This study attempted to explore the hemodynamics and potential mechanisms driving pulmonary circulation in status of ventricular fibrillation (VF) following continuous-flow left ventricular assist device (CF-LVAD) implantation.An ovine CF-LVAD model was built in small-tailed Han sheep, with the pump speed set as 2,400 rpm. VF was induced following ventricular tachycardia using a temporary pacemaker probe to stimulate the right and left ventricular free walls. The central venous pressure (CVP), pump flow (PF), pulmonary artery flow (PAF) and other major indicators were observed and recorded after VF.Low-flow systemic and pulmonary circulation could be sustained for 60 min under VF with sinus atrial rhythm after CF-LVAD implantation. The CVP gradually increased. The mean PF declined from 1.80 to 1.20 L/min, and the mean PAF decreased from 1.62 L/min to 0.87 L/min. Under VF with atrial fibrillation, the systemic and pulmonary circulation couldn’t be sustained. The CVP jumped from the 5 mmHg baseline to 12 mmHg, the mean PF rapidly decreased from 3.45 L/min to 0.79 L/min, and the PAF declined from 3.94 L/min to 0.77 L/min.The atrial rhythm and function might be essential for the circulation maintenance in patients with VF after CF-LVAD implantation. Mechanical circulatory support (MCS) with continuous-flow left ventricular assist device (CF-LVAD) has been preferably used as a “bridge” device before a heart transplantation and regarded as one of the long-term treatment options for patients with end-stage heart failure. Nonetheless, ventricular arrhythmias (VA) including ventricular fibrillation (VF) which is common in malignant arrhythmias, are frequent after CF-LVAD implantation with an incidence of about 20–60% , 2. UndeThe right heart function is still crucial after CF-LVAD implantation given its role in driving pulmonary blood return to the left heart, which is important for the systemic circulation, even though the CF-LVAD can substitute for the left ventricle to perform the systolic function thereby sustaining the systemic circulation. Theoretically, the VF following CF-LVAD implantation is accompanied by complete loss of the right ventricular squeezing, leading to reductions in CF-LVAD preload and cardiac output, which eventually results in circulatory collapse. To the contrary, no clinical signs of serious circulatory failure are found in VF patients with CF-LVAD in the shorter term, instead some non-specific symptoms such as fatigue, chest tightness or drowsiness –7.Currently, the hemodynamics of VF after CF-LVAD implantation remains elusive. In this study, an acute ovine CF-LVAD model was devised in small tail Han sheep. The systemic and pulmonary circulation was observed and the potential mechanism driving the pulmonary circulation was explored, which may provide possible theoretical explanations for the VF after CF-LVAD implantation.HeartCon Ventricular Assist Device  was applied as the CF-LVAD, with the body made with titanium alloy and a maximum auxiliary flow of 10 L/min .Two healthy adult male Small Tail Han sheep, each aged 16- and 18-month and weighed 56 and 58 kg, were used as model A and model B. All the two sheep were purchased from Xi’an Dilepu Biology & Medicine Co., Ltd (SCXK [Shanxi] 2014-004). All the two sheep were housed in separate cages for 2 weeks, and no abnormal clinical signs or blood indicators were observed. All protocols and experimental procedures were approved by the Institutional Animal Care and Use Committee of TEDA International Cardiovascular Hospital. Animal experiments were performed in accordance with the National Institutes of Health guidelines for the Care and Use of Laboratory Animals and the Regulations for the Administration of Affairs Concerning Experimental Animals (2017.03.01 edition) published by the State Council of the People’s Republic of China. At the end of the experiment, the animals were euthanized by injection of high concentrations of potassium chloride under anesthesia.The two sheep were subjected to 24-h fasting and 20-h water deprivation prior to operation. After animal sedation by intramuscular injection of xylazine (1.0 mg/kg), the surgical site was exposed, and the neck skin was prepared. Vascular access was obtained through the great saphenous vein, and an intravenous bolus of propofol (60–200 mg) was injected. Tracheal intubation was then performed with parameters including tidal volume 8–12 ml/kg/min, frequency 12–20 times/min, inspired oxygen concentration 40–100%, positive end-expiratory pressure 5–10 mmHg (1 mmHg = 0.133 kPa) and sevoflurane inhalation 2–4%. A nasogastric tube was inserted for decompression. The arterial puncture was achieved through the left ear to obtain arterial access, and central venous access was obtained via puncture of the left internal jugular vein. Anesthesia was maintained by continuous infusion of dexmedetomidine (0.5–1 mg/kg/h) and succinylcholine (50–100 mg/h).A thoracotomy was performed at the left fifth intercostal space, and a lidocaine drip (2 mg/min) was initiated to prevent arrhythmias. The pericardium was incised from the apex to the pulmonary artery, and the heart was suspended in a pericardial cradle. The site for pump placement was determined according to the apex position. After obtaining a whole-blood clotting time greater than 450s by intravenous bolus injection of 1.0 mg/kg heparin, the descending thoracic aorta was dissected for outflow graft anastomosis. A partial occlusion clamp was applied, and the pump’s 10-mm outflow graft was sewn end-to-side to the descending aorta with 4-0 Prolene sutures. Hemostasis of the anastomotic site was obtained to reduce the effect of excessive bleeding on capacity loading. The sewing ring was attached to the left ventricular apex with 8 interrupted sutures. The left pleural cavity was filled with warm normal saline. A cruciform incision was made on the beating heart. Then a ventricular punch was advanced through the ventricular sewing ring, the left ventricular core was removed, and the pump was inserted into the left ventricular cavity and secured. The pump was started at 2,000 rpm; then, the artificial blood vessel was opened after full gas exhausting. In the context of circulatory stability, a temporary pacemaker electrode was implanted in the free wall of the right ventricle and left ventricle, respectively.The pump speed was adjusted to 2,400 rpm, and baseline data were recorded after stable vital signs and circulatory stability were obtained. The ventricular rate was controlled by pacing, with the initial rate as 180 beats/min at an increasing rate of 20 beats/min. Rates at 180 beats/min, 200 times/min, 220 times/min and above were recorded and the corresponding circulatory conditions were studied.A multi-channel physiological recorder  was used to record the heart rate (HR), aortic pressure (AOP) (the measurement point was aortic root), central venous pressure (CVP) , left atrial pressure (LAP) and left ventricular pressure (LVP) etc. A double-channel ultrasonic flowmeter  was operated to obtain real-time pump flow (PF) (the measurement point was pump outflow graft) and pulmonary arterial flow (PAF). A blood gas analyzer  was applied to perform arterial blood gas (ABG) analysis every 10–15 min. A color doppler ultrasound  was used to calculate right/left ventricular ejection fraction (RVEF/LVEF) and assess aortic valve function by cardiac surface ultrasound every 10–15 min.The baseline pump speed of both model A and model B was 2,400 rpm. Supported by CF-LVAD, the LVEF and RVEF respectively were 65 and 48% in model A while 72 and 64% in model B; the mean PF and PAF respectively were 1.80 and 1.62 L/min in model A while 3.54 and 3.94 L/min in model B; the CVP was 6 mmHg in model A and 5 mmHg in model B . The basUnder ventricular tachycardia (VT) following CF-LVAD implantation, CVP showed a gradual upward trend while PAF exhibited a downward trend with the increase in ventricular rate . When thThe cardiac electrical activity, PF, PAF and atrial/ventricular pressure of the animal models are described in Ventricular fibrillation was induced in both the model A and model B when the ventricular rate reached 320 beats/min, while there was distinct difference. In model A, VF occurred with sinus atrial rhythm and is accompanied by gradually increased CVP  and waveform amplitude (from 3 mmHg baseline to 7 mmHg at 60 min) with increasing duration. Both LVP and AOP were lower than the normal baseline after VF. Both mean PF and PAF went down while were kept at 1.20 and 0.87 L/min, respectively, during the whole process of VF. The cardiac electrical activity, PF, PAF, CVP, and LVP/AOP after VF were detailed in In model B, VF occurred with AF, accompanied by rapid increase in the mean CVP (from 5 mmHg baseline to 12 mmHg) along with irregular waveform and reduced amplitude. In the meantime, the mean PF (3.54–0.79 L/min) and PAF (3.94–0.77 L/min) declined rapidly with the loss of regular waveform. The LVP and RVP also dropped rapidly, and the RVP fell to nearly 0 mmHg. The cardiac electrical activity, PF, PAF, and LVP/RVP after VF were detailed in Ventricular tachycardia commonly occurs with hemodynamic disorders, together with accelerated ventricular rate and dramatically shortened period of ventricular diastole with deceased filling pressures, resulting in cardiac output reduction. VF is the major cause of sudden cardiac death immediately followed by severe hemodynamic disorders, systemic and pulmonary circulation arrest, and significantly depressed myocardial contractility caused by hypoxia and acidosis. CF-LVAD is mainly developed as an additional pump to the left ventricle to maintain the pumping function. Meanwhile, the native right ventricle remains important for maintaining the normal function of CF-LVAD, as it is responsible for complete pulmonary circulation, which is essential for the maintenance of hemodynamics and provides sufficient preload for CF-LVAD. Theoretically, VF occurs with the stop of native right ventricular contraction instantly followed by pulmonary circulation arrest, resulting in CF-LVAD dysfunction due to insufficient preload. However, patients with CF-LVAD support can survive with less severe clinical symptoms during onset VF, and in short period there may be no serious signs of hemodynamic failure –7, 9, 10In this study, a CF-LVAD was implanted in small tail Han sheep and VF was induced by increasing ventricular rate using a temporary pacemaker. Our observational study demonstrate that both the model A and model B exhibited stable hemodynamics when VT occurred. In the meantime, with the increase in the ventricular rate, the RAP increased and the RAF decreased, while the PAF was eventually stable at a certain low level. When the ventricular rate reached 320 beats/min, VF was induced in both the models with distinct difference. In model A, VF occurred with sinus atrial rhythm, accompanied by gradual increase in the RAP and the difference between