Mediastinitis after coronary bypass grafting (CABG) increases the risk of the internal mammary artery (IMA) graft obstruction, and has a detrimental effect on long-term survival. The pathogenesis for this increased mortality is poorly understood. In the present study, we aimed to investigate the relationship between mediastinitis and persistently elevated cardiac-specific biomarkers [troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)] and C-reactive protein (CRP) at mid-term follow-up following CABG.n = 41) vs. randomly selected non-exposed (non-mediastinitis) controls (n = 41) cohort. Serum samples for measurements of NT-proBNP, TnT, and CRP were obtained at a median follow up time of 2.7 (range 0.5–5.2) years after CABG surgery.The epidemiologic design was of an exposed  and TnT levels  were significantly higher in the mediastinitis group than in the control group. Patients with mediastinitis had also higher body mass index (BMI) and were more likely to have diabetes and previous myocardial infarction. There was no difference in serum CRP level between the groups. After controlling for potential confounders , the presence of mediastinitis was associated with higher levels of log NT-proBNP (p = 0.02) and log TnT (p = 0.04).NT-proBNP (mean 65.0 pg/ml vs. 34.8 pg/ml, Mediastinitis increases the concentrations of cardiac-specific biomarkers NT-proBNP and TnT at mid-term follow-up, representing persistent myocardial injury and impaired cardiac function. The incidence of mediastinitis after coronary artery bypass grafting (CABG) is low; around 1%. However, this feared complication is associated with an increased risk of morbidity and decreased long-term survival . In addiC-reactive protein (CRP) is a stable and reliable marker of inflammation, and has been shown to give prognostic information in a wide number of atherosclerotic disorders, as well as HF, reflecting the involvement of inflammatory pathways in these disorders , 14. Numwww.cdc.gov) . The diagnosis was based upon the criteria established by the Centres for Disease Control and Prevention (cdc.gov) , 16.p = 0.87)  and 41 non-exposed (non-mediastinitis), controls. Blood samples were collected and analyzed for; (1) NT-proBNP, (2) TnT and (3) CRP. Blood samples were obtained at routine examination at a median follow up time of 2.7  years after primary CABG surgery. All CABG patients who had developed post-operative mediastinitis during 4.7 years follow-up, from September 2005 to April 2010, were considered as exposed patients. The non-exposed cohort was a random control sample of 41 patients without mediastinitis , collect = 0.87) . Evaluatescribed . All casThe levels of TnT were determined by a third-generation high-sensitivity assay on an Elecsys , with a level of detection of 0.01 μg/L. CRP concentrations were measured with a chemiluminescent enzyme-labeled immunometric high-sensitivity assay , with a limit of detection of 0.1 mg/L. Serum NT-proBNP was determined with a sandwich immunoassay on an Elecsys 2010 (Roche Diagnostics).via the multivariate linear regression models to control for the variables with confounding effect in the relationship between presence of mediastinitis and outcome. All markers were logged when considered as outcomes in the multivariate model (P < 0.05 (two-sided) were considered statistically significant.The IBM SPSS 20.0 software  was used for data management and analysis. Data are presented as mean ± SD for continuous variables and as percentages for categorical variables. NT-proBNP, CRP, and TnT were not normally distributed and were log-transformed. Differences in the level of NT-proBNP, CRP, and TnT between mediastinitis patients and controls were assessed using a non-parametric statistic (Mann Whitney U test) as the distribution of those markers were not Gaussian and very skewed . Associate model . P < 0.0p = 0.03). In contrast to these differences, there was no difference in number of stenotic coronary arteries with 2.7 (±0.5) in the mediastinitis group and 2.8 (±0.4) in the control group .This was a cohort study of exposed (mediastinitis) and non-exposed (random controls without mediastinitis) patients chosen from the same source population. Baseline characteristics are presented in p = 0.007) (p = 0.004), but not for CRP (p = 0.14) (Patients with mediastinitis following CABG had significantly higher levels of NT-proBNP as compared with those without this complication 65.0 (±63.6) pmol/l vs. 34.8 (±34.8) pmol/l  . A simil = 0.14) .p = 0.02) and log TnT (p = 0.04).In the present study we showed that patients with VAC-treated mediastinitis after CABG, had significantly higher serum levels of NT-proBNP and TnT, but not of CRP, compared with patients without mediastinitis even 2.7 years (median) following CABG. Cardiac biomarkers like NT-proBNP and TnT are useful for prediction of cardiac events and mortality , and raiMediastinitis is a severe complication after CABG, and is associated with increased risk of early and late cardiovascular death . In a prLevels of NT-proBNP rise with increasing degree of cardiac wall stress secondary to ventricular enlargement and maladaptive cardiac remodeling seen in patients with HF and after MI . ImportaAlthough the exact reasons for the increased levels of NT-proBNP and TnT in patients with mediastinitis remain unknown, a possible explanation may be the significantly higher prevalence of cardiometabolic risk factors in the mediastinitis group. It is well-established that metabolic syndrome leads to structural and functional left ventricular remodeling, preclinical or clinical systolic and/or diastolic dysfunction and fibrosis . Howeverper se as an inflammatory condition could potentially be a contributing factor, but the lack of difference in CRP levels between the two groups, makes this possibility unlikely. However, low-grade myocardial inflammation that is not reflected by systemic CRP levels cannot be excluded. Moreover, mediastinitis may lead to an accelerated coronary ischemia and artery spasm, potentially contributing to ischemic cardiomyopathy. Also, the presence of mediastinitis in the early period following CABG, increases the risk of IMA-graft obstruction, but not saphenous vein grafts (SVG) (Persistent mediastinitis ts (SVG) . The mecThe present study has some limitations. First, our study groups are relatively small with some additional methodological limitations such as the retrospective design and lack of long-term outcome data; however we believe our results are of topical interest, hypothesis generating and should trigger lager prospective studies with longer follow-up to investigate the association of post-CABG mediastinitis with cardiac biomarkers as well as with serum biomarkers of inflammation. Second, serum biomarkers were retrospectively collected and the study lacks some relevant data. Therefore, our conclusions should be interpreted cautiously. Third, the lack of data on mortality and morbidity, including cardiac related hospitalizations and the incidence of recurrent angina. Fourth, only baseline left ventricular EF by echocardiography was included. Data on global longitudinal strain derived by speckle-tracking echocardiography or diastolic dysfunction were not available. Similarly, echocardiographic data during follow-up was not collected. Fifth, cardiac magnetic resonance (CMR) imaging is a gold standard for assessment of persistent myocardial inflammation, subendocardial injury and scar and fibrosis. Our findings suggest that mediastinitis following CABG surgery could induce a degree of myocardial dysfunction potentially contributing to the increase in short- and long-term mortality in these patients. However, CMR was not included in the present study. Larger prospective studies in the future that also include echocardiography and CMR should examine whether elevated TnT and NT-proBNP concentration could be used as prognostic markers for long term survival after CABG.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The study was approved by the Regional Medical Ethics Committee, and represents a multi-center collaboration between Oslo University Hospital, Rikshospitalet, Feiring Heart Clinic, Oslo Heart Center and Akershus University Hospital. The institutions maintain the same diagnostic criteria and treatment with active and prospective epidemiologic surveillance of hospital infections. Written informed consent was obtained from all participants.IR: data collection, project administration, and original draft. IR, PA, and SS: conceptualization, formal analysis, methodology, supervision, validation, visualization, and writing. IR and SS: literature search. RL, OR, TU, and SR: review and editing. PA and SS: critically revised the manuscript. All authors read and approved the final version before submission.


