricular volumes and ejection fraction (LVEF) were derived from the cine images and infarct size was determined on the LGE images. Normal distribution of relaxation times was achieved by log-transformation.Twenty of the 43 patients (47%) had MVI. Infarct cores with MVI had significantly lower T1-values  and lower T2*-values  than infarct cores without MVI. Border zone T2*-values did not differ between patients with and without MVI; however, border zone T1-values were significantly longer in patients with MVI than in patients without MVI . As would be expected, remote T1-values did not differ between patients with and without MVI . A significant correlation was found between T2*-values and LVEF , and between T2*-values and infarct size . For T1-values, however, these relations did not exist.Patients with reperfused AMI have shorter T1- and T2*-relaxation times in the infarct core when MVI is present. In the adjacent border zone, T1-relaxation times are longer in patients with MVI. This has important implications for the interpretation of pre-contrast T1-mapping values shortly after AMI.No disclosures need to be made.


Global longitudinal strain and mitral annular plane systolic excursion (MAPSE) have been validated as an echocardiographic measure of longitudinal function in patients with aortic stenosis (AS). Cardiac magnetic resonance imaging (CMR) offers a simple and easy measure of MAPSE and been validated in various patient groups. Longitudinal function in aortic stenosis is usually reduced before a reduction in ejection fraction is seen. We sought to investigate the impact of TAVI upon longitudinal function and global ejection fraction in patients treated for symptomatic severe AS.We prospectively enrolled 52 patients with symptomatic severe aortic stenosis undergoing TAVI over a 5 year period from March 2009 to March 2014. Patients with contraindications to CMR were excluded and all patients provided informed written consent. All patients underwent an identical 1.5T CMR protocol  at baseline and at a median of 6 months following TAVR. Multi-slice, multi-phase cine imaging was performed using a standard steady-state free procession pulse sequence in the short and long axis  340 mm) to cover the entire left and right ventricle. Longitudinal atrioventricular motion was measured at the septal and lateral mitral annulus in the 4 chamber cine view  were studied. There was no significant change in the overall LV ejection fraction 6 months following TAVI compared to baseline. All three measures of longitudinal function  were significantly improved 6 months following TAVI . Presence or absence of late gadolinium enhancement did not impact on the baseline MAPSEaverage  or have impact on the change in MAPSEaverage following TAVI .52 patients  male, AVA 0.6 ± 0.2 cmLongitudinal left ventricular function, as assessed using MAPSE, improved following TAVI for severe aortic stenosis. MAPSE may be a more sensitive marker of left ventricular recovery following TAVI than global LV ejection fraction.This study was part funded by the British Heart Foundation (PG/11/126/29321).


Using breath-held cardiac magnetic resonance T2 mapping at 1.5T, Usman et al. (CircCardiovascImaging2012) detected moderate allograft rejection . With modern immunosuppression grade 2R rejection has become a rare event, but the need remains for a technique that permits the discrimination of absent (grade 0R) and mild rejection (grade 1R). We therefore investigated whether an increase of magnetic field strength to 3T and the use of real-time navigator-gated respiration compensation allow for an increase in the sensitivity of T2 relaxation time detection that is necessary to achieve this discrimination.After orthotopic heart transplantation, acute allograft rejection can lead to loss of function. Histological reading of endomyocardial biopsy remains the "gold standard" for guiding immunosuppression, despite its methodological limitations (sampling error and interobserver variability). The measurement of the T2 mapping on the same day. Reading of T2 maps was blinded to the histological results. For final analysis, 3 cases with known 2R rejection at the time of T2 mapping were added, yielding 21 T2 mapping sessions. A respiration-navigator-gated radial gradient-recalled-echo pulse sequence  was applied to obtain 3 short-axis T2 maps , which were segmented according to AHA guidelines . The highest segmental T2 values were grouped according to histological rejection grade and differences were analyzed by Student's t-test, except for the non-blinded cases with 2R rejection. The degree of discrimination was determined using the Spearman's ranked correlation test.Eighteen patients received EMB  and cardiac T2 maps allowed for visual differentiation of the rejection degrees . The 0R (n = 15) and 1R (n = 3) degrees demonstrated significantly different T2 values .The high-quality Ts Figure , and the2 mapping at 3T discriminates between no and mild cardiac allograft rejection. Confirmation of these encouraging results in a larger cohort should consider a study able to show equivalency or superiority of T2 mapping.This pilot study demonstrates that non-invasive free-breathing cardiac TEmma Muschamp Foundation (RBvH), Swiss National Science Foundation .