right atrial systolic and diastolic blood pressures while reductions in the LVP, PF, and PAF. However, the reductions in PF and PAF were not significant. Circulation could be sustained and there was no significant acid-base disorder. During the whole process (60 min), the right ventricular ejection was still effective . In model B, VF occurred with AF, resulting in rapid increase in the RAP while reduction in the difference between right atrial systolic and diastolic blood pressures. Additionally, the LVP and RVP rapidly decreased to nearly 0 mmHg, while the PF and PAF also showed a significant downward trend. The circulation under this circumstance could not be sustained.Dib et al.  and JaksFirstly, under normal physiological conditions, Fontan circulation requires negative thoracic pressure. For surgical reasons, the negative thoracic pressure in the animal model was lost in the present study. As a result, the right atrium and right ventricle are not simply conduits for blood flow under VF following CF-LVAD implantation . Upon veMoreover, to maintain the hemodynamics after VF following CF-LVAD implantation, RAP should be also equal to or greater than the pulmonary arterial pressure as the Fontan circulation, while the value might be lower than 12 mmHg. Different from the dependence of Fontan circulation on pulmonary vascular development, CF-LVAD implantation can reduce pulmonary vascular resistance, i.e., afterload of the right heart. In addition, the CF-LVAD will fully replace the left ventricle after VF to complete pulmonary circulation with the right atrium via cooperating with the left atrium with sinus rhythm to reduce pulmonary vascular resistance.Combining the findings mentioned above, the present study believed that sustained atrial sinus rhythm is the hemodynamic characteristic under non-typical VF after CF-LVAD implantation. We found that the RAP and compensation in the right atrial contractility increased after blood return to the right atrium from the superior and inferior vena cava, which directly drove the blood flow from the non-functional right ventricle to the pulmonary artery and subsequently to the non-functional left ventricle through the pulmonary vein and left atrium. Finally, the blood was pumped into the systemic circulation by the CF-LVAD . During Presently, the cause of VF after CF-LVAD implantation remains undetermined. Besides, routine ECG or ECG monitoring is not able to clearly illustrate the atrial rhythm under a VF condition after implantation. Hence, patients with CF-LVAD implantation might present VF with sinus atrial rhythm as described in the current study. Based on our findings and previous research , for thoThere are some limitations to this study. First, the present study does not allow causal interpretation because it is an observational case study with a small sample size, although the now present findings serve as a sound basis for further mechanistic studies. Second, the VF with CF-LVAD model in this study was acute and without negative thoracic pressure, different with the chronic VF in clinical practice. However, the hemodynamics of the two types is supposed to be similar. Further larger-scale experimental studies and chronic animal experiment should be devised to explore the effect of long-term/recurrent VF on the hemodynamics and multi-organ functions.The hemodynamics in the context of VF after CF-LVAD implantation resembled but was not identical to the Fontan circulation. The atrial rhythm and function might be necessary for maintenance of the pulmonary and systemic circulation under VF after implantation.liuzg@tedaich.com.The original contributions presented in this study are included in the article/The animal study was reviewed and approved by Institutional Animal Care and Use Committee of TEDA International Cardiovascular Hospital.X-YY and J-WS: drafting article, design, data collection, data analysis, data interpretation, and critical revision of manuscript. Y-SR, Y-LC, T-WL, J-MZ, and Z-FH: concept/design, data collection, and data interpretation. Y-RZ and Z-AF: data collection. Z-GL: concept/design, data interpretation, critical revision of manuscript, and approval of manuscript. All authors contributed to the article and approved the submitted version.


A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR.18F]flurpiridaz in a total of 56 mice (7–8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake  was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging.Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [App was substantially higher in orchiectomized males , and low serum testosterone levels were linked to a blunted resting myocardial perfusion  as well as an enhanced CFRApp . In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females.Orchiectomy resulted in a significant decrease of resting myocardial perfusion , while myocardial perfusion at stress remained unchanged . Accordingly, CFROur experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.The online version contains supplementary material available at 10.1007/s00259-022-05675-2. Of note, [18F]flurpiridaz PET proved to be particularly accurate for CFR measurements in patient populations where tissue attenuation correction is challenging — including women and obese patients — suggesting that challenges of tissue attenuation correction can be overcome by the relatively high spatial resolution of images obtained with [18F]flurpiridaz flurpiridaz PET-MPI.Molecular mechanisms affecting coronary microcirculation are still under investigation and care must be taken in the interpretation of decreased CFR values. Previous studies have reported sex differences in the prognostic value of PET-derived CFR  as well Female and male FVB/N mice were purchased from Janvier Labs (France). Prior to shipment, animals were randomized into subgroups that were subjected to either sham-surgery or gonadectomy (Gx) at the age of one month. All animal experiments were performed in accordance with the Swiss animal welfare laws and were approved by the Cantonal Veterinary Office of Zurich (Switzerland). Mice were housed under specific pathogen-free conditions in individually ventilated cages with continuous free access to water and food ad libitum.18F]Flurpiridaz PET was conducted in a total of 56 animals (7–8 months) that were anesthetized with 1.3–1.9% isoflurane in oxygen-enriched air (1:1). Body temperature was monitored with a small rectal thermistor. [18F]Flurpiridaz was administered via tail-vein injection 60 s after scan start (0.6–8.2 MBq). Tracer distribution was recorded in dynamic PET acquisition mode over a time period of 41 min, before a mixture of regadenoson (0.1 μg/g), and a second dose of [18F]flurpiridaz was injected via a pre-installed intravenous catheter. In analogy to the rest scans, stress scans were acquired for 41 min. PET imaging was performed with a Super Argus PET/CT tomography , followed by a CT scan for anatomical information. PET data were reconstructed with a user-defined protocol at a voxel size of 0.3875 × 0.3875 × 0.775 mm3. PET data were processed with PMOD v.3.8 . A volume of interest (VOI) delineating the myocardium was drawn manually by PMOD v.3.8 . Average myocardial [18F]flurpiridaz uptake from 20 to 40 min post injection, calculated from % injected dose per mL of the myocardium (% ID/mL), was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported [App) was calculated as the ratio between myocardial [18F]flurpiridaz uptake following vasodilator stress and at resting conditions. The term “apparent” is used because CFRApp values were calculated without an arterial input function flurpiridaz uptake in both groups , which was not the case for gonadectomized animals . Representative baseline and hyperemic PET-MPI images of the male myocardium are depicted in Fig. Gonadectomy was confirmed by assessment of serum sex hormone levels as well as by visual confirmation of the absence of testicular tissue in male mice and the absence of ovarian tissue in female mice at the time of organ harvesting. Testosterone levels were diminished in gonadectomized males, while progesterone serum concentrations were substantially reduced in gonadectomized females  and enhanced baseline heart rate in males  and with heart rate reserve .Low serum testosterone levels were associated with a blunted resting myocardial perfusion . Along this line, the reduction in myocardial perfusion was linked to a reduced cardiac function on CMR, as evidenced by the reduced stroke volumes and LVEF in testosterone-deprived males. The concept that reduced baseline myocardial perfusion is a secondary effect of cardiac remodeling processes was further supported by the notion that orchiectomy, but not oophorectomy, prompted a significant reduction in LV mass, while no differences in body weight were observed between experimental groups.In the present experimental study, withdrawal of male, but not female, sex hormones increased CFR18F]flurpiridaz, which to date provides the highest spatial resolution among contemporary PET-MPI probes. Further, by performing rest and stress PET-MPI, we demonstrate that the vasodilatory effect of testosterone translated into increased myocardial perfusion at resting conditions, but not following injection of the pharmacological stressor. While the pharmacological stressor prompted maximal vasodilation, independent of testosterone levels, our findings imply that testosterone may act as a key modulator of CFRApp by selectively increasing resting myocardial perfusion. Along this line, high testosterone exposure in sham males may have resulted in the observed sex difference in CFRApp values for sham animals as the latter was reversed by gonadectomy.Consistent with our findings, previous reports have linked high testosterone hormone levels to an increased coronary vasodilation. As such, testosterone was found to trigger vasodilation in an in vitro study in isolated rabbit coronary arteries . SimilarIn agreement with previous reports, we found that low testosterone was associated with a reduction of LV mass , 19. TheTo date, few exploratory clinical studies have assessed the role of female sex steroids on myocardial perfusion and CFR. In agreement with our findings, Campisi et al. found that short- and long-term administration of 17β-estradiol did not affect myocardial perfusion . SimilarApp were only observed in sham animals and diminished following gonadectomy in our study. While a CFR < 2.0 is considered abnormal in humans according to current ECS guidelines [13N]ammonia and [15O]water. We anticipate that the availability of [18F]flurpiridaz, which allows PET-MPI in research facilities without an on-site cyclotron, will lead to an increased use of PET-MPI in rodents, thereby providing a valuable tool for CFR quantification by small animal imaging in future studies. Other factors that may directly or indirectly affect the measurement of CFR include the underlying animal strain, sex, and