Because the posterior wall of the aorta and left atrium are interlocked, the amplitude of motion of the aortic wall (AMAW) may reflect cardiac and vessel functions. This study examined the relationship between cardiac and vessel functions and AMAW.Patients with cardiovascular diseases or patients undergoing health examinations who visited a participating hospital and underwent echocardiography and brachial–ankle pulse-wave velocity (baPWV) examinations were registered. The correlations between echocardiographic indices, ankle–brachial index, and baPWV and AMAW on M-mode echocardiography were analyzed.r =  − 0.1587), ejection fraction , wall thickness (r =  − 0.1598), peak early diastolic mitral annular velocity (E) to peak early diastolic mitral annular velocity ratio , and baPWV (r =  − 0.1928) significantly correlated with AMAW. In the stratified multiple regression analysis, E/e’  and mean baPWV  in patients with an EF of ≥ 60% (n = 114) significantly correlated with AMAW. In patients with an EF of < 60% (n = 70), E/e’  significantly correlated with AMAW.Overall, 184 patients were enrolled. Heart rate (Because E/e’ correlated with AMAW in patients with an EF of < 60% or ≥ 60%, AMAW might be an indicator of left atrial pressure elevation. Moreover, because AMAW correlated with baPWV in patients with an EF of ≥ 60%, changes in the restricted left atrial volume might influence diastolic dysfunction. AMAW may be related to cardiac and vessel functions. In echocardiography, the M-mode has been the most frequently used modality since its introduction. However, displaying a two-dimensional structure is difficult, because the ultrasound line is fixed. This fact reduces the frequent use of the M-mode. Nevertheless, the M-mode offers an advantage through the high sampling rate, which results in high time resolution . The M-mThis retrospective study comprised 184 patients who underwent echocardiographic examination and whose ankle–brachial index/pulse-wave velocity were measured. These tests were performed within a period of 1 month. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of St. Mary’s Hospital (K19-0903). The subjects underwent the aforementioned examinations between January 2016 and December 2019 at the member hospitals of the ECL48 group, Fukuoka; the group includes the Kurume University Hospital, St. Mary’s Hospital, and Shin-Koga Hospital in Kurume; Sasaguri Hospital in Kasuya; Asakura Medical Association Hospital in Asakura; and Saiseikai Omuta Hospital in Omuta. Echocardiographic images, including two-dimensional echocardiography, M-mode echocardiography, and Doppler studies, were obtained using standard parasternal and apical views. This study employed an “all comers” design. Patients with cardiovascular disease or individuals coming for a health examination who visited a participating hospital and underwent echocardiography and baPWV examinations were registered.During the conventional two-dimensional echocardiographic examination, left ventricular end-diastolic and end-systolic volumes were measured using the biplane modified Simpson method, and the ejection fraction (EF) was calculated. M-mode echocardiography was performed to measure the interventricular septal thickness, posterior wall thickness, maximum and minimum left atrial diameters, aortic diameter, end-diastolic left ventricular diameter, and AMAW Fig. . The ratp < 0.05 using bilateral test.All variables are expressed as means ± standard deviations. Univariate regression analyses were performed to compare the echocardiographic indices, Doppler indices, baPWV, and ankle–brachial index. Multiple regression analyses were performed using the indices that significantly correlated with AMAW in the stratified univariate analyses. Data analyses were performed using JMP Pro . Statistical significance was set at r =  − 0.1587), EF (r = 0.3240), wall thickness (r =  − 0.1598), E/e’ (r =  − 0.2463), and baPWV (r =  − 0.1928) significantly correlated with AMAW (Table r =  − 0.20459) and E/e’ (r =  − 0.19403) significantly correlated with AMAW in patients with an EF of ≥ 60%, and E/e’ (r =  − 0.28611) and wall thickness (r =  − 0.26258) significantly correlated with AMAW in patients with an EF of < 60% (Table Patient characteristics are summarized in Table EF r = 0.240, wallEF r = 0.240, wallThe motion of the aortic wall on M-mode is a well-known phenomenon . FeigenbContrastingly, M-mode echocardiography is a fundamental function and is included in almost all devices. Therefore, AMAW can be measured not only with new devices but also with older devices. AMAW might be one of the most easily measurable echocardiographic indices.AMAW influences left atrial function, because the posterior wall of the aortic root and left atrium are interlocked. Therefore, AMAW might be related to both atrial and vessel functions. In the univariate analysis, heart rate, EF, wall thickness, E/e’, and baPWV significantly correlated with AMAW. EF might be the source of power for aortic movement as it is the index of motion. Pratt et al. suggested that left ventricular ejection contributes to the aortic root motion . StratifThe measure of systemic arterial stiffness, known as baPWV, is measured using brachial and tibial arterial wave analyses . Aortic Although decreased AMAW might be directly correlated with atherosclerosis, reduced endothelial function and restriction of the left atrium may decrease left ventricular diastolic function.The major limitations of this study were its retrospective design and small sample size. In this study, stratified multiple regression analyses were performed to investigate the relationship between AMAW and various indices of cardiac and vessel functions. For these analyses, a wide range of cardiac and vessel functions and a large number of subjects for investigation were considered necessary. Therefore, patients with heart failure as well as those who came only for health check-ups were included in this study. However, the sample size may have been insufficient. Additionally, the echocardiographic data were limited to general indices given the retrospective nature of this study. Therefore, despite being important factors, the left atrial volume and left atrial emptying fraction could not be analyzed. Future research should include patients with heart failure in particular.AMAW on M-mode correlated with EF, baPWV, and E/e’. Thus, AMAW may be defined based on vascular status and cardiac function. Because the aortic root restricts the left atrium, AMAW may influence left atrial function. Furthermore, AMAW might be one of the indicators of left atrial function.


Patients with a single ventricle, who have not undergone surgery, reportedly have a lower survival rate. Furthermore, multiple pregnancies are rare among these females. We reported a case of anesthesia management of cesarean section in an uncorrected single-ventricular multi-pregnancy woman and review the anesthesia management of the published similar cases.+6 weeks of gestation.An uncorrected single ventricular pregnant woman with a cardiac function of New York Heart Association class II, who had experienced one spontaneous abortion and three vaginal deliveries, was scheduled for cesarean section at 37: Echocardiography revealed a complex congenital heart disease in the mother: a single ventricle (the left ventricle is dominant), atrioventricular valve ectopic, double-inlet left ventricle, abnormal location of the great arteries, probably pulmonary stenosis, atrial septal defect, and left-to-right shunt. The fetus was in breech presentation with umbilical cord around the neck.Cesarean section was successfully performed under the combined spinal epidural anesthesia with careful monitoring.: Both mother and newborn recovered good and were discharged from the hospital 5 days after surgery without any adverse reactions.Single ventricular pregnant woman with a cardiac function of New York Heart Association class I–II could tolerate pregnancy and delivery well. Both general and regional anesthesia are applicable to cesarean section in these patients. The principle of anesthesia management is to maintain the appropriate balance between systemic vascular resistance and pulmonary vascular resistance, as well as to maintain preload and cardiac output. Pregnancy and its accompanying hemodynamic alterations increase the burden on this ventricle, resulting in a significantly increased risk of maternal morbidity or mortality.Patients with an uncorrected single ventricle rarely survive to adulthood. Pregnancy and delivery rarely occur among these patients. Since single-ventricular pregnancy was first reported in 1963, only a few studies have addressed perioperative anesthesia management in these pregnant women.2The publication of this case was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College, and written consent was signed by the patient for the purpose of research and publication.+6 weeks of pregnancy. She was diagnosed with congenital heart disease (CHD) at the age of 10 years and received no particular treatment. The patient was a gravida 5, para 0, abortion 1 female. She had given birth to three live children through vaginal delivery and experienced one spontaneous abortion. The physical examination revealed a heart rate (HR) of 90 beats/min, blood pressure (BP) of 130/84 mm Hg, respiratory rate of 21 breaths/min, oxygen saturation of 85%, and body temperature of 36.6°C. The arterial blood gas analysis (ABG) before oxygen therapy showed a pH of 7.46, partial pressure of carbon dioxide (PaCO2) of 28.0 mm Hg, and partial pressure of oxygen (PaO2) of 49.0 mm Hg. Her biochemical examination results, including routine blood tests, coagulation, hepatic and renal functions, serum electrolytes, myocardial damage markers, and brain natriuretic peptide, were normal. The patient reported no particular discomfort during the first and second trimesters, but she recently complained of reduced activity tolerance. As shown in Figure A 35-year-old woman  was hospitalized at 372 of 26 mm Hg, PaO2 of 55 mm Hg, arterial oxygen saturation of 88.7%, hemoglobin of 117 g/L, hematocrit of 38%, base excess in the extracellular fluid compartment of −5.3 mmol/L, bicarbonate (HCO3−) levels of 18.5 mmol/L, lactate levels of 1.7 mmol/L, potassium (K+) levels of 3.6 mmol/L, and calcium (Ca2+) levels of 1.11 mmol/L.After entering the operating room, the patient received 100% oxygen via a facemask. Her vital signs before anesthesia included a HR of 105 beats/min, BP of 154/87 mm Hg, and oxygen saturation of 91%. Left radial arterial cannulation was then performed under local anesthesia to monitor BP dynamically. Prior to anesthesia, the ABG revealed a pH of 7.46, PaCOAfter hydration with 300 mL Ringer's lactate, a combined spinal epidural anesthesia was performed in the left lying position with 2.0 mL of 0.67% ropivacaine, administered intrathecally at the L2-3 intervertebral space. This was followed by insertion of a 3-cm