Executive dysfunction has been observed in patients with left-sided anterior corona radiata infarction. However, whether left-sided posterior corona radiata infarction could cause executive dysfunction is unclear. Also, whether secondary damage in the left frontal white matter following ipsilateral posterior corona radiata infarct is causal or not and contributes to the occurrence and development of executive dysfunction, is still uncertain.Twelve patients with posterior corona radiata infarction underwent diffusion tensor imaging (DTI) and an executive functional assessment at week 1 (W1), week 4 (W4), and week 12 (W12) after onset. Color duplex sonography and Transcranial Duplex Scanning (TCD) were performed at W1 and W12. Twelve healthy volunteers of similar ages and educational histories were examined as controls and assessed once.In the patients, we observed an increased mean diffusivity (MD) and a decreased fractional anisotropy (FA) in the left frontal white matter from W1 to W12. There were no significant changes in cerebral blood flow in patients between W1 and W12 according to the result of Color duplex sonography and TCD. Patients showed progressively impaired executive function during 12 weeks. Significant correlations were found between increased MD and decreased FA in the left frontal white matter with impaired degree of executive function.This study demonstrates that DTI detected secondary damage in left-sided frontal white matter in patients with acute infarction at the ipsilateral posterior corona radiata. This change may be correlated with executive functional changes in these patients. The term ‘executive functions’ is used to describe high-order cognitive processes which include control, integration, organization and maintenance of other cognitive abilities . ExecutiRecently, accumulating studies have shown histopathological and radiological changes occurring in nonischemic remote brain regions that have synaptic connections with the primary lesion site. For example, after cerebral infarction in the middle cerebral artery (MCA) territory, neuronal and/or axonal degeneration, loss, dysfunction and gliosis have been found in the ipsilateral thalamus, substantia nigra, and distal pyramidal tract, all of which were remote from the MCA territory –12]. Th. Th12]. The recent development of diffusion tensor imaging (DTI), an MRI technique, has shown promise for detecting microstructural changes which are not identified by traditional MRI. For example, progressive decreased fractional anisotropy (FA) values in the pyramidal tract, proximal and distal to a subcortical cerebral infarct or pontine infarct over 1 to 12 weeks, were found; this means important loss of structural components in the pyramidal tract above and below the primary infarcts ,[12]. InIn this study we tested the hypothesis that there is axonal loss in the left-sided frontal white matter in patients following acute ipsilateral posterior corona radiata infarction as revealed by DTI. We also examined correlations of the DTI parameters with executive function in these patients.The research protocol was approved by the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-Sen University, and informed consent was obtained from all participants. We selected 12 consecutive patients  between October 2008 and May 2013 in the Department of Neurology and Stroke Center, the First Affiliated Hospital, Sun Yat-Sen University, within 7 days of a focal infarct in the left posterior corona radiata, without any other signal abnormalities on T1-weighted fluid attenuated inversion recovery (T1-FLAIR) and T2-weighted images. Patients with ILA, significant cerebral atrophy, unstable vital signs or a history of central nervous system disorders were excluded. Demographic characteristics and vascular risk factors were recorded in each patient. All patients were investigated with conventional MRI, DTI and executive functional assessments at 1 week , 4 weeks , and 12 weeks  following a pre-defined protocol. Infarct volume was estimated from the T2-weighted FLAIR images at W12. For every patient, we looked for a control of the similar age (±3 years) and educational history (±2 years) with no current or previous neurological or psychiatric disease. Twelve controls were recruited over the same period and examined once by DTI and an executive functional assessment.2 and diffusion-sensitive gradients were applied along 15 