age. Indeed, our findings imply that sex hormones significantly affect the measurement of CFR. Similarly, others have observed age-dependent changes of myocardial perfusion and CFR in mice flurpiridaz availability, and thus tracer delivery to the myocardium. Indeed, regadenoson-induced changes in abdominal arterial flow may have resulted in an overall underestimation of the CFRApp values in our study. In the absence of an arterial input function, the latter cannot be excluded. Nonetheless, [18F]flurpiridaz exhibits higher uptake values in the heart compared to most other major organs, which limits the influence of extracardiac perfusion variability [App and baseline heart rate, establishing causality warrants further investigations into molecular pathways that translate testosterone effects into changes in coronary vasoregulation and cardiac adrenergic signaling.There are limitations to this study that should be noted. First, the findings obtained from this study are based on rodent data and may not be directly extrapolated to humans. However, previous reports have shown that testosterone-mediated regulation of autonomic function seems to be largely conserved across species –39. Secoiability . FinallyApp, respectively, these findings were not observed in females. To the best of our knowledge, this is the first study assessing the effect of orchiectomy and oophorectomy on myocardial perfusion and flow reserve using small animal PET. With regard to the translational relevance of the present findings, accounting for the variability in testosterone exposure may help to improve diagnostic accuracy of PET-derived CFR in specific patient populations and identify patient subpopulations that profit most from this diagnostic modality.In conclusion, our results indicate that sex differences in myocardial perfusion are primarily driven by testosterone. While orchiectomy and blunted serum testosterone levels were associated with a reduced baseline myocardial perfusion and an enhanced CFRESM 1(PNG 91 kb)High Resolution Image (TIF 497 kb)ESM 2(PNG 213 kb)High Resolution Image (TIF 639 kb)


In the current practice, graft ischaemia and reperfusion injury (IRI) is considered an inevitable component in organ transplantation, contributes to compromised organ quality, inferior graft survival and limitations in organ availability. Among all the donor organs, the heart is most vulnerable to IRI and the tolerated ischaemic time is the shortest.in situ NMP circuit was established, then underwent ex situ NMP and implanted under NMP support. The post-transplant graft function was monitored.By combining adapted surgical techniques and normothermic machine perfusion (NMP), we performed the first case of ischaemia-free beating heart transplantation (IFBHT) in man. The donor heart was procured after an ex situ NMP, the donor heart beat with sinus rhythm and adequate ventricular contraction, consumed oxygen and lactate, suggesting a good cardiac function. The dynamic electrocardiogram demonstrated an absence of ischaemic injury of the donor heart during the entire procedure. The echocardiogram showed an immediate graft function with a left ventricle ejection fraction (LVEF) of 70%. The patient was discharged on post-transplantation day 20 and was followed up for 8 months with normal cardiac function and life.The donor heart was procured, preserved, and implanted under a continuously perfused, normothermic, oxygenated, beating state. During This study shows the feasibility of IFBHT procedure, which might be able to completely avoid graft IRI, has thus the potential to improve transplant outcome while increasing organ utilization.This study was funded by National Natural Science Foundation of China, Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology, and Guangdong Provincial International Cooperation Base of Science and Technology. We searched for clinical studies on heart transplantation using machine perfusion as a preservation method. Previous studies have documented the safety and efficacy of ex situ normothermic machine perfusion and hypothermic oxygenated perfusion  for heart transplantation. However, the donor heart still suffers ischaemia during procurement and implantation. Ischaemia-free organ transplantation (IFOT) is an entirely new approach during which the organ is procured, preserved and implanted with continuous blood supply. Our group has shown the feasibility of this approach in liver and kidney transplantation.We searched PubMed using the terms ‘machine perfusion’, ‘This is the first report of ischaemia-free beating heart transplantation (IFBHT), confirming that this approach is feasible and safe. Considering that the donor heart is the most susceptible organ to ischaemia reperfusion injury, IFBHT offers an opportunity to improve transplant outcome and increase organ availability in heart transplantation.The concept of IFOT is feasible in liver, kidney and heart transplantation. By avoiding graft ischemia, IFOT is a promising approach to overpass organ shortage and post-transplant complications. Future studies should show “hard” clinical advantage, optimize the technology, and provide a positive cost-effectiveness analysis.Alt-text: Unlabelled boxHeart transplantation is the gold standard treatment for patients with end-stage heart failure.,Among all the donated organs, the donor heart is the most vulnerable to IRI, which largely limits the selection of donor hearts. For instance, donor hearts with an ischaemic time over 6 h or age older than 60 years are frequently discarded.To ameliorate donor heart IRI, efforts have been made in developing novel protection and preservation methods.We have taken an entirely novel approach avoiding ischaemia during heart transplantation and have developed an ischaemia-free beating heart transplantation (IFBHT) procedure. This approach is based on extensive pre-clinical work in large animals. Herein we present the first IFBHT in man.echocardiogram (ECHO) study showed enlargement of the left and right atrium, and the left ventricle, with a left ventricle ejection fraction (LVEF) of 27%, and an estimated pulmonary artery systolic pressure (PASP) of 56 mmHg. The contrast enhanced cardiac magnetic resonance (MR) study showed enlargement of the heart with extensive myocardial fibrosis; based on morphological changes together with a LVEF of 16%, the patient was diagnosed with a non-ischaemic dilated cardiomyopathy. Therefore, the patient was listed for a heart transplant. Preoperatively, the patient needed to undergo a surgical placement of an intra-aortic balloon pump (IABP) through the femoral artery. The patient was also receiving non-invasive ventilation for respiratory support.A 67-year-old male patient, presented with chest tightness and shortness of breath for four months. The On June 26th, 2021, a donor heart from our hospital was allocated to this patient through the China Organ Transplant Response System (COTRS). The donor was a 29-year-old man who died of a head trauma. Brain death was confirmed after intensive care treatment for 10 days. There was no history of cardiopulmonary resuscitation prior to organ donation. The pre-procurement creatine kinase MB (CK-MB) isoenzyme, and cardiac troponin I (cTnI) were 56 unit per litre and 0.012 ng per mililitre. The electrocardiogram (ECG) findings were within normal range (appendix p 3). An ECHO could not be done due to the presence of pneumomediastinum.During organ procurement, the donor was managed according to international standards.The heart NMP was conducted using a heart–lung machine . The main components include an automatic pressure and flow-controlled perfusion system, a membrane oxygenator , a leucocyte filter, an arterial filter, a heater-cooler unit, an autonomous power unit, and a programmable sequencer . Around ex situ NMP, the perfusion pressure, flow, temperature and contractility of ventricles were monitored. The arterial and venous perfusate samples were collected and analysed with a handheld lactate analyser . The heart rate and rhythm were monitored by ECG and visual assessment.During The composite definition of transplantability included (1) the perfusate pH value higher than 7.3 without continuous use of bicarbonate; (2) evidence of lactate clearance, including a downward trend of the lactate level in the perfusate or presence of arteriovenous lactate gradient with a final lactate level lower than 5.0 mmol per litre; (3) a coronary vascular flow of greater than 500 ml per min under a perfusion pressure of 60–100 mmHg; (4) heart beating with sinus rhythm rate of around 60–100 beat per min; (5) adequate right ventricular contraction without obvious evidence of wall motion abnormality. The donor heart was only accepted when it met all the above criteria.A pulmonary artery catheter (PAC) was placed under ultrasound guidance for PVR or trans-pulmonary gradient and pulmonary artery pressure measurement at the start of surgery. The central venous pressure was then monitored continuously, and blood gas analysis was performed intermittently to maintain a stable inner milieu. A TEE probe was placed after the induction of anesthesia, and a comprehensive examination was performed for early detection of hemodynamic instability. During operation, the anesthetic depth was titrated to maintain it at the E2-D1 level on Narcotrend monitoring  with hemodynamic stability.Post-CPB anesthetic management required close monitoring of PVR and pulmonary pressures with a PAC and a comprehensive TEE evaluation. Initial TEE focused on thorough de-airing of the cardiac chambers and on graft function.The post-transplant care was done according to our standard protocol. The patient received an induction therapy with Basiliximab (20 mg) intraoperatively and on day 4. Tacrolimus  and mycophenolate  were used for maintenance therapy with a target trough FK506 level of 8–10 ng/ml. Sulperazone, Vancomycin and Micafungin Sodium were used for prophylaxis therapy.The study protocol (2021-02) was approved by the Ethical Committee of The First Affiliated Hospital, Sun Yat-sen University.Funding did not influence study design, data collection, data analysis, data interpretation, or writing of the manuscript. The corresponding authors had full access to all data at any time and take final responsibility for the submission.umbilical tapes were positioned circumferentially. The aortic root and right atrium were sutured in a purse-string manner. After the donor was fully heparinized, the aortic root (for perfusion), right atrium and left ventricular apex (for drainage) were cannulated and connected to the heart-lung machine. The superior and inferior vena caval veins were clamped. The distal ascending aorta was cross-clamped and in situ retrograde coronary perfusion was started through the proximal ascending aorta directly from the heart-lung machine. The pulmonary artery and left atrium were cut open to vent the heart and maintain it in a decongested