multiorifice epidural catheter. The patient was then placed in the supine position with a left tilt of 20°. Surgery began when the bilateral dermatomal-blockade level reached T4. Three minutes later, a 2.55-kg newborn girl was delivered. Once the umbilical cord was clamped, 100 μg of carbetocin was slowly injected to provide an adequate uterine tone. The maternal hemodynamics were generally stable, but she experienced a brief episode of postural hypotension (systolic BP reached as low as 85 mm Hg) upon changing her position from left tilt to supine prior to surgery. However, her hypotensive episode lasted less than 2 minutes because it was quickly corrected with intravenous ephedrine. The newborn maintained an APGAR score of 10 from 1 to 10 minutes after birth. The instant umbilical cord ABG revealed a pH of 7.37.2 of 25 mm Hg, PaO2 of 69 mm Hg, arterial oxygen saturation of 95.4%, hemoglobin of 126 g/L, hematocrit of 39%, extracellular fluid compartment of −7.2 mmol/L, HCO3− of 17 mmol/L, lactate levels of 2.7 mmol/L, K+ of 3.7 mmol/L, and Ca2+ of 1.07 mmol/L. Postoperative pain relief was achieved by patient-controlled intravenous analgesia containing sufentanil and butorphanol. She and her baby were discharged from the hospital 5 days later. No congenital cardiac anomalies were detected in the baby.The surgical procedure lasted 80 minutes, and the total amounts of fluid input and output were 500 mL and 700 mL (400 mL of urine and 300 mL of estimated blood loss), respectively. At the end of the surgery, the ABG revealed a pH of 7.44, PaCO3 Successful pregnancy and delivery are rare in uncorrected cases. A literature search was conducted in PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) using the combination strategy with the following keywords: (pregnancy) AND ((single ventricle) OR (univentricular heart)) AND ((anesthesia) OR (cesarean section)). All available cases were summarized, and only 16 pregnant women with an uncorrected single ventricle underwent cesarean section, with 17 pregnancies  years, and the median gestational age at delivery was 36 (range: 27–40) weeks. Apart from single ventricle, multiple congenital heart anomalies, such as transposition of the great arteries  and PS , were commonly detected. Seven patients had pulmonary hypertension , and three progressed to Eisenmenger syndrome . Most patients were cyanotic with a median basal oxygen saturation of 84.75% (range: 69%–97%). Except for four patients who received general anesthesia , all cases were conducted under regional anesthesia . There were two neonatal deaths , one died for pulmonary hemorrhage Several studies have shown that adult patients characterized with double-inlet left ventricular morphology and perfectly balanced circulation with some degree of PS could survive with mild-to-moderate symptomatology and preserved ventricular function.–24 In our case, the woman had a similar ventricular morphology and probably PS. She had a preserved cardiac function (NYHA class II) without apparent cyanosis during gestation, and tolerated the multiple labors and delivery.The natural history of patients with unoperated single ventricle is poor with a survival rate of ∼30% in the first year of life and a median survival age of 14 years. The anesthetic goal in patients with uncorrected single ventricle should be a balance between systemic vascular resistance and pulmonary vascular resistance (PVR) to avoid intracardiac shunt deterioration. Moreover, the cardiac output (CO) should be stabilized to avoid a forward flow reduction through either pulmonary or systemic circulation. Due to the potential of a right-to-left shunt, peripheral intravenous injection and infusion should minimize the risk of air embolism. Furthermore, appropriate postoperative analgesia contributes a lot to avoiding the catecholamine secretion that increases PVR, reduces pulmonary blood flow, and results in severe cyanosis.To achieve good maternal and fetal outcomes, pre-pregnancy counseling as well as peripartum and intrapartum management should be provided by a multidisciplinary management team, including at least one cardiologist, obstetrician, and anesthetist.,28 Ergometrine and prostaglandin F analogues  should be avoided in patient with a single ventricle. Besides, fluid balance is an important determinant of a favorable outcome.Since spinal anesthesia provides a reliable analgesic effect, and the epidural catheter is retained to maintain the anesthesia while extending the surgical time, the combined spinal epidural anesthesia method was chosen. Since regional anesthesia can cause systemic hypotension, fluid infusion was administered in advance, and invasive BP monitoring was performed before anesthesia. The dosage and volume of the intrathecal anesthetics were carefully titrated to maintain the dermatomal level below T4. The patient experienced supine hypotension syndrome after she was placed in the supine position. Then, a vasoconstrictor was immediately administered. The commonly used vasopressors for obstetrical patients include phenylephrine, methoxamine, ephedrine, and norepinephrine. Carbetocin, an oxytocin analog, is routinely administered during cesarean section to reduce postpartum hemorrhage after delivering the fetus. Since oxytocin induces peripheral vasodilatation, hypotension, and increases CO (mediated by an increased HR and stroke volume), oxytocin agents should be infused under the slowest effective dose in single ventricular patients.In summary, this case showed that pregnant single ventricular women with a NYHA class of I–II could tolerate pregnancy and delivery. Both general and regional anesthesia are applicable to cesarean section in these patients. The principle of anesthesia management is to maintain the appropriate balance between systemic vascular resistance and PVR, and to maintain the preload and CO.Conceptualization: Ji Wang.Data curation: Yu Du, Yingzi Yang-Liu.Methodology: Yu Du, Bin Chen.Writing – original draft: Yu Du, Yingzi Yang-Liu.Writing – review & editing: Bin Chen, Ji Wang.


However, the high rate and diminutive size of the mouse heart is a challenge, resulting in low resolution and poor signal-to-noise. Here we describe a refined high-resolution 31P-CMRS technique and apply it to a novel double transgenic mouse (dTg) with elevated myocardial creatine and creatine kinase (CK) activity. We hypothesised a synergistic effect to augment energetic status, evidenced by an increase in the ratio of phosphocreatine-to-adenosine-triphosphate (PCr/ATP).Phosphorus cardiovascular magnetic resonance spectroscopy (31P-CMRS measurements of the left ventricle (LV) utilising a two-dimensional (2D), threefold under-sampled density-weighted chemical shift imaging (2D-CSI) sequence, which provided high-resolution data with nominal voxel size of 8.5 µl within 70 min. (1H-) cine-CMR data for cardiac function assessment were obtained in the same imaging session. Under a separate examination, mice received invasive haemodynamic assessment, after which tissue was collected for biochemical analysis. Myocardial creatine levels were elevated in all mouse hearts, but only dTg exhibited significantly elevated CK activity, resulting in a 51% higher PCr/ATP ratio in heart , that was absent from adjacent skeletal muscle. No significant differences were observed for any parameters of LV structure and function, confirming that augmentation of CK activity does not have unforeseen consequences for the heart.Single transgenic Creatine Transporter overexpressing  and dTg mice  mice were anaesthetised with isoflurane to acquire 31P-CMRS methodology for the in vivo assessment of energetics in the murine heart which enabled high-resolution imaging within acceptable scan times. Mice over-expressing both creatine and CK in the heart exhibited a synergistic elevation in PCr/ATP that can now be tested for therapeutic potential in models of chronic heart failure.We have developed an improved  The myocardial creatine kinase (CK) system has an important role in maintaining energy provision in the heart . The mit31P-CMRS) has allowed the measurement of high energy phosphates in the failing human heart, typically expressed as the ratio of phosphocreatine (PCr)/ATP, since ATP levels are relatively stable and obtaining absolute values is technically challenging , total acquisition time ~ 67 min). The sampling pattern is shown in Fig. 2, resulting in a voxel volume of ~ 8.45 µl. A line broadening of 60 Hz was applied to improve the SNR of the resulting spectra.Mice were anaesthetised with 4% isoflurane in 100% medical oxygen and maintained on a nose cone at 1.5–2% throughout. Mice were placed prone on a thermo-regulated cradle with electrocardiogram (ECG) and respiratory gating. Data were acquired on a 9.4 T CMR system comprising of a DirectDrive2 console, a 120 mm i.d., 0.6 T/m, shielded gradient set , a linear double-tuned, actively decoupled escribed . In brie1 saturation effects was carried out in Excel 2014 , and T1 values for PCr and ATP in the mouse myocardium at 9.4 T were taken from the literature [The data were reconstructed using IDL 8.2  and spectra corresponding to voxels placed in the myocardium and blood were fitted in the time domain using in-house software . A voxelterature .2, matrix size 128 × 128, TE/TR = 1.7/4.6 ms, 15° sinc excitation pulse, number of averages NT = 8. The number of frames per cardiac cycle was determined by the heart rate. Data were analysed using the three-dimensional guide-point modelling as reported previously [LV cardiac function was obtained in the same imaging session. Eight to ten contiguous, 1-mm-thick slices were then acquired in short-axis orientation covering the entire heart using an ECG-triggered and respiratory gated multi-frame, two-fold undersampled compressed-sensing accelerated  sequenceeviously , 24.For haemodynamic assessment, the LV was cannulated via the right carotid artery with a 1.4F Millar pressure catheter . Mice were given 15 min equilibration before measurements were taken under baseline and stimulated conditions using a Powerlab 4SP . Mice were then killed by intravenous overdose of pentobarbitone.. [Hearts were excised, rinsed with saline, blotted on tissue, LV and right ventricle (RV) dissected, then rapidly frozen using Wollenberger tongs chilled in liquid nitrogen. Samples were stored at − 80 °C until utilised. Frozen LV tissue was powdered for quantification of total creatine levels by HPLC using the method of Teerlink et al.  and norm. . CK isoe. .Each data set was analysed by a single operator who was blinded to genotype. Data are presented as mean ± standard deviation and all statistical tests were calculated using GraphPad Prism . An unpaired Student’s t-test was used for comparison of means between two groups. An F-test was applied to compare variances and an Anderson–Darling test to check for normality of residuals.31P-CMRS spectra from voxels in the septal wall of (A) a CrT-OE and (B) a dTg mouse respectively, with