gradient directions. In addition, a reference image without diffusion weighting (b = 0 s/mm2) was acquired. Fifteen repeats were acquired and averaged to improve signal to noise ratio. The scanning baseline was parallel to the antero-posterior commissural (AC-PC) line. Axial slices were obtained using a fast spin echo T2 .MRIs were performed using a 1.5-tesla MRI system  equipped with gradient hardware allowing up to 23 mT/m. T1-FLAIR, fast spin echo T2-weighted imaging, traditional FLAIR and DTI were performed. Typical acquisition parameters of conventional MRI were: T1-FLAIR , T2-FLAIR . DTI was obtained with an echo planar imaging (EPI) sequence . DTI was acquired with a b factor of 1,000 s/mm2) defined as quasi-circular, the white matter around the posterior horn (an area of 224 mm2) defined as quasi-circular, the centrum semiovale defined as ellipse (an area of 780 mm2) on a slice from the FLAIR images and then transferred to the DTI image on the same slice  . With the Figure . The tha FA maps . DTI mapThe examinations with Color duplex sonography of the extracranial carotid arteries were performed with the patients at W1 and W12 and controls at recruitment. All measurements were performed by the angiologist who was blinded for the clinical status of the study patients and controls. The internal carotid artery (ICA) was explored using a 10-MHz linear-array transducer . The subjects were in the supine position with their heads slightly elevated and turned 25° to 40° to the contralateral side for the ICA measurements. Peak systolic velocity (PSV) and end diastolic velocity (EDV) were measured 1 to 2 cm above the carotid bulb in the ICAs. Intima-media thickness (IMT) and luminal diameter (DIA) of the ICAs were measured on magnified B-mode. The distance between the leading edge of the luminal echo and the leading edge of the media/adventitia echo was measured as the IMT.The patients underwent TCD scanning at W1 and W12 and controls were scanned at recruitment. Bilateral mean flow velocity was continuously and simultaneously monitored by a 2-MHz phased array transducer  by the angiologist who was not familiar with the clinical status of the study patients and controls. The highest signal was sought at a depth ranging  through the temporal bone window. Mean flow velocity was calculated and recorded automatically when the ‘record’ function of the Doppler instrument was activated.A ‘brief executive assessment’ was also conducted which include four tests often used clinically: the Trail making B-A test, the Verbal fluency assessment, the Digit span backwards test and the Digit symbol test. This has been considered to be a sensitive tool for detecting deficits in patients and distinguishing these deficits from the cognitive effects of healthy aging ,15]. Be. Be15]. t-test. Executive assessments were compared between the patient and the control groups using a Student’s t-test. These parameters and clinical scores then were analyzed using Fisher’s Least Significant Difference (LSD) test for multiple testing. The Color duplex sonography and TCD parameters obtained at W1 and W12 were compared with a two-tailed Student’s t-test. Spearman rank correlation analysis was used to determine associations between changes in brief executive assessment scores and the DTI parameter changes in left frontal white matter and thalamus. The changes in executive function scores over time and the DTI parameter changes were defined as follows:MD and FA values obtained at W1, W4, and W12 in patients were first compared with those of controls with a two-tailed Student’s ΔExecutive scores or DTI Parameter values = Value measured at W12 − value measured at W1Twelve patients  and twelve controls  were recruited in the study. All patients and controls were right-handed. Each patient had one or more vascular risk factor Table .3  on T2 images at W12. No definite abnormal signals were observed in controls.Participants completed all traditional MRI and DTI examinations. Within the first week from stroke onset, T2-weighted and T2-FLAIR images showed focal hyperintensity confined to the left-sided posterior corona radiata in each patient Figure B and C, −3 mm2/s and 0.809 ± 0.108 × 10−3 mm2/s; posterior periventricular white matter 0.824 ± 0.099 × 10−3 mm2/s and 0.816 ± 0.088 × 10−3 mm2/s; centrum semiovale 0.764 ± 0.093 × 10−3 mm2/s and 0.771 ± 0.095 × 10−3 mm2/s; thalamus 0.836 ± 0.069 × 10−3 mm2/s and 0.840 ± 