state. The pump flow was adjusted to maintain the mean aortic pressure between 60 and 100 mm Hg  was thus weaned off and the use of IABP was resumed. Drainage tubes were placed in the pericardium and mediastinum.On successful transition from CPB and removal of venous and aortic cannulae, protamine was given to reverse the heparin. Immediate evaluation of post-bypass coagulopathy was performed to ensure adequate reversal. The heart exhibited satisfactory contractility and pulmonary artery pressure after weaning from CBP. The heart rate, rhythm and blood pressure were stable. Video 2 shows the intraoperative TEE monitoring with synchronous dynamic ECG monitoring. The ECG showed no abnormality of the ST segments. The intraoperative TEE showed an immediate graft function with a LVEF of 70% (Video 2). Lactated Ringer's solution (1500 ml), normal saline (600 ml) and fresh frozen plasma (200 ml), washed red blood cells (460 ml) plus platelets (1 unit) were infused during the operation.The recipient operation time was 308 min, and the patient was transferred to the intensive care unit (ICU) for close monitoring.The recipient received a routine immunosuppression and antibiotics therapy in our center. The patient was extubated by day 2. The use of vasoactive drugs and IABP was discontinued on day 3. Although the levels of myocardial injury markers increased post-transplantation (appendix p 2), daily ECG showed no obvious evidence of myocardial ischaemia (appendix p 3). Daily ECHO demonstrated normal cardiac function with a LVEF greater than 75%; PASP dropped to 16 mm Hg post-transplantation. The patient had an acute kidney injury which recovered without the requirement for hemodialysis. Acute rejection and vascular complications did not occur. The patient was discharged on post-operative day 20. A routine chest CT scan showed multiple cavities in the left and right upper lungs on day 34, suggesting a fungal infection. The patient had no fever, cough and shortness of breath. After antifungal therapy, the cavities became smaller. Until this report written, the patient has been followed up for 8 months with normal graft function as assessed by ECHO with LVEFs greater than 60%.Since the first successful human heart transplant in 1967,During NMP, we confirmed the excellent quality of the cardiac graft by measuring perfusion pressure and flow; we also observed a downward trend of the lactate profile after NMP, as well as normal sinus rhythm and myocardial contractility. Importantly, the intraoperative TEE monitoring and visual inspection indicated continuous excellent cardiac function during the whole procedure. Therefore, the graft viability and function are well preserved during IFBHT. The levels of troponins and natriuretic peptides still increased post-transplantation, although no obvious ECG change indicated the presence of myocardial ischaemia. It is still unknown whether IFBHT can reduce the levels of these markers when compared to the conventional technique. The gold standard to assess graft IRI is pathological assessment of biopsy samples. For the safety of the patient, we did not conduct a biopsy in this first case. We are developing a protocol to conduct biopsies pre-procurement, at the end of NMP and after reperfusion during IFBHT to assess graft IRI.ex situ heart machine perfusion strategies. The organ care system (OCS) is to perfuse the heart in a normothermic, oxygenated, beating state.,There are at least two ex situ liver NMP,ex situ NMP is yet to be defined. Accumulated data will support an international consensus on the criteria.There are certain limitations concerning IFBHT that require further innovation. Firstly, this report only showed the feasibility of IFBHT. A well-designed trial to demonstrate both short-term and long-term benefits of our approach is on the way. Secondly, the heart was from a standard criteria donation after neurological determination of death (DNDD) donor in this case. The extended criteria donor hearts probably benefit the most from the novel procedure. The hearts from donation after circulatory determination of death (DCDD) donors might also benefit from IFBHT after regional normothermic perfusion.In summary, this first case report shows the feasibility of IFBHT. This novel approach has potentially broad applications. From a clinical perspective, the technique may offer the opportunity to expand the donor pool to donors that are currently considered marginal. The approach may furthermore allow to reduce rates of primary non-function, acute rejection and CAV, thus improving transplant outcomes. From a research perspective, our approach is expected to significantly contribute to an improved understanding of the complex interaction between IRI and alloimmunity.HXS is the conceptor of IFBHT; he organized the animal experiments and clinical trial, and critically revised the report. YSL, RJ, CYH, GZY and HXS designed the procedure and study protocol. YSL, RJ, JN and GZY analyzed the data and wrote the report. CL, MSY, SH, SYX and ZYL assisted design of NMP protocol and the preclinical preparation, as well as collected NMP parameters. LYQ, CYH, WTL and LHZ, assisted the design of the procedure, preclinical preparation and the operation. JN, XW, CYL, CXX, CXJ, GFQ, HWQ, and DYG assisted the design of the protocol and preclinical preparation. XGX and YMX analyzed the data and drafted the figures. BN and SGT critically revised the manuscript.Original data statistical analysis plan, informed consent form, and ethics committee approval are available and can be shared upon request. All available participant data will be de-identified. To access data, a request should be submitted to the corresponding author with a scientific proposal including objectives. The steering committee of this study will discuss and evaluate all requests and decide whether data sharing is appropriate. Data will only be shared after a data sharing agreement is fully executedThe Lancet Regional Health – Western Pacific.The authors of this manuscript have no conflicts of interest to disclose as described by


Manganese-enhanced magnetic resonance imaging can provide a surrogate measure of myocardial calcium handling. Its repeatability and reproducibility are currently unknown. Sixty-eight participants: 20 healthy volunteers, 20 with acute myocardial infarction, 18 with hypertrophic and 10 with non-ischemic dilated cardiomyopathy underwent manganese-enhanced magnetic resonance imaging. Ten healthy volunteers were re-scanned at 3 months. Native T1 values and myocardial manganese uptake were assessed for intra and inter-observer repeatability. Scan-rescan reproducibility was assessed in ten healthy volunteers. Intra-observer and inter-observer correlation was excellent in healthy volunteers for mean native T1 mapping [Lin’s correlation coefficient (LCC) 0.97 and 0.97 respectively] and myocardial manganese uptake (LCC: 0.99 and 0.96 respectively). Scan-rescan correlation for native T1 and myocardial manganese uptake was also excellent. Similarly, intra-observer correlations for native T1 and myocardial manganese uptake in patients with acute myocardial infarction (LCC: 0.97 and 0.97 respectively), hypertrophic (LCC: 0.98 and 0.97 respectively) and dilated cardiomyopathy (LCC: 0.99 and 0.95 respectively) were excellent. Limits of agreement were broader in patients with dilated cardiomyopathy. Manganese-enhanced magnetic resonance imaging has high repeatability and reproducibility in healthy myocardium and high repeatability in diseased myocardium. However, further study is needed to establish robustness in pathologies with diffuse myocardial fibrosis. Conventional cardiac magnetic resonance with gadolinium enhancement allows for quantification of myocardial fibrosis which has utility in the assessment of viability in ischemic cardiomyopathy. Furthermore, it allows for prognostication in a variety of cardiac conditions including myocarditis, dilated cardiomyopathy, hypertrophic cardiomyopathy, amyloidosis6, arrhythmogenic right ventricular dysplasia7 and Fabry’s disease8. However, gadolinium-based contrast media only allow for the assessment of the extracellular space.Cardiac magnetic resonance imaging has a major role in the diagnosis, evaluation of myocardial function and tissue characterization of a range of cardiovascular diseases9. In brief, after intravenous administration in humans, manganese dipyridoxyl diphosphate undergoes dephosphorylation and transmetallation with zinc to release manganese ions into the plasma11. Being, a calcium analogue, manganese is actively taken up by voltage-gated calcium channels in viable myocardium whereas abnormal myocardium has reduced or no uptake. Myocardial manganese uptake can be calculated using Patlak kinetic modelling14, thereby providing a measure for myocardial calcium handling16. Indeed, manganese-enhanced T1 mapping can detect dysfunctional myocardial calcium handling in patients with cardiomyopathies and can distinguish between normal and pathological myocardium18Magnetic resonance imaging using manganese-based contrast media has the ability to provide intracellular contrast of viable myocardium. Manganese was the first clinical magnetic resonance imaging contrast medium to be used in vivo, resulting in shortening of T1 relaxation in the heart, liver, kidneys and pancreasRepeatability of the assessment of manganese-enhanced magnetic resonance imaging and its scan-rescan reproducibility have not been established and is a necessary step for its future clinical application. The aims of this study were to establish the intraobserver and interobserver repeatability of manganese-enhanced T1 mapping and kinetic modelling of myocardial manganese uptake as well as provide early data on overall scan-rescan reproducibility.The study was conducted in accordance with the Declaration of Helsinki, with the favourable ethical opinion of the South-east Scotland Research Ethics Committee 2  and with the written informed consent of all participants.19 and angiographically proven coronary artery disease. Patients were required to be clinically stable with reduced left ventricular ejection fraction (≤ 50% by echocardiography) secondary to one or more acute ischaemic events.Adult (≥ 18 years of age) healthy volunteers (n = 20) were recruited as part of the MEMORY study [NCT04623788]. Patients with acute myocardial infarction (n = 20), hypertrophic cardiomyopathy (n = 18) or non-ischemic dilated cardiomyopathy (n = 10) were recruited from the Edinburgh Heart Centre as part of the MEMRI study [NCT03607669]. Patients with acute myocardial infarction were required to have a ST-segment elevation myocardial infarction according to the universal definition of myocardial infarction21. Hypertrophic cardiomyopathy was defined as left ventricular hypertrophy  in the absence of hemodynamic stresses21. Non-ischemic dilated cardiomyopathy was defined by the presence of impaired left ventricular systolic function (ejection