the voxel locations indicated on the anatomical 1H-images. PCr and α-, β-, and γ-ATP resonances can clearly be seen, with the [We generated a new model of constitutive CK-M overexpression specifically in the heart and crossed this with a pre-existing line overexpressing the CrT (CrT-OE) to make dTg animals. All comparisons are between single transgenic CrT-OE and the dTg mice. Figure with the , 3-DPG rWe have previously shown that CK activity and isoenzyme distribution is unaltered in CrT-OE compared to wild-type littermates . However31P-CMRS, the ratio of PCr/ATP was found to be 51% higher in dTg hearts compared to CrT-OE  and was significantly correlated with total creatine values in the dTg only . There was a significant difference between the elevations in these relationships (P < 0.002) indicating that for any given value of creatine, the dTg hearts contained more PCr  > 100 nmol/mg protein Fig. B, which We have previously found that very high levels of creatine (> twofold) is associated with LV hypertrophy and dysfunction in the CrT-OE mouse , 28, and31P metabolic imaging technique that provides the highest resolution reported to date (voxel volume: 8.5 µl), which is > 3.5 × smaller than in our previous study [We have reported on the implementation of a us study . The useus study . With th31P data acquisition resulted in substantial T1 saturation of the resonances in the spectra. This required correction of the PCr and ATP signal intensities resulting from the fitting of the spectra to obtain accurate PCr/ATP ratios in the myocardium. Signal contamination from the blood arising from partial volume effects, as evidenced by the presence of a [1 saturation. Since both the myocardial and blood spectra were simultaneously acquired in the same animal, no correction for T1 of blood resonances is therefore required. Similarly, a reference spectrum from an ex vivo blood sample is not required therefore eliminating the need to account for ex vivo sample degradation or for inter-animal variation.The short TR used for the nce of a , 3-DPG rnce of a , 3-DPG/γThe CK system in our experimental groups, which were matched for age (i.e. 22 weeks ± 3 weeks), is fully developed and myocardial creatine levels can therefore be expected to be static in the mature animal , 29.., who did not measure CK-M activity directly, but described a ~ 70% higher levels for both CK-M protein expression and total CK activity. Herein, we observed a similar 69% increase in total CK activity, driven by a 2.2-fold increase in CK-M-specific activity. Although this was measured in dTg mice, we did not previously observe changes in CK activity in the CrT-OE model [An inducible mouse model of CK-M-OE has previously been described by Gupta et alOE model . This suOE model , ischaemOE model  and doxoOE model . NotablyOE model .ATP) [Over-expression of the CrT results in accumulation of myocardial creatine, which, within a therapeutic range of 1.2 to twofold above normal values, has been shown to be cardioprotective in models of ischaemia/reperfusion injury , 33. HowATP) . This suATP) . Future 31P imaging technique suitable for the in vivo assessment of high energy phosphates in mouse heart. Application of this technology to a novel mouse model with increased levels of both creatine and creatine kinase activity demonstrated a synergistic increase in PCr/ATP ratio. Future proof-of-principle studies will test the therapeutic potential of this approach in chronic heart failure, with high-resolution 31P-CMRS providing mechanistic insight via assessment of cardiac energetics.In conclusion, we report on a refined high-resolution


With modest undersampling (R = 2), the speed gain of 2in1-RARE-EPI relative to Multi-Spin-Echo and Multi-Gradient-Recalled-Echo references is limited. Further reduction in scan time is crucial for clinical studies investigating T2 and T2* as imaging biomarkers. We demonstrate the feasibility of further acceleration, utilizing compressed sensing (CS) reconstruction of highly undersampled 2in1-RARE-EPI. (2) Methods: Two-fold radially-undersampled 2in1-RARE-EPI data from phantoms, healthy volunteers (n = 3), and multiple sclerosis patients (n = 4) were used as references, and undersampled . For each echo time, images were reconstructed using CS-reconstruction. For T2 (RARE module) and T2* mapping (EPI module), a linear least-square fit was applied to the images. T2 and T2* from CS-reconstruction of undersampled data were benchmarked against values from CS-reconstruction of the reference data. (3) Results: We demonstrate accelerated simultaneous T2 and T2* mapping using undersampled 2in1-RARE-EPI with CS-reconstruction is feasible. For Rextra = 6 (TA = 01:39 min), the overall MAPE was ≤8% (T2*) and ≤4% (T2); for Rextra = 12 (TA = 01:06 min), the overall MAPE was <13% (T2*) and <5% (T2). (4) Conclusion: Substantial reductions in scan time are achievable for simultaneous T2 and T2* mapping of the brain using highly undersampled 2in1-RARE-EPI with CS-reconstruction.(1) Background: Radial RARE-EPI MRI facilitates simultaneous T The radial sampling of k-space data implemented in 2in1-RARE-EPI promotes acceleration through undersampling. This approach reduces scan time and eliminates the risk of slice misregistration, as the T2 and T2* maps are inherently co-registered. In general, the benefits of quantitative mapping come with the drawback of increased scan time, since multiple images with different contrast weightings need to be acquired. This limits the implementation of quantitative mapping in routine clinical practice and broader clinical studies. In our previous study, the acquisition time for simultaneous T2 and T2* mapping was reduced to 77% of the comparable reference methods Multi-Spin-Echo (MSE) and Multi-Gradient-Recalled-Echo (MGRE) due to the use of the hybrid acquisition and a modest radial undersampling factor (R = 2) [2 and T2* mapping, such as Spin- and Gradient-Echo (SAGE) [2 and T2* mapping, 2in1-RARE-EPI samples k-space spokes in a hybrid acquisition in an echo train consisting of a RARE module followed by an EPI module.Brain lesions in multiple sclerosis (MS) have MRI characteristics that can be used to aid diagnosis and to discriminate among different lesion types. Given these features, parametric mapping of multiple MR contrasts would be highly clinically relevant ,2,3. NevARE-EPI) . SimilarARE-EPI) ,6,7, the (R = 2) . Unlike o (SAGE) ,9,10,11 o (SAGE) , which u2 and T2* as imaging biomarkers in MS, including application in a drug trial [2 mapping in cartilage and liver [2* mapping of a mouse tumor [2 mapping of the mouse heart [Additional reduction in scan time will further enhance patient comfort and compliance, and is a fundamental precursor for broader clinical studies on the potential of Tug trial . A promiug trial ,16,17,18ug trial ,20. Firsug trial ,22,23. Pse tumor , and T2 se heart . However2 and T2* mapping with accelerated 2in1-RARE-EPI, in phantoms, healthy volunteers, and MS patients, and provide practical recommendations.Here, we demonstrate the first application of CS reconstruction for simultaneous T2 decay), followed by the acquisition with an EPI module (T2* decay). A pulse sequence diagram of 2in1-RARE-EPI is depicted in In 2in1-RARE-EPI, the MR signal is first acquired with a RARE module . The following imaging parameters were used: FOV = (232 × 232) mm2, matrix size = 256 × 256, slice thickness = 5 mm, no. of slices = 3, TR = 2000 ms, NRARE = 14, NEPI = 18, echo-spacing (RARE/EPI) = 6.5 ms/2.3 ms, receiver bandwidth = 610 Hz/px, no. of shots (NS) = 200, acquisition time (TA) = TACalib + NS*TR = 07:12 min. For the phantom study, a single slice and FOV = (212 × 212) mm2 were used. The acquisition of 200 shots with a matrix size of 256 × 256 corresponds to an undersampling factor of R = 2 for the TE images.The MR data were acquired with 2in1-RARE-EPI at 3.0 T  using the body RF coil for transmission and a 32-channel head RF coil  for signal reception. The radial k-space data were corrected for gradient delays based on a calibration scan acquired prior to each scan , filled with water-based solutions of the iron oxide nanoparticle-based contrast agent Resovist . The iron oxide nanoparticles decrease T2 and T2* of the solvent, depending on their concentration in the solution. For the phantom, different solutions with iron concentrations ranging between 2.3 to 12.3 μg Fe/mL were used. Specifically, the tubes were filled with solutions of the following iron concentrations (from left to right and top to bottom): 5.9, 4.6, 6.15, 6.15, 4.01, 4.01, 2.95, 2.95, 2.3, 2.3, 12.3, 8.02 μg Fe/mL and 3.51 μg Fe/mL outside the tubes.The phantom was designed to mimic the T2) and four MS patients . For the in vivo study including healthy volunteers, three slices were acquired, which covered the lateral ventricles. For the in vivo study including MS patients, three slices covering MS specific lesions were acquired, which were selected based on a 2D T2-weighted RARE scan.The in vivo feasibility study included three healthy volunteers  = 23.6–25.9 kg/m2 decay), followed by the acquisition with an EPI module (T2* decay). For T2 and T2* mapping, a linear least-square fit was applied to the images reconstructed from k-space data acquired at the same echo times (TEs) within the echo train. For T2 mapping, the first echo was excluded from the fit to limit the effect of stimulated echoes. This approach is generally effective at reducing stimulated echo contamination, however, it may still result in erroneous estimations of T2, particularly for very low T2 values [In 2in1-RARE-EPI, the MR signal is first acquired with a RARE module  NUFFT [S, the expected quadratic deviation of a true, but unknown, image rt from the measured data y isλ such thatThe two-fold radially-undersampled 2in1-RARE-EPI data, used as reference, were undersampled at each TE by removing every nth k-space spoke. Undersampling factors of RT) NUFFT ,26 for tT) NUFFT ,28 impleT) NUFFT ,30,31 foT) NUFFT ,33. IndiT) NUFFT ,35,36,37T) NUFFT . We emplT) NUFFT ,40,41. Gλ with a tolerance of 0.1% in the data deviation. Using this adapted form of the discrepancy principle, high reconstruction quality could be achieved with automatic tuning for most images. The above condition could not be met for the highest SNR echoes in the RARE module, and for the first echoes of the EPI module without retrospective undersampling. In these cases, a small, fixed λ value of 2.5 × 10−5 was employed to ensure the reduction of aliasing artifacts with only minimal deviation from the measured data.The NUFFT and coil sensitivity induced errors are proportional to the signal level, and thus highest in the k-space center, while the measurement noise is uniformly distributed. We exploited this fact by considering only the k-space periphery in the computation of the deviation of the reconstruction from the measured data. For this purpose, we selected only the highest ur study . Importa2 and T2* derived