0.075 × 10−3 mm2/s, respectively, all P > 0.05) and FA , the data obtained in the left regions in controls were selected to compare those values in patients.In controls, in the absence of any significant difference between the left and right regions for MD . There was a significant increase of MD and decrease of FA in the left frontal white matter from W1 to W12 (P < 0.05). No obvious MD or FA value changes were found in the right frontal white matter (P > 0.05). There were no significant differences of MD and FA in the left and right posterior periventricular white matter and centrum semiovale from W1 to W12 (P > 0.05). In the thalamus, a significant increase of MD in the left thalamus was found between W1 and W12 (P < 0.05), and no obvious MD value changes were found in right thalamus (P > 0.05). There was no significant difference of the FA values in left and right thalami between W1 and W12. No significant differences of MD and FA in the posterior periventricular white matter or centrum semiovale were detected from W1 to W12 (P > 0.05)  were not significantly different compared with those of controls (P > 0.05).The Color duplex examination of luminal diameter and IMT measurements were performed in all the ICAs of the subjects. The mean values of all data were given in Table P > 0.05).All subjects had accessible cranial window for TCD and underwent 0.5 to 1 hour of TCD monitoring. Mean flow velocity values (MFV) were shown in Table P < 0.05). There was statistical difference in the presence of Trail making B-A, Verbal fluency assessment and Digit symbol tests between patients and controls at W4 and W12, and Digit span backwards test at W12  and Digit symbol test .As illustrated in Figure To the best of our knowledge, this is the first prospective study using DTI to observe secondary changes in the left frontal white matter remote from the ipsilateral posterior corona radiata.Previous studies have shown that focal cerebral infarcts can lead to remote tissue alterations within connected regions related to Wallerian degeneration ,10],,. BecauseFrontal-subcortical circuit was defined as including the frontal cortex, caudate, pallidum, thalamus, genu of internal capsule, anterior internal capsule, anterior corona radiata, and anterior centrum semiovale . In thiset al. and our team in patients after an acute isolated MCA territory infarction . A . A et alIn our patients, there was no abnormal signal in the frontal area at W1 and W12, which means no new ischemic lesions exist in the frontal area between W1 and W12. There was also no significant change of blood flow in the frontal area between W1 and W12 in patients as measured by the evaluation of carotid artery stenosis and hemodynamics of ACA, MCA and PCA performed with Color duplex sonography and TCD, suggesting that frontal dysfunction would not be attributed to potential hemodynamic changes.et al. reported significant executive dysfunction in patients with anterior corona radiata infarction, but failed to find executive change in patients with posterior corona radiata infarction –,[29,[29et alExecutive dysfunction was observed in the patients with left posterior corona radiata infarction. The axonal loss in the left frontal white matter after stroke was detected by DTI. The abnormalities of MD and FA in the region may be correlated with executive function changes in the patients.ACA: anterior cerebral arteryCT: computed tomographyDIA: luminal diameterDTI: diffusion tensor imagingEDV: end diastolic velocityEPI: echo planar imagingFA: fractional anisotropyICA: iInternal carotid arteryILA: ischemic leukoaraiosisIMT: Intima-media thicknessLSD: Least Significant DifferenceMCA: middle cerebral arteryMD: mean diffusivityMFV: Mean flow velocity valuesMMSE: Mini-Mental State ExaminationMRI: magnetic resonance imagingPCA: posterior cerebral arteryPSV: peak systolic velocityTCD: Transcranial Duplex ScanningT1-FLAIR: T1-weighted fluid attenuatedion inversion recoveryWMLs: white matter lesionsThe authors declare that they have no competing interests.CL designed the study, collected the data and wrote the manuscript, CD carried out image post-processing, GL conducted the MR images analysis, LC and JZ assisted with the data collection, JL assisted with the statistical analysis, ZO assisted with the data collection, YZ participated in the design of the study, AX interpreted the results. All authors read and approved the final manuscript.