fraction ≤ 50% within 12 months) and left ventricular dilatation , in the absence of abnormal loading conditions  and coronary artery disease20.The diagnosis of hypertrophic cardiomyopathy and dilated cardiomyopathy were based on echocardiography or magnetic resonance imaging according to European Society of Cardiology guidelinesAll participants were scanned on a Siemens MAGNETOM Skyrafit 3 T scanner  with a 30-channel body matrix coil. Electrographic gated breath-hold steady-state free procession long-axis cine images in two, three and four chamber views were acquired. Short axis cine images covering the entire left ventricle were taken at 8-mm slice thickness, 2-mm gap, field of view 300 × 400 mm, matrix 208 × 256, repetition time 2.9 ms, echo time 1.2 ms, flip angle 64–790, temporal resolution < 50 ms, with 30 phases per cardiac cycle, in-plane image resolution 1.1 × 1.5 mm to 1.3 × 1.7 mm.All participants underwent gadolinium enhanced magnetic resonance imaging, followed by manganese-enhanced imaging. This was performed at least 48 h apart. Additionally, healthy volunteers underwent repeat manganese-enhanced magnetic resonance imaging, 3 months following baseline imaging.23 and in patients, T1 mapping was acquired with shortened modified Look-Locker inversion recovery  sampling pattern and the following typical parameters: slice thickness 8.0 mm with 1.6-mm gap, field of view = 360 × 280 mm, repetition time 388.8 ms; echo time 1.07 ms, matrix 256 × 115. To minimize image artefacts, acquisition was performed with the region of interest (the heart) at isocentre, a small shim volume applied around the myocardium, and a large field of view (400 mm). All T1 mapping was acquired with non-rigid motion correction. The same parameters were used for scan-rescan reproducibility with the chosen slice being matched visually by the supervising cardiologist using appropriate anatomical landmarks to ensure the same location was being analysed.For healthy volunteers, T1 mapping was acquired with a modified Look-Locker inversion recovery sequence17.Late gadolinium enhancement images were acquired following intravenous gadobutrol  using a single breath hold per slice with a short-axis stack, and long-axis orientations. A full short-axis T1 stack was acquired prior to and 10 min after contrast administration as described previously17. Following a full short-axis native T1 stack, a single mid-ventricular short-axis slice was identified and performed at this location every 2.5 min for 30 min after starting manganese infusion, at which point a full short-axis T1 stack was repeated  at 1 mL/min; Exova SL Pharma, Wilmington, Delaware, USA] and has been described previouslyA single mid-ventricular slice was chosen for healthy volunteers. For patients, the short-axis slice was identified by the supervising cardiologist, guided by late gadolinium enhancement imaging, native T1 maps and cine images to represent abnormal myocardium  as described previouslyAll images were assessed for artefacts caused by susceptibility effects and cardiac or respiratory motion. The presence of artefacts led to the exclusion of all affected myocardial segments. Endocardial and epicardial borders were manually defined on all conventional short-axis images for volumetric and wall motion measurements and were then copied to corresponding T1 map images for analysis with minimal manual adjustments. The left ventricular basal short axis slice was identified as the image containing at least 50% of circumferential myocardium at end diastole. Papillary muscles were included in the mass and excluded from volumetric analysis.Segmental variation in native and post-manganese T1 and myocardial manganese uptake (Ki) was only assessed in healthy volunteers. T1 values were derived from segments 7–12 (mid-ventricular slice) of a standard 16-segment model, as well as septal  and global  values. After contouring, an additional epicardial and endocardial offset of 20% was applied automatically to minimize partial volume effect for all T1 map analyses.24. Peri-infarct tissue was defined as late-gadolinium enhancement negative but with elevated T1 in the area at risk (> 2 × SD) in the infarct related artery territory. For patients with hypertrophic cardiomyopathy, regions of interest were drawn in areas with hypertrophy and fibrosis (guided by late gadolinium enhancement). In patients with dilated cardiomyopathy, regions were drawn in the mid-septal wall, due to lack of late-gadolinium enhancement  who underwent repeat manganese-enhanced cardiac magnetic resonance imaging 3 months after baseline scanning.25. Kinetic modelling was based on a Patlak two-compartment model formulation14. In brief, the model consists of (i) a reversible compartment (ve), comparable to intravascular and interstitial space and (ii) an irreversible compartment (vi) comparable to the intracellular space, in which irreversible accumulation of the contrast agent is anticipated during the imaging period (30 min). The arterial concentration (derived from blood pool T1) represents contrast agent delivery into myocardial tissue and constitutes the arterial input function.To derive quantitative estimates and to assess differential manganese uptake, kinetic model analysis was performed, as described previously14, demonstrating that an apparent unidirectional influx constant (Ki) for the transfer of manganese from plasma to irreversible compartments vi, can be measured, using Eq.  respectively. This formulation is equivalent to the Patlak model 12 and describes that if a contrast medium is irreversibly trapped in the tissue within the imaging period, the instantaneous tissue concentration divided by the instantaneous arterial concentration plotted against the integrated arterial concentration divided by the instantaneous arterial concentration, will result in linearization of the data. The gradient of this line represents the apparent unidirectional influx constant Ki, which equals:k1, k2, and k3 are the individual rate constants of the compartmental model presented. A visual representation of the influx constant Ki is given in Supplementary Fig. Skjöld et al.previously derived a Patlak model formulation for cardiac manganese-enhanced magnetic resonance imagingt-tests, mixed effects model, linear regression analysis and Lin’s concordance correlation coefficients. Group variance was examined with the Brown-Forsythe test. Coefficient of variation (%) was defined as the average of means divided by the standard deviation of mean difference. Repeatability and reproducibility were determined using Bland–Altman analysis and bias (mean difference) is presented alongside 95% limits of agreement. Statistical analysis was performed using GraphPad Prism . Statistical significance was taken as a two-sided P-value < 0.05.Data are expressed as mean ± standard deviation or mean  for continuous variables or median [interquartile range] where not normally distributed. Categorical variables are presented as number (percentage). Data were analysed using paired or unpaired Student’s Seventy-eight infusions of manganese dipyridoxyl diphosphate were completed during the course of the study . There were no changes in the electrocardiogram, heart rate or blood pressure following manganese dipyridoxyl diphosphate administration . Two healthy volunteers and one patient with dilated cardiomyopathy experienced mild transient nausea for < 10 s after commencing manganese dipyridoxyl diphosphate infusion, spontaneously resolving without intervention. Otherwise, administration of manganese dipyridoxyl diphosphate was well tolerated with no adverse reactions reported during or immediately after administration or after seven days of follow up.In twenty healthy volunteers, a total of 120 segments were analysed. Six segments, predominantly the infero-lateral wall (segment 11), were excluded due to artefact. The mean septal native T1 was 1218 ± 24 ms , with excellent correlation  uptake in healthy volunteers was 8.4 ± 0.7 mL/100 g of tissue/min and similarly had excellent correlation on repeated measurement  and estimates of mean myocardial manganese uptake  in healthy volunteers, with all showing excellent correlations  and myocardial manganese uptake , hypertrophic (non-fibrosis) or dilated cardiomyopathy were 1395 ± 72, 1185 ± 35 and 1208 ± 60 ms respectively. On repeated analysis by the same observer, there were no differences between mean myocardial T1 values  and hypertrophic cardiomyopathy (fibrosis) on repeat analysis. Similarly, there was excellent correlation and Bland–Altman plots demonstrate narrow limits of agreement . Similar to traditional imaging with gadolinium, there is variation in measurements between vendors and different T1 mapping techniques, and further work is required to ensure consistency across different platforms and scanners.Manganese-enhanced magnetic resonance imaging has shown promise as a surrogate marker of myocardial calcium uptake in patients with ischemic and non-ischemic cardiomyopathiesOur study has some limitations. First, we were not able to perform scan-rescan measurements on patients with hypertrophic and dilated cardiomyopathy. It would be important to confirm that this technique has similar reproducibility in diseased states if it is to be used for serial scanning to assess disease progression or treatment interventions. Second, healthy volunteers were scanned using ShMOLLI T1 and patient cohorts underwent MOLLI T1 mapping. Our aim was to assess the reproducibility of manganese-enhanced magnetic resonance imaging in healthy and pathological myocardium. As such, we are not comparing patients with healthy volunteers. Furthermore, we have demonstrated that manganese-enhanced magnetic resonance imaging has strong intra- and inter- observer repeatability using either MOLLI or ShMOLLI T1 mapping. However, it is essential for future studies to assess this further. Third, performing a statistical test for defining cut-off for normal versus abnormal myocardial manganese uptake (Ki) was not in the scope of our study. This should be the focus of future work to define a normal reference range for these tracer kinetic parameters. Finally, manganese dipyridoxyl diphosphate is currently not readily or widely available for clinical use although we anticipate that this is likely to change in the near future.In conclusion, although larger studies are required, our data suggest that manganese-enhanced T1 mapping and kinetic modelling is a repeatable and reproducible technique in healthy myocardium. Furthermore, this technique demonstrates high repeatability in ischaemic and non-ischaemic cardiomyopathy. However, it does require further study to assess repeatability and reproducibility in different cardiac pathologies with diffuse or subtle fibrosis, such as patients with dilated cardiomyopathy, as well as defining normal reference ranges for these novel measures of myocardial calcium handling.Supplementary Information.