from CS-reconstruction of the undersampled data were benchmarked against T2 and T2* obtained from CS-reconstruction of the reference data (Rextra = 1). For analysis of the phantom study, seven ROIs (size = 9 × 9 pixels) were placed within the phantom  were selected for each subject, which were placed within the following anatomical brain regions: the globus pallidus, thalamus, and frontal (periventricular) white matter, in both, the left and right hemisphere  were selected to cover MS lesions identified in four patients.To assess the feasibility of undersampling, regression and Bland–Altman plot analyses were performed for every undersampling factor. T phantom a, corresmisphere b,c. For 2 and T2* differences, 2 and T2* values among the reference and undersampled data did not follow a Gaussian distribution in all cases.Multiple linear regression was used to assess the agreement between the reference and undersampled data, which also takes into account the effects of ROI and subject, and their interaction. For the Bland–Altman plot analyses, the median of the T2 and T2* derived from undersampled 2in1-RARE-EPI was calculated relative to the corresponding T2 and T2* deduced from the CS-reconstruction of the 2in1-RARE-EPI reference (Rextra = 1) according to:2(*)(Rextra) and T2(*) the T2 and T2* values derived from 2in1-RARE-EPI with and without retrospective undersampling, respectively. The calculation of the MAPE was performed for the same ROIs used for the regression and Bland–Altman plot analyses. Differences in MAPE among Rextra factors were analyzed using the non-parametric repeated-measures Friedman test, followed by the Dunn’s post-hoc test with the Benjamini–Hochberg correction for multiple comparisons. Data were analyzed using R v.3.6.3.Furthermore, the median absolute percentage error (MAPE) of T2 and T2* maps of the phantom and in vivo studies obtained with 2in1-RARE-EPI for Rextra = 1–12. 2 and T2* maps of the phantom. For the T2 maps, increasing the undersampling rate to Rextr ≥ 6 (TA reduced to ≤01:39 min) resulted in a minor increase in T2 for low iron concentrations (T2(Rextra) ≥ 100 ms). Despite this, no visible change in the T2 maps was apparent. In the T2* maps, undersampling artifacts were apparent at Rextra = 8 and became more pronounced with increasing undersampling.2 and T2* maps of the brain of a healthy 30-year-old female volunteer. Increasing undersampling to Rextra = 10 (TA reduced to 01:12 min) resulted in a minor reduction of high spatial frequency information, which became apparent in the small gyri of the brain.2 and T2* maps of the brain of a 30-year-old female MS patient are depicted in extra = 10 resulted in a minor reduction of high spatial frequency information. The periventricular MS lesions were clearly delineated up to Rextra = 12 in the T2 maps. In T2* maps, these lesions were clearly delineated up to Rextra = 10.The TFor closer examination, the results of the regression and Bland–Altman analyses are depicted in 2 depicted in the scatter  and T2* . This corresponds to a decrease of the adjusted R2 of 7% and 10% for the T2 and T2*, respectively, when increasing Rextra from 2 to 12. For T2, a minor increase of the limits-of-agreement (LOAs) from −2.35 ms and 2.46 ms at Rextra = 2 to −7.41 ms and 6.16 ms at Rextra = 12 (TA reduced to 01:06 min) was observed. The median of the T2 differences showed a minor decrease from 0.05 ms at Rextra = 2 to −0.62 ms at Rextra = 12. These results show that 2in1-RARE-EPI-based T2 mapping supports high undersampling in conjunction with CS reconstruction. For T2*, the scatter plots  and T2* . This corresponds to a decrease of the adjusted R2 of 18% and 54% for the T2 and T2*, respectively, when increasing Rextra from 2 to 12. The adjusted R2 of T2* at Rextra = 8 is decreased by 34% relative to Rextra = 2. The results of the Bland–Altman plot analysis of T2 showed a minor increase of the LOAs from −3.62 ms and 3.36 ms at Rextra = 2 to −6.00 ms and 5.71 ms at Rextra = 12. The median of the T2 differences was −0.13 ms at Rextra = 2 and −0.15 at Rextra = 12. The Bland–Altman plot analysis of T2* showed an increase of the LOAs from −5.48 ms and 5.55 ms at Rextra = 2 to −16.95 ms and 17.76 ms at Rextra = 12. The median of the T2* differences increased from −0.04 ms at Rextra = 2 to 0.40 ms at Rextra = 12.The in vivo study in healthy volunteers showed increased variance of Tsampling . The mul2 variance with increasing undersampling for the ROIs covering the lesions  and T2* . This corresponds to a decrease of the adjusted R2 of 6% and 20% for the T2 and T2*, respectively, when increasing Rextra from 2 to 12. The Bland–Altman plot analysis showed an increase of the LOAs from −4.86 ms and 4.94 ms at Rextra = 2 to −13.65 ms and 12.09 ms at Rextra = 12. The median decreased from −0.04 ms at Rextra = 2 to −0.78 ms at Rextra = 12. For T2*, the LOAs obtained from the Bland–Altman analysis increased from −7.27 ms and 5.76 ms at Rextra = 2 to −16.67 ms and 17.42 ms at Rextra = 12. The median of the T2* differences increased from −0.75 ms at Rextra = 2 to 0.37 ms at Rextra = 12.The in vivo study in MS patients revealed an increase in the T lesions . The sca and T2* a,c. The 2 and T2* for the phantom study. There was a significant difference in the MAPE of T2 of the 7 ROIs placed within the phantom among different undersampling factors Rextra . There were significant differences of the MAPE of T2 between Rextra = 6, 8, and 12 and Rextra = 2 . The overall MAPE of T2 . There were significant differences between Rextra = 10–12 and Rextra = 2 . The overall MAPE of T2*  for the six ROIs placed in the brain. There were significant differences of the MAPE of T2 between Rextra = 8–12 and Rextra = 2 . This shows the consistency of the T2 measurement within subjects for Rextra below 8. For T2*, there were significant differences in the MAPE among the various undersampling factors (p = 7.3 × 10−7). There were significant differences of the MAPE of T2* between Rextra = 6–12 and Rextra = 2 . This shows the consistency of the T2* measurement within subjects for Rextra below 6. The overall MAPE of T2 and T2*. There were significant differences of the MAPE of T2 between Rextra = 8–12 and Rextra = 2 . This shows the consistency of the T2 measurement within subjects for Rextra below 8. For T2*, there were significant differences in the MAPE among the various undersampling factors (p = 1.8 × 10−4). There were significant differences of the MAPE of T2* between Rextra = 6–12 and Rextra =2 . This shows the consistency of the T2* measurement within subjects for Rextra below 6. The overall MAPE of T2 and T2* . This can likely be explained by the reduction of high spatial frequency information in highly undersampled images, leading to smoothing of the lesion sharpness, and reduced contrast between the lesions and surrounding tissue with lower T2.The Bland–Altman plots of the T2 of T2 and T2* with increased undersampling in the phantom study compared to the in vivo studies can be explained by the higher degree of sparsity in the phantom images compared to images of the brain, which promotes accurate recovery of true signal intensities for higher undersampling factors [2 of T2 and T2* was lower for the in vivo study with MS patients compared to the healthy volunteers. This can be attributed to the fact that in the case of MS patients, the T2 and T2* values within all ROIs have a larger range than in the ROIs of the healthy volunteers, and thus the additional variance contributed by the undersampling is proportionally smaller.The smaller relative decrease of the adjusted R factors . We obse2* mapping based on 3D single point imaging (SPI) with CS reconstruction in ex vivo rat tissue and an in vitro cell phantom [2 of about 10–12% for an increase of the undersampling factor from 2 to 10, which is lower than the values observed in our in vivo studies. However, there a number of differences between the two studies that can explain these discrepancies. In the SPI approach, only one k-space point is sampled within a TR, which increases the accuracy of R2* measurements, due to a higher sampling rate of the signal decay, but at the expanse of considerably longer scan times. Furthermore, the 3D single point sampling of k-space allows for a higher degree of freedom in the undersampling pattern, which can substantially increase the performance of CS reconstruction at high undersampling factors [A previous study that investigated the performance of R phantom  shows a  factors ,43. This2* is higher and increases more strongly with increasing undersampling compared to the MAPE of T2. This can be explained by the hybrid acquisition of the MR signal in 2in1-RARE-EPI, in which the MR signal is first acquired with a RARE module to capture the T2 decay, followed by the acquisition with an EPI echo-train to capture the T2* decay. This results in a lower SNR of the TE images used for T2* mapping, which manifests as an increased MAPE of T2*. Notwithstanding this SNR constraint, the overall MAPE of T2* was <5% in the phantom studies for Rextra ≤ 12, and <8% in the in vivo studies for Rextra ≤ 6. The overall MAPE of T2 remained <4.4% for Rextra ≤ 12 in the phantom and in vivo studies.The analysis showed that the MAPE of T2 and T2* decay within each TR, the measurement of T2* values could be impaired for tissues exhibiting very low T2 values. This could be due, e.g., as a result of increased iron deposition, which is a pathological feature of some neurodegenerative diseases, including MS. The lowest T2 values of the tissues investigated in the current study are about 60 ms, which does not impact the T2* measurement. Evaluating simultaneous T2 and T2* mapping with 2in1-RARE-EPI for lower T2 values will require further studies, including an adaptation of the length of the RARE and EPI module to achieve optimal results.Due to the consecutive sampling of the Tn = 3, slice thickness = 5 mm) to demonstrate the feasibility of our approach. This could be easily scaled up to meet the needs of clinical applications, by reducing the slice thickness and increasing the total number of slices acquired. Reduced slice thickness would also mitigate partial volume effects and result in a better coverage of lesions. Given the high SNR we observed for the 2in1-RARE-EPI using the imaging parameters of the current study, we expect the results presented here to also hold for lower slice thicknesses. The long TR used in the 2in1-RARE-EPI will allow for acquisition of additional slices without increasing the acquisition time.In this study, we used a limited slice coverage (extra = 6 (Reff = 12), the acquisition time for simultaneous T2 and T2* mapping can be reduced from 07:12 min to 01:39 min. An extra undersampling of Rextra = 12 (Reff = 24) permits a scan time as short as 01:06 min. The 2in1-RARE-EPI approach is compatible with the concept of using different undersampling rates for the RARE module and for the EPI module. This approach would permit an improvement of the RF deposition economy of the RARE module. Even further scan time reductions could be achieved by employing simultaneous multi-slice imaging techniques which are compatible with 2in1-RARE-EPI [The scan time reduction shown in this work will benefit patient compliance, and enhances the robustness to bulk motion. With an extra undersampling factor of RRARE-EPI ,45,46.The current study is a proof-of-concept demonstration of the feasibility of using undersampled 2in1-RARE-EPI in a realistic clinical context, and was not designed or powered to detect group differences. Further clinical studies with larger numbers of patients will be needed to robustly test the sensitivity to group differences.2 and T2* mapping can be substantially reduced, by utilizing high radial undersampling in 2in1-RARE-EPI together with CS-reconstruction. This improvement comes at the cost of only minor reductions of high spatial frequency information, and provides a proof-of-concept technical foundation to support the implementation of quantitative mapping in routine clinical practice. This approach could also be applied to broader clinical studies on the potential use of T2 and T2* as imaging biomarkers of neuroinflammatory and neurodegenerative diseases, thereby expanding previous work [2 and T2* maps. The potential range of clinical applications for accelerated 2in1-RARE-EPI for T2 and T2* mapping extends well beyond MS to several other pathologies in the brain and other target organs.We demonstrate that the scan time for simultaneous Tous work ,48,49 us