This is a case of eosinophilic myocarditis which had large left-ventricular thrombus seen on echocardiography and cardiac magnetic resonance imaging which was successfully treated with a highly selective direct Factor Xa inhibitor—rivaroxaban. Trans-thoracic echocardiography demonstrated a dilated left ventricle (LV) and globally impaired systolic function and apical LV thrombus. Further examination by cardiac magnetic resonance imaging demonstrated an LV thrombus in the apex measuring 28 × 14 mm and sub-endocardial apical fibrosis on late gadolinium enhancement imaging. Endomyocardial pattern of fibrosis seen in the LV (‘V sign’) is typical for eosinophilic myocarditis. He was treated with Prednisolone 10 mg for 2 months and standard heart failure therapy. For the LV thrombus a highly selective direct Factor Xa inhibitor, rivaroxaban 20 mg was initiated instead of warfarin in light of logistic issues due to COVID-19 pandemic. After 9 months of treatment, the eosinophil count went down to 0.03 × 109/L and the LV thrombus resolved to leave a fine rim of organized thrombus only, which has a relatively lower risk for systemic embolization .A 76-year-old gentleman with hypereosinophilia (6.21 × 102 Even though we are not the first to report successful thrombus resolution with this treatment strategy, it is worth reporting our imaging findings to further add to the evidence database so that there is a motive for future prospective design studies, which explore the role of glucocorticoids and rivaroxaban in eosinophilic myocarditis.This case highlights that a multi-faceted personalized treatment using disease-modifying agents and anticoagulation has a synergistic role in the resolution of myocardial inflammation and of the thrombus. This treatment strategy has been shown in limited cases previously.


Fifteen out of thirty-eight had transient minor side effects with no major adverse events. MOCO image quality was better than non-MOCO . Reversible perfusion defects were seen in 4/38 patients with lower segmental mean MPRI in the area of the perfusion defect, nearing statistical significance when compared to non-transplant patients with no defects . The global MPRI of the 16 patients who had undergone orthotopic heart transplant was significantly lower than the non-transplant patients . Regadenoson is a safe and effective coronary vasodilator for pediatric stress perfusion MRI with MOCO producing better image quality and allowing for semi-quantitative assessment of perfusion deficits that correlate with qualitative assessment.Myocardial stress perfusion magnetic resonance imaging is a non-invasive tool to assess for myocardial ischemia and viability. Pediatric myocardial stress perfusion MRI can be challenging due to multiple intravenous lines, sedation, inadequate breath holding, fast heart rates, and complex anatomy. We performed a retrospective analysis in 39 children to evaluate safety and efficacy of regadenoson, a coronary vasodilator administered via a single intravenous line (6–10 mcg/kg), with respiratory motion correction (MOCO) and semi-quantitative blood flow analysis. Stress response data and adverse events were recorded, and image quality compared between native and MOCO reconstructions, assessing for perfusion deficits. Semi-quantitative analysis compared myocardial perfusion reserve index (MPRI) between patients who had a focal perfusion defect, patients who had undergone an orthotopic heart transplant, and non-transplant patients with no focal defects. Stress perfusion was completed in 38/39 patients (median age 15 years with a 41 ± 27% rise in heart rate ( Stress perfusion cardiac MRI is used as a non-invasive tool for qualitative and quantitative evaluation of myocardial blood flow through the coronary microcirculation and has been established in the diagnosis and risk stratification of coronary artery disease in adults ,2,3,4,5.Adenosine, a coronary vasodilator, is the pharmacologic agent most used for stress perfusion MRI . ChallenLastly, respiratory motion correction techniques have been shown to reduce exposure to anesthesia in children undergoing cardiac MRI  and haveThe purpose of our study was therefore to (1) report our experience with the safety and feasibility of using regadenoson for myocardial stress perfusion MRI in a pediatric population, (2) evaluate the impact of MOCO on stress perfusion image quality, and (3) use semi-quantitative analysis to compare differences in myocardial perfusion reserve in patients with and without qualitative perfusion defects.This HIPAA compliant retrospective study was approved by the Institutional Review Board (IRB) at Ann and Robert H. Lurie Children’s Hospital of Chicago on 7 June 2016 (IRB 2016-544). Consent for this study was waived per IRB protocol.All consecutive pediatric patients (age 0–21 years), who underwent a clinically indicated stress perfusion MRI with regadenoson from December 2014 to September 2017 were included in this retrospective review. Demographic data including gender, age, height, weight, and body surface area were recorded. Clinical history including original diagnosis, any surgical procedures performed and specific indication for the stress perfusion MRI examination were documented.Patients were advised to refrain from the use of caffeine containing products for 24 h prior to the study. Informed consent for the clinically indicated stress MRI examination was obtained on the day of the study. Informed consent included a detailed review of the procedure and potential side effects of regadenoson . A pediatric cardiologist, pediatric radiologist, cardiac MR technologist and a pediatric nurse were present for the study. Anesthesia was provided as needed per clinical protocol. A cardiac resuscitation cart was present outside the MRI scan room.Studies were performed on a 1.5-Tesla (T) clinical MRI scanner . 2). T2 mapping was performed followed by contrast injection. Three T2-prepared bSSFP images with T2-prep times of 0, 24, and 55 ms were acquired in a breath-held fashion in 3 short axis orientations—base , mid (between base and apex), and apex  through the left ventricle . Next, T1 mapping with a MOLLI sequence was used to measure native (pre-contrast) longitudinal relaxation T1 times of myocardium at the same three levels as well as within the blood pool. Pre-contrast T1 maps were obtained using a single-breath-hold, ECG-triggered, MOLLI sequence . Regadenoson was used to perform myocardial stress perfusion at a dose of 6–10 mcg/kg (up to a maximum dose of 400 mcg) [2). Once the required images were acquired, a single dose of 75 mg of intravenous aminophylline was given to reverse the effects of regadenoson. In the duration between stress and rest perfusion, ECG-gated 2-D cine bSSFP imaging of the ventricles was obtained in short-axis from base to apex. A second dose of 0.05 mmol/kg dose of a gadolinium-based contrast agent was given and contrast-enhanced first pass perfusion imaging at rest was obtained. Then, the final, third dose of 0.05 mmol/kg of a gadolinium-based contrast agent was injected with post-contrast T1 mapping. Segmented inversion–recovery sequences in three orientations: 4-chamber, 2-chamber, and short axis from base to apex  were used to obtain LGE images between 20–30 min from the time of the initial contrast injection. For LGE sequences, the inversion time was selected using an inversion time scout scan to optimally null the normal myocardium. The various contrast agents administered over the duration of the study included gadopentate dimeglumine , gadobenate diglumine , gadoterate meglumine  at 3 mL/s.In a standard clinical manner, image localizer scans, 2D cine bSSFP images in two- chamber, three-chamber and four-chamber planes were obtained   while clVital signs were evaluated upon arrival, prior to scanning, and immediately prior to administration of regadenoson. Heart rate and blood pressure were documented periodically for an hour following regadenoson . The time from administration of regadenoson to peak heart rate and the time required to return to baseline heart rate were documented. Patients were monitored for an hour after the completion of the study prior to discharge.Adverse events and need for termination of the study were documented. Arrhythmia, hypotension, atrioventricular block, and bronchoconstriction were considered major adverse events. Tingling in the limbs, gastrointestinal effects such as nausea and abdominal pain, anxiety, and chest pain were considered minor adverse events.Images from each examination were reviewed in consensus by 2 experienced cardiovascular imagers (a pediatric radiologist with 20 years of experience and a pediatric cardiologist with 12 years of experience in cardiac MRI), who were blinded to the clinical report impression. Qualitative analysis was performed based on consensus recommendations developed by the Task Force for Post Processing of the Society for Cardiovascular MR (SCMR) ,22. BothSemi-quantitative myocardial perfusion analysis  was perfThe short-axis cine steady-state free precession images of the left ventricle were processed to obtain the left ventricular volumes at end diastole and end systole . The left ventricular end diastolic volume indexed to body surface area (LVEDVi) and the left ventricular ejection fraction (LVEF) were calculated. Pre and post contrast T1 images were contoured and ECV was calculated using standard methodology .t-test  or a Wilcoxon rank-sum test  was performed between cases and controls. Bland–Altman plots were created to compare interobserver and intraobserver variability. Significance was determined by p < 0.05.Categorical variables are expressed as numbers and percentages. Continuous variables are presented as means ± standard deviations or median (with interquartile range–IQR) as appropriate. To assess significant group differences, an unpaired 2 (IQR 1.48–1.83). The clinical diagnoses are listed in Thirty-nine consecutive pediatric patients,  underwent a clinically indicated myocardial stress perfusion MRI with regadenoson from December 2014 to September 2017. One patient’s study was terminated prior to completion due to emesis in the MRI room after regadenoson infusion, and thus 38 patients completed the protocol. None of the patients underwent general anesthesia. The median age at the time of the study was 15 years (IQR 12–17) with a median weight of 61 kg (IQR 51–75), median height of 163 cm (IQR 154–170), with a body surface area of 1.67 mOf the 38 patients, 12 received a weight-based dose of 6 mcg/kg of regadenoson, one received a dose of 10 mcg/kg of regadenoson and the remaining (n = 25) received the maximum adult dose of 0.4 mg. The average time between end of administration of regadenoson to administration of aminophylline was 3 ± 1 min.p < 0.005). There was no difference in the rise in heart rate for the patients who received weight-based dosing (6 mcg/kg) as compared to the patients who received a standard dose of 0.4 mg (p = 0.7). Peak heart rate occurred at 2 ± 1 min after administration of regadenoson and returned to baseline on an average 23 ± 19 min after peak heart rate. There was one patient who continued to have a heart rate higher than baseline 60 min after regadenoson but had no associated symptoms. The average systolic blood pressure was 109 ± 12 mm Hg and decreased to 98 ± 11 mm Hg (p < 0.005), at 6 ± 7 min after administration of regadenoson. The average diastolic blood pressure was 65 ± 11 mm Hg and decreased to 47 ± 9 mm Hg (p < 0.005), at 9 ± 7 min after administration of regadenoson. No patients needed in-hospital admission for prolonged monitoring.After administration of regadenoson, the average baseline heart rate rose from 86 ± 17 beats per minute (bpm) to 118 ± 18 bpm, showing a 41 ± 27% rise in heart rate  had transient secondary side effects such as limb tingling (n = 4), nausea/gastrointestinal discomfort (n = 3), anxiety (n = 3), chest pain (n = 3), and headache (n = 2). All 15 had complete resolution of symptoms prior to the end of the exam.p < 0.005) and during stress . The presence of a dark rim artifact was frequent during stress, both in the MOCO and non MOCO images .On a 5-point Likert scale, 100% of the studies were of adequate or better image quality as reported in consensus by two experienced cardiovascular imagers. The image quality of MOCO reconstructions was significantly better than native reconstructions, both at rest . The global MPRI of the four patients with reversible perfusion deficits did not differ from the patients without perfusion defects. The segmental MPRI in the four patients with reversible perfusion defects, using segments that were noted to be abnormal on the qualitative assessment, were compared to the mid septal MPRI of the non-transplant patients, and were noted to be lower nearing statistical significance 0.78 ± 0.22 vs. 0.99 ± 0.36, p = 0.07).The global MPRI of the 16 patients who had undergone orthotopic heart transplant was significantly lower than the non-transplant patients  or intraobserver  variability in the measurement of the global MPRI as determined by assessing the intraclass correlation. Bland–Altman plots were created to depict the inter- and intra-observer differences in the global mean MPRI. . The mean LVEF was normal in both groups although higher in those with perfusion deficits . The pre-contrast global T1 values were significantly lower in those with perfusion deficits as compared to those without, but still within normal range for both groups . There was no significant difference in the post contrast global T1 values  and ECV  in patients with and without perfusion deficits.There was no significant difference in LVEDVi between the patients with perfusion deficits and those without perfusion defects (85 mL/mThe clinical course of the four patients with the reversible perfusion deficits is described in In our experience, regadenoson is a safe and effective agent to induce myocardial pharmacological stress in children undergoing stress perfusion MRI for various indications. Our study showed that regadenoson did not have any major adverse side effects such as arrhythmias, hypotension, atrioventricular block, or bronchoconstriction. The only patient in whom the study was terminated, was secondary to anxiety followed by an episode of emesis. Overall, our study did have a somewhat higher incidence of minor events as compared to prior pediatric studies , althougIn the adult population , and a sRegadenoson, with its selective adenosine A2 receptor target activity makes it an ideal choice to diagnose myocardial ischemia in children with suspected fixed coronary artery obstruction, allowing for maximal coronary vasodilation. Although there is no direct evidence of maximal coronary vasodilation with regadenoson, the significant rise in heart rate that was demonstrated in this study and in prior investigations ,26 showsStress MRI has been shown to have high specificity and sensitivity for detection of coronary artery disease in large adult trials ,5. In adResearch in the quantitative analysis of myocardial perfusion has been driven by the desire to obtain observer independent and reproducible measures of myocardial perfusion. Its use in the clinical realm is restricted by the time-consuming operator interaction needed for analysis. New automated software can significantly decrease the amount of time needed by the operator thereby bringing us closer to incorporating quantitative analysis into clinical use . Semi-quPediatric myocardial stress perfusion can be performed safely using regadenoson, in a closely monitored setting. The utility of MOCO imaging improves the image quality for qualitative analysis of perfusion deficits. Semi-quantitative assessment of myocardial perfusion is feasible and reliable. It can be used as an adjunct tool in determining the presence of inducible myocardial perfusion deficits. Larger pediatric studies evaluating the association of myocardial perfusion reserve with clinical outcomes are warranted.


Leaving TR unrepaired at the time of LVAD implantation?16.See Article page Gomez Hamacher and colleagues describe the impact of tricuspid valve insufficiency on the performance of left ventricular assist devices (LVADs).The authors found that in the situation of isolated left heart failure, LVAD performance was not significantly impacted in the TR group, except for a reduction in LVAD outflow relative to the no-TR group. This may be a physiological response of the LVAD to reduced inflow. Sudden imposition of severe TR in a normally functioning right ventricle reduces forward stroke volume as regurgitant flow occurs. Reduced right ventricular (RV) stroke volume translates into reduced pulmonary venous inflow and reduced inflow to the device.The study question is based on the clinical dilemma of what to do about tricuspid insufficiency when placing an LVAD. Unfortunately, the authors' choice of an left ventricular coronary ligation model and a short recovery period results in pure left ventricular failure with normal RV function. Thus, their study design narrows the utility of the model to answer the study question, because preserved RV function does not often occur in the scenario of LVAD placement. However, there are cases with preserved RV function and TR, and the authors' findings have applicability for these patients.The impact on LVAD performance is a consideration when contemplating whether to leave an LVAD patient with TR. Other considerations, such as the effects of TR on renal functionThis remains an important and irksome study question. We look forward to hearing more from these authors in the future.