This study aimed at evaluating left ventricular myocardial pixel-wise T2* using two truncation methods for different iron deposition T2* ranges and comparison of segmental T2* in different coronary artery territories.R2 and SNR truncation. T2* was analyzed at different iron classifications. At low iron classification, T2* values were also analyzed by coronary artery territories.Bright blood multi-gradient echo data of 30 patients were quantified by pixel-wise monoexponential T2* fitting with its R2 truncation produces a significantly higher T2* value than the SNR method when low iron is indicated.The right coronary artery has a significantly higher T2* value than the other coronary artery territories. No significant difference was found in classifying severe iron by the two truncation methods in any myocardial region, whereas in moderate iron, it is only apparent at septal segments. The Clear T2* differentiation between the three coronary territories by the two truncation methods is demonstrated. The two truncation methods can be used interchangeably in classifying severe and moderate iron deposition at the recommended septal region. However, in patients with low iron indication, different results by the two truncation methods can mislead the investigation of early iron level progression. Cardiac magnetic resonance imaging (MRI) by multi-gradient echo (MGE) has become a widespread method for the non-invasive assessment of myocardial iron deposition –3. MyocaThe established myocardial T2* is assessed by either pixel-wise quantification , 18, 19 In the bright blood mode, signal plateau or offset can occur at longer TEs. This offset is due to noise bias, heterogeneous iron distribution in myocytes, signal offset, myocardial blood volume, motion artifact, or iron-poor tissue contributions . TherefoR2), known as the R2 truncation method, can also be a criterion to exclude data points at longer TEs [Another way to handle the signal plateau is by truncating higher TE data when the signal intensity reaches the noise level , 18, knonger TEs , 12. Comnger TEs , 22, 23.R2 truncation methods in evaluating the pixel-wise T2* value for LV myocardial iron detection and analyze and compare the T2* values of the different coronary artery territories in the low iron deposition category, especially in the absence of major iron deposition before its progression.It is known that different coronary arteries supply different circumferential regions of the left ventricle (LV) , as showShort-axis images of 40 patients were acquired using a clinical routine MGE cardiac MRI protocol between February 2009 and May 2016. The data were analyzed retrospectively, and the hospital review board waived the informed consent requirement. Motion correction was not performed, but images from ten patients were excluded due to respiratory motion blurring. The remainder of 30 included patients consisted of six patients with thalassemia , six with hemochromatosis , thirteen with suspected cardiomyopathy , and five patients with sickle cell disease , congenital dyserythropoietic anemia , chemotherapy (14 year), blood transfusion , or congenital heart disease .2 that reflects the patient size, a body matrix coil of 6–9 elements and a spine matrix coil of 12–24 elements were used. The MGE sequence used a number of excitation (NEX) of 1 and a reconstructed voxel size of 1.56 × 1.56 × 10 mm3. Phase resolution sampling of 50% was applied using 18–24 cardiac cycles per breath-hold with five segments in each heartbeat. Eighteen patients were scanned at the apical, mid-ventricular, and basal short-axis slices, while the rest were only scanned at the mid-ventricular slice. Four patients undergoing multiple follow-ups were acquired four complete short-axis slices at the three standard locations and three at mid-ventricular. Therefore, a total of 22 apical, 37 mid-ventricular, and 22 basal short-axis slices were acquired  without enabling parallel imaging. From 2009 till 2011, the Avanto scanner  was used on 18 patients. From 2012 till 2016, the Aera scanner  was used on the subsequent 12 included patients. Depending on the field of view of 275–362 × 400 mmy, K, TE, and T2* represent the signal intensity, a fitting constant, echo time of the MGE image series, and myocardium transverse relaxation time. A default non-linear least square curve fitting (MATLAB lsqcurvefit function) with trust-region-reflective was used to perform the fitting with a minimum K, and T2* constraint values were kept to be 0.Custom-written software  was used to apply pixel-wise myocardial T2* quantification on all segments by a classic monoexponential fitting  as follob represent the noise factor, pixel-wise signal intensity, and the standard deviation of a region of interest of air background, respectively. The noise factor accounts for underestimating noise derived from complex-magnitude data, assessed using the root of the sum of square (SoS) reconstruction and equals 0.71 for up to 32 coil elements according to Table Two monoexponential truncation methods were adopted in this study. The SNR truncation method used pixel's SNR as a longer TE data point exclusion criterion with the SNR defined by the following equation :2\docume2 truncation used pixel's fitting R2 as the longer TE data point exclusion criterion. The exclusion will automatically exclude the point until the monoexponential fitting R2 exceeds a threshold value of 0.995 [Using the custom-written software, the SNR truncation method automatically excluded any pixel-wise TE data point with SNR below 2.5  starts fof 0.995 , 12 or, A cardiac radiologist with more than 10 years of experience performing semi-automatic LV epicardial and endocardial contours segmentation. The segmentation is conducted using custom-written software developed in MATLAB version 7.14; The MathWorks, Natick, MA, USA adapted from another study . The AHAInvasive iron deposition measurement was not conducted in this study. Therefore, iron deposition pathology was indicated by normal, moderate iron deposition, or severe iron deposition based on medians of pixel-wise T2* in the AHA segments. T2* classification for normal pathology  was T2* > 20 ms, while for moderate iron deposition was 10 ms ≤ T2* ≤ 20 ms and for severe iron deposition was T2* < 10 ms , 33.A flow chart of data assessment is shown in Fig. P < 0.05 was considered statistically significant.IBM SPSS Statistics software version 23  was used for statistical testing. Multiple comparisons by one-way analysis of variance with Bonferroni post hoc test was used for normally distributed data. Kruskal–Wallis test analysis with Dun-Bonferroni post hoc test was used for non-normally distributed data. Shapiro–Wilk test was performed to test the normality of data distribution. According to the classic monoexponential fitting method, from a total of 442 segments, 360 segments of 29 patients were classified as without iron deposition, 64 segments of 21 patients with moderate iron, and 18 segments of three patients with severe iron deposition, as shown in Fig. Of 22 patients with data allowing for a complete AHA 16-segment model analysis, 20 had a global monoexponential T2* without iron deposition. One patient with congenital dyserythropoietic anemia had severe iron deposition in 14 segments, with only two segments classified as moderate. Another patient with thalassemia had a majority of moderate iron deposition segments with three severe iron deposition segments and only one segment at the borderline without iron classification. After a one-year follow-up, the patient had five segments classified as moderate and eleven segments without iron classification. Visual inspection showed a minor region of susceptibility artifact at the inferolateral region on 53 out of 59 collected segments.P < 0.01), as shown in Fig. R2 truncation, no significant difference was found between the RCA and the LAD (P > 0.05). No significant difference was found between the LCx and the LAD by the three fittings (P > 0.05).Evaluated by the three monoexponential fitting methods on 20 patients without global iron deposition, the RCA territory had a higher T2* value than the LAD and the LCx territories (P < 0.05).Histogram analysis on each territory in Fig. R2 truncation method consistently produced higher segmental T2* values in the absence of iron deposition at all investigated regions (P < 0.01), as shown in Table R2 goodness of fitting maps, presented in Fig. R2 fitting of the two methods tends to reduce. On its majority pixels, the R2 truncation method used four early TE points to quantify T2*, i.e., 87.83%, 83.97%, and 93.99% of total pixels at the global myocardium, septal, and inferolateral regions, respectively. Meanwhile, the SNR truncation method used all TE points for the T2* quantification at the exact locations, i.e., 98.16%, 99.81%, and 92.81% of total pixels.Compared to the classic monoexponential and the SNR truncation method, the s P < 0.0, as showR2 truncation method were significantly higher than the T2* resulted from the other two fitting methods (P < 0.001). Table R2 truncation method used four TE points in the majority of 86.56% pixels to quantify T2* while the SNR truncation method used all TE points in 88.92% pixels. Meanwhile, at septal and inferolateral regions, even though a different use of TE points in the majority of pixels remains (Table P > 0.05). Segmental T2* quantification by the three monoexponential fitting methods was not significantly different in severe iron deposition segments at any investigated region (P > 0.05). Table In moderate iron deposition classification at the global myocardium region, the T2* values from the ns Table , the T2*R2 truncation, as shown in Fig. In all iron deposition classification and at different analyzed locations, the elimination of later TE points increased the T2* values when quantified by the This study demonstrated T2* heterogeneity in different circumferential regions according to coronary artery territories. T2* differences were also apparent when the analysis focused on the coronary arteries' contribution in supplying blood on segments. A consistent T2* heterogeneity by the two truncation methods was also found in the territories analysis based on its contribution on segments.T2* variation occurred from different pixel-wise monoexponential curve fitting truncation methods. These apparent discrepancies apply either to the myocardium (AHA 16-segment model) or at the septal and inferolateral regions.. Therefore, the difference can influence clinical decision-making, especially in the myocardial region indicated with moderate iron deposition and without iron deposition, for the early treatment of patients with thalassemia, hemochromatosis, cardiomyopathy, and sickle cell disease.It is known that some center prefers mid-ventricular septal to detect iron loading , 10, 14,2 truncation likelihood in eliminating later TE points shows that the method is sensitive to pixel-wise signal intensity fluctuation to produce optimum R2 fitting. It is known that the source of the signal's fluctuation can be from partial volume voxel, cardiac motion, flow artifact, or fat and water phase oscillation [R2 until its maximum threshold, in this study 0.995, will push the TE point's elimination to meet the required R2 setting and leads to bias T2* measurement for iron deposition determination. An example is a possible missing chance of early iron deposition identification, as shown in the comparison between Fig. K value of Eq. R2 truncation [The nature of Rillation . Therefouncation .R2 fitting, as shown in the comparison between Fig. R2 fitting of the R2 truncation method in the presence of susceptibility artifact. TE points elimination can lead to a high T2* value, as shown in Fig. TE point elimination's main idea was to eliminate the influence of signal plateau at longer TE due to noise and artifact , 22. TheThe SNR truncation eliminates later TE points when its signal's SNR is below a certain threshold. This procedure will dominantly eliminate TE points in the presence of signal plateau at longer TE. This truncation means that the method will selectively eliminate TE points when the signal's SNR is below the susceptibility artifact regions' threshold. Several studies have reported that TE truncation, at 1.5 T was mainly apparent after 10 ms , 45, 46.At severe iron classification, even though truncated until 4 points, the similarity of T2* between the two truncated methods with the classic monoexponential is acquired due to the capture of fast relaxation component at early TE as shown in Fig. It is important to realize that T2* heterogeneity on circumferential regions can be explained due to the different contributions of coronary artery territories on each segment . The preIn the RCA territory, it seems that other territories also support segments 4 and 10. Therefore its T2* was lower compared to segments 3 and 9. Broader T2* range at segment 15 was explained due to the support of all territories at this segment. Meanwhile, in the LCx territory, segment 5 has lower T2* variability due to its exclusive support only by the LCx, as shown in Fig. Similar T2* heterogeneity by the two truncation methods on coronary artery territories and circumferential regions reflects a different iron deposition progression on different locations. This clear finding is observed when the analysis used the dominant coronary artery segments as suggested in Fig. When later TE points elimination is conducted to avoid any influence of signal plateau due to artifacts, the SNR truncation method is preferable to achieve the goal, as demonstrated in this study. However, it is essential to consider that the accuracy of the T2* values obtained with different fitting methods does not directly reflect tissue iron status . A diffeHere, the comparison of pixel-wise fitting methods and the influence of noise and artifact in T2* quantification of the myocardium was limited to the bright blood mode. Even though a low NEX was performed in this study, an attempt to increase NEX might reduce noise but at the expense of increasing scanning time , 44. ThiFurthermore, rather than correcting for artifact contributions in the MGE data analysis, one might prefer to optimize the MGE imaging method to reduce and eliminate artifacts before the curve fitting (beyond the scope of this study). Another limitation is that this study used different scanners and slightly different TEs for acquiring the MGE series, relying on previous studies confirming the MRI sequence's reproducibility , 10. TheA limited number of patients each year who follow the MGE MRI clinical routine in our center also holds the strength of the analysis. The validation of the T2* measurement with the patient’s total body iron or other cardiac MR evaluations –58 is reIn conclusion, this study shows that focusing the coronary artery territories analysis based on the artery contribution on the segments produces a consistent T2* heterogeneity pattern by the two truncation methods. Moreover, the indication of severe and moderate iron deposition at the recommended septal region can be classified interchangeably by the two T2* truncation methods. Nevertheless, T2* differences remain in the region with no iron indication suggesting further investigation to avoid misleading early iron progression investigated by the two methods.


Transcatheter mitral valve prostheses are designed to capture the anterior leaflet and surgical techniques designed to fully preserve the subvalvular apparatus at prosthetic valve insertion both serve to shorten the anterior mitral leaflet height, thus effectively incorporating it into the anterior annulus. This study quantifies the acute effects of incorporating the anterior mitral leaflet into the annulus on left ventricular function.Fourteen adult sheep  underwent a mechanical mitral valve insertion on normothermic beating-heart cardiopulmonary bypass, with full retention of the native mitral valve but with placement of exteriorized releasable snares around the anterior mitral leaflet. Continuous measurements of left ventricular mechano-energetics were recorded throughout, alternating incorporating and releasing of the anterior mitral leaflet to the mitral annulus. Echocardiography confirmed the incorporation into the annulus and release.The independent indices of left ventricular contractility  were both significantly impaired when the anterior mitral leaflet was incorporated to the annulus and restored after release, as were the hemodynamic parameters: cardiac output, stroke volume, stroke work, and left ventricular pressure decreased by 15%, 17%, 23%, and 11%, respectively. Echocardiography demonstrated increased sphericity of the left ventricle during anterior mitral leaflet incorporation.Incorporating the anterior mitral leaflet to the anterior annulus adversely affected left ventricular contractility, caused distortion of the left ventricle in the form of increased sphericity, and impaired hemodynamic parameters in normal ovine hearts. Schematic representation of anterior mitral leaflet (AML) incorporation to the anterior annulus and its adverse effects on LV contractility, geometry, and hemodynamic parameters in normal ovine hearts. Compared with AML release, incorporating the AML to the mitral annulus was associated with significant decreases in LV contractility and in cardiac output by 15%, stroke volume by 17%, stroke work by 23% and LVP by 11%. Incorporating the AML to the mitral annulus preserves annulo-papillary continuity but adversely affects valvular–ventricular interaction resulting in impaired LV function.Incorporating the AML to the annulus fixes the free edge of the leaflet to the anterior annulus, acutely impairs LV function and distorts ventricular shape. Surgical techniques that similarly immobilize the AML and transcatheter mitral valves that capture the AML, effectively incorporating it into the annulus might adversely affect LV function through the valvular–ventricular interaction.121 and 123.See Commentaries on pages Mitral valve surgery aims to correct hemodynamic parameters without impairing left ventricular (LV) function. As opposed to the concept of annulo-papillary continuity, which implies a passive interaction, valvular–ventricular interaction (VVI) is based on complex mechanical dynamics between the mitral valve and the LV wall through the papillary muscles, the chordae tendineae, and mitral leaflets.The objectives of this study were to evaluate the acute effects of AML incorporation on LV function and contractility. Based on the importance of the AML to the VVI and the disappointing survival rates following transcatheter mitral valve insertion, we hypothesized that incorporating the AML to the mitral annulus would impair LV function.Fourteen healthy adult Merino first cross sheep  received humane care in accordance with the requirements of the Australian code for the care and use of laboratory animals. Animals underwent a minimum acclimatization period of 14 days.Sheep were premedicated intravenously with a combination of methadone at 0.2 mg/kg and midazolam at 0.4 mg/kg. Anesthesia was induced by administering propofol intravenously to effect, to facilitate orotracheal intubation. Anesthesia was maintained with inspired 1% to 2% isoflurane delivered in an air/oxygen mixture and ketamine at an intravenous infusion rate of 20 μg/kg/min. Morphine injections at 0.5 mg/kg intravenously were repeated every 4 hours. Mechanical ventilation was initiated to maintain end tidal carbon dioxide pressure between 35 and 50 mm Hg and oxygen saturation >93% measured using pulse oximetry. Central venous and arterial pressures were continuously monitored via fluid-filled catheters in the external jugular vein and the aortic arch, respectively. Arterial blood gas, electrolyte analysis, blood lactate levels, and activated clotting times were measured periodically throughout the anesthetic to assess physiological status and ensure normal organ perfusion. Noradrenaline infusions were administered to effect (0.1-1 μg/kg/h intravenously) to support the maintenance of normotension.Each sheep was positioned in right lateral recumbency and a left lateral thoracotomy was performed via the fifth intercostal space. The pericardium was opened, and the heart was supported in a pericardial cradle.A transit-time ultrasonic flow probe  was placed around the main pulmonary artery to measure the cardiac output. Central venous and aortic blood pressure were recorded via fluid-filled manometer catheters in the external jugular vein and the aortic arch. A straight pressure volume conductance catheter  was inserted transapically into the LV with the tip positioned in the ascending aorta for stabilization in 8 sheep and a pigtail conductance catheter was inserted in a retrograde fashion via a left carotid artery cutdown in 6 sheep. The catheter was calibrated using the Millar pressure volume loop system control software before cardiopulmonary bypass (CPB) and was connected to a data acquisition hardware device  for reliable data acquisition. All recording devices were linked to a data analysis software program  that allowed simultaneous acquisition of all signals. A Rummel tourniquet was placed loosely around the inferior vena cava.CPB was established with right atrial and aortic arch cannulation. Normothermia was maintained with a perfusion pressure of 70 mm Hg and a flow rate similar to the pre-bypass cardiac output. No cardioplegia was used.The empty beating heart was partially filled and a left atriotomy was performed through the atrial appendage whereupon the mitral valve was immediately rendered incompetent to prevent air embolism. The native mitral valve was fully retained. Two 4–0 polypropylene sutures were placed through the mitral annulus at the level of each trigone, around the anterior leaflet chordae of each papillary muscle then through the center of the anterior mitral annulus and then exteriorized through the roof of the left atrium adjacent to the aorta. Each suture was then passed through a snare so that snaring the sutures would incorporate the AML to the anterior mitral annulus. A third suture encircled the snaring sutures adjacent to the AML and was exteriorized through the LV wall midway between the papillary muscle bases to ensure complete release of the AML  The exteOnce off bypass, baseline LV mechano-energetic measurements were recorded under stable hemodynamic conditions before any mitral intervention (AML incorporation or release). The AML was sequentially incorporated to the anterior annulus and released during continuous monitoring of LV dynamics. AML incorporation and release procedures were performed multiple times, allowing multiple measurements of the influence of AML incorporation then release on LV mechano-energetics. All hemodynamic data representing data points were collected and averaged over a period of 20 seconds during hemodynamic stability, within 1 minute after mitral intervention. Stroke volume and stroke work measurements were calibrated from the instantaneous cardiac output recorded using the pulmonary artery transit-time ultrasonic flow probe. For each intervention and when the animal was hemodynamically stable, pressure-volume relationships were measured during end expiration breath-holds with temporary occlusion of the inferior vena cava using the Rummel tourniquet. In 5 sheep there was difficulty maintaining adequate oxygenation measured by pulse oximetry and blood gas analysis despite 100% inhaled oxygen. In these sheep, it was not considered appropriate to perform multiple breath holds with inferior vena caval occlusion during periods of AML incorporation to the annulus and so the contractility studies were not performed.Epicardial 2-dimensional and color-Doppler echocardiography  was performed to rule out cardiac abnormalities before establishing CPB. Echocardiography confirmed that the AML incorporation and release mechanisms worked appropriately . EchocarAt the end of each study, the sheep was put to death by rapid exsanguination into the CPB reservoir. The heart was excised, and the accuracy of the prosthetic valve insertion and incorporation to the annulus/release system were confirmed .2 test. Normally distributed variables were described using mean and standard deviation and nonnormal data as median and interquartile range. As multiple within subject measures were obtained, within subject means were calculated for each dependent variable. Within subject means for each variable were tested using the Wilcoxon signed-rank test for nonparametric paired data, and a paired t test for parametric data. Thus, there were 14 data pairs for the hemodynamic tests, 9 for the contractility measures, and 6 for the echocardiography measures. The effects of repeated incorporation/release for each of the dependent variable per subject were tested using a 1-way analysis of variance for repeated measures. All data were described using median and interquartile range for presentation in the figures and tables. Analyses were also examined using a linear mixed model, where the fixed effect was incorporation/release trial, and the random effect was the subject. Results from the linear regression analysis were all significant and consistent with the findings of the paired analysis. All calculations were performed using Stata version 13 .Normality of dependent variables was tested using the D'Agostino KP = .0015), stroke volume by 17% (P < .0023), stroke work by 23% (P = .0001), LV end systolic pressure by 8% (P = .0230), and mean LV pressure by 11% (P = .0016) (P = .0058). No significant difference was observed for LV end-systolic and end-diastolic volumes, dP/dt max, and heart rate  in 14 sheep . Signifi= .0016) . After Aart rate .Table 1DP = .0277) and 10% (P = .0431), respectively, compared with its release.  (P = .03) and an increase in diameter by 1.0 ± 0.23 mm (P = .2).Echocardiographic measurements in 6 sheep showed that incorporating the AML was associated with a significant increase in LV cavity sphericity in diastole (P = .04) . This waFor each dependent variable tested, there was no bias observed within the repeated AML incorporation/release during the experiment.A normothermic beating heart ovine model was used to avoid myocardial ischemia associated with cardioplegic arrest. This enables multiple open-heart interventions on CPB to be performed without an extended recovery period. Externalized sutures were used to incorporate the anterior mitral leaflet to the anterior annulus in a releasable fashion so that multiple measurements were taken on each side of instantaneous changes in the anterior mitral leaflet during periods of hemodynamic stability. The AML incorporation to the annulus by snares was intended to mimic various techniques that have been reported but did not replicate any reported technique.,,,The chordal annulo-papillary connection prevents excessive diastolic dilation.,,,The long axis of the LV shortens during systolic ejection but the distances from the papillary muscle tips to their ipsilateral fibrous trigones remain near constant,Incorporating the AML caused an acute impairment of LV function through disturbance of the VVI despite maintenance of annulo-papillary continuity. In this study, incorporating the AML reduced the ESPVR by 61%. In a previous study by Hansen and colleagues,The VVI is a complex dynamic where Newtonian forces are applied between the mitral valve and the LV.,The diastolic baffle effect of the AML improves the laminar flow through the LV and the axisymmetry of the transmitral vortex ring during diastole, reducing energy dissipation associated with flow turbulence.The extent of impairment of LV contractility seen in this study is unlikely to be explained solely by the removal of the baffle effect or by the diastolic restriction of the LV long axis, or even by the combination of the 2, both of which are diastolic components of the VVI. Therefore, it is reasonable to consider that a systolic component of the valvular–ventricular support has been disturbed. The force required to prevent the leaflets prolapsing into the atrium (closing force) is estimated at just more than 50% of the total chordal force.These results are likely to be applicable to transcatheter mitral valve replacement systems designed to capture and incorporate the AML to the mitral annulus for annular fixation of the prosthesis. The first reported human implantation was for a patient with grade IV mitral incompetence with severe LV impairment.Likewise, in surgical prosthesis insertion, it is desirable to achieve maximal preservation of the VVI. Therefore, surgical techniques that retain the AML during mitral valve replacement should not be based on incorporating the leaflet to the mitral annulus. Our study did not assess the ability of the LV to adapt to the effects of incorporation. If adaptation occurs predominantly in the form of restoration of stroke volume rather than correction of end diastolic volume, the observed reduction in LV volumes and increased LV ejection fraction will be seen as beneficial. This may be misleading if the restoration of stroke volume is at the expense of the ability to increase stroke volume with exercise. A plethora of complete chordal-sparing techniques have been described.Variations in creating the animal models are unavoidable, but every effort was made to reduce the variation. All procedures were performed by a senior cardiothoracic surgeon (H.S.P.) experienced in both human and ovine mitral valve surgery. The accuracy of measurement of absolute LV volumes was limited because the conductance catheter was only calibrated once before CPB and required adjustment of its position after CPB. However, there was no apparent catheter movement during the incorporating and releasing procedures and so the comparative measurements should be considered to be valid.Only a limited number of echocardiographic measurements were taken in 6 sheep in accordance with the protocol of specific assessments. We did not measure papillary muscle movements or distances from the annulus. In retrospect, this would have been of interest.This study did not assess the ability of the LV to adapt to the effects of AML incorporation. It is possible that the changes observed in LV geometry and function following AML incorporation would become less significant after a period of adaptation.The relationship between the extent of AML incorporation and the severity of LV dysfunction was not assessed. Incorporation was complete or absent. It seems unlikely that the relationship would be linear. Lesser degrees of incorporation that might occur with transcatheter valves or with various surgical forms of chordal preservation might have minimal adverse effects on LV function. None of the sheep had mitral regurgitation with attendant LV enlargement, which limits the comparison to patients selected for transcatheter mitral valve repair or mitral valve replacement.The results of this study demonstrate that incorporating the AML to the mitral annulus during mitral valve replacement acutely and adversely affects LV contractility, causes distortion of the LV in the form of increased sphericity, and impairs hemodynamic parameters . ClinicaThe authors reported no conflicts of interest.Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.The