Pregnancy-related acute myocardial infarction (PAMI) is rare but life-threatening. The incidence of PAMI is growing over time for multiple reasons, and the management of parturients with acute myocardial infarction is challenging in terms of diagnosis and treatment. To date, there are still no clear guidelines on the best practice for PAMI. We present a case of a 41-year-old woman with PAMI at 31 weeks of pregnancy. Through multidisciplinary collaboration, successful outcomes were achieved for both the mother and fetus. Pregnancy-related acute myocardial infarction (PAMI) is relatively infrequent but is associated with notable maternal or fetal morbidity and mortality . The incA 41-year-old woman at 31 weeks gestation, gesta3, para1, with a history of previous correction surgery of patent ductus arteriosus, was admitted to the emergency department (ED) after suffering sudden crushing pain in the precordial area, accompanied by radiation on the left shoulder and back, toothache for 4 h. Electrocardiogram (ECG) showed ST-segment elevation in leads I, aVL, and V2–V6  and the The patient's symptoms were not relieved, so an interventional cardiologist performed emergent percutaneous coronary intervention (PCI) for the puerpera. Cardiac angiography showed that the left anterior descending (LAD) artery was 100% occluded , and theA multidisciplinary team including an obstetrician, cardiologist, anesthesiologist, pediatrician and pharmacologist was established. The MDT considered pregnancy before 34 weeks has a high risk of cardiovascular events and low fetal survival and eventually reached a consensus that cesarean section would be performed two weeks after PAMI.Cesarean section was scheduled at 34 weeks and 3 days of gestation. After the patient entered the operating room, electrocardiography, pulse oxygen saturation, invasive blood pressure and bispectral index  monitoring were routinely monitored. Endotracheal intubation was performed after induction. Anesthesia was maintained using sevoflurane and remifentanil. Intraoperative temperature monitoring was performed with a temperature probe. Forced air warming and warmed intravenous fluids were used to maintain the patient's core temperature. A transesophageal echocardiographic probe was then inserted, and cardiac function was monitored in real time. The examination showed decreased left ventricular function. There were multiple wall motion abnormalities, including apical septal dyskinesia . No valvShe was monitored for 6 days postoperatively in the CCU, without postpartum hemorrhage, anginal symptoms or ECG changes. Echocardiographic examination did not show significant alterations, and myocardial enzymes showed no evidence of new ischemia.Ten days after the cesarean section, the patient was discharged from the hospital. The patient and the child performed well at 6-month and one-year follow-up.PAMI is different from AMI in general patients in terms of etiology, diagnosis, and therapy. The management of pregnant patients with acute myocardial infarction is challenging and requires close cooperation between the obstetrician, cardiologist, neonatologists and anesthesiologist. Therefore, we need to better understand the pathophysiology and management of PAMI and formulate an individualized anesthesia protocol for maternal and fetal safety.P-SCAD) (43%), angiographically normal coronary arteries (18%) and coronary thrombosis (17%)  .Pregnant women with cardiac disease require appropriate anesthesia, cardiac, and obstetric management during the perinatal and postpartum period. Guidelines from the American Heart Association (AHA), European Society of Cardiology (ESC), Society of Maternal Fetal Medicine (SMFM) and American College of Obstetricians and Gynecologists (ACOG) suggest a “Pregnancy Heart Team” care for pregnant patients with complicated cardiac disease . In our Myocardial revascularization and the rapid establishment of optimal cardiac treatment to limit cardiac remodeling are emergency interventions to improve maternal cardiac prognosis. The goal of management in the acute phase is to restore or preserve myocardial perfusion and cardiac function. The majority of AMI during pregnancy is caused by spontaneous coronary hematoma/dissection. The mechanism is unknown and may be related to changes in hormone levels during pregnancy. The mechanism of atherosclerosis is completely different from that of common AMI patients. In principle, if coronary angiography suggests a subintimal hematoma, as long as the vessel is not completely occluded and forward blood flow exists, then PCI is not recommended. Otherwise, the subintimal hematoma will extend and cause more problems. Generally, the hematoma is completely absorbed, and the blood vessel returns to normal in approximately one month. However, it was impossible to distinguish whether it was a hematoma or a thrombosis secondary to common plaque rupture during angiography in this patient; moreover, the blood vessel was completely occluded, so interventional treatment had to be performed. It was very difficult to pass the guiding wire, and guiding wires with different hardnesses were replaced three times. Finally, the occlusion segment was forcibly passed with the assistance of the microcatheter. Angiography showed no calcification in the local area. Any new devices, including balloons, stents, and intravascular ultrasound catheters, could no longer pass through the occlusion, and the cardiologist determined that it was caused by endothelium prolapse, which blocked the lumen. On the other hand, the biggest concern of PCI in pregnancy is radiation exposure. According to previous research, the radiation exposure of patients during procedures such as coronary angiography is estimated to be <20 mGy, while the fetal share of radiation is estimated to be 0.074 mGy. At doses below 50 mGy, there is a negligible risk of fetal teratogenicity following radiation exposure, while fetal damage may occur at doses above 150 mGy  is generally the preferred agent due to its easier administration and more predictable effect. Neuraxial anesthesia should be avoided for at least 12 h after subcutaneous prophylactic dose of LMWH and at least 24 h for therapeutic dose of LMWH according to The American Society of Regional Anesthesia (ASRA) Guidelines and the SOAP Consensus Statement .For women with acute myocardial infarction during pregnancy, choosing the right timing for delivery is crucial. In the case of acute myocardial infarction, delivery should be postponed a few weeks after AMI to reduce hemodynamic stress immediately after the event , if possThere is no general consensus on the recommended mode of delivery for pregnant women with AMI. The advantages of vaginal delivery include less blood loss and a lower risk of infection, venous thrombosis, and embolism and should be recommended for most women . MihaljeThe decision to choose regional or general anesthesia is multifaceted. Both regional and general anesthesia have advantages and disadvantages in pregnant women with acute myocardial infarction. It is preferred to choose neuraxial anesthesia for cesarean delivery whenever possible in women with cardiac disease . In YildIntraoperative anesthesia management goals include ensuring coronary perfusion and avoiding tachycardia and excessive ventricular end-diastolic volume, maintaining cardiac output and myocardial contractility, adequate arterial oxygen content, and maintaining body temperature and internal environment stability.Adequate hemodynamic monitoring is essential to reduce perioperative morbidity and mortality in cardiac patients. On the one hand, intraoperative transesophageal echocardiography (TEE) can be used as an important tool to dynamically monitor the changes in cardiac function of patients with severe comorbidities or if hemodynamic instability is expected or occurs intraoperatively. In the absence of ECG changes during myocardial ischemia, regional wall motion abnormalities have been reported in a significant proportion of patients. Because mechanical abnormalities (systole and diastole) precede electrical abnormalities during ischemia, TEE has the advantage of early identification of myocardial ischemia . On the The postpartum period is a time of increased risk of cardiovascular disease-related maternal morbidity and mortality . PostopeThe management of parturients with acute myocardial infarction is challenging in terms of diagnosis and treatment, and successful outcomes for both the mother and fetus come from the efforts of a multidisciplinary team of obstetricians, cardiologists, anesthetists and pediatricians. There are still no clear guidelines on the best practice for the PAMI. Our case demonstrates that multidisciplinary collaborative management, precise timing of surgery, and individualized perioperative management may help improve maternal outcomes and neonatal health for pregnant women with PAMI undergoing cesarean delivery.


IDH mutation status in histologically lower-grade gliomas. Strong exponential correlations were found between rT1/T2 and each of T1- and T2-relaxation times in eight subjects . In a test cohort of 25 patients, mean rT1/T2 (mrT1/T2) was significantly higher in IDHwt tumors than in IDHmt tumors (p < 0.05) and the optimal cut-off of mrT1/T2 for discriminating IDHmt was 0.666–0.677, , which was validated in an external domestic cohort of 29 patients . However, this result was not validated in an external international cohort derived from TCIA/TCGA . The t-Distributed Stochastic Neighbor Embedding analysis revealed a greater diversity in image characteristics within the TCIA/TCGA cohort than in the two domestic cohorts. The failure of external validation in the TCIA/TCGA cohort could be attributed to its wider variety of original imaging characteristics.The current study aimed to test whether the ratio of T1-weighted to T2-weighted signal intensity (T1W/T2W ratio: rT1/T2) derived from conventional MRI could act as a surrogate relaxation time predictive of  IDH mutation status helps choose the most appropriate treatment strategy. Rapid and aggressive surgical intervention should be pursued for IDH-wildtype (IDHwt) gliomas, which have a poor prognosis1. In contrast, finding an optimal balance between maximal resection and preservation of the quality of daily life is of utmost importance for IDH-mutant (IDHmt) World Health Organization (WHO) grade 2 and 3 gliomas (lower-grade gliomas: LrGGs), as these present a more favorable prognosis5. There have been great efforts within the research community to develop noninvasive imaging techniques that can predict IDH mutation status in gliomas, including magnetic resonance spectroscopy (MRS)8, perfusion- and diffusion-weighted magnetic resonance imaging (MRI)10, and machine learning with conventional MRI12. Whereas these techniques rely mainly on quantitative or semi-quantitative MRI measurement, qualitative imaging features such as the “T2 fluid-attenuated inversion recovery (FLAIR) mismatch sign” have proven to be powerful imaging surrogate markers for predicting IDH mutation status in tumors that appear to be histologically LrGGs15. These qualitative imaging features are derived from radiologically quantitative measurements such as the T1- and T2-relaxation time16. Ideally, tissue relaxation time should be directly measured by MR relaxometry; however, this has not yet been incorporated into routine imaging protocols as it requires additional scan time.Genetic characterization is an essential diagnostic work-up in patients with glioma, as presurgical prediction of the 19 and could potentially be used as an imaging surrogate for tissue relaxation time. The aim of the present study was to test the hypothesis that rT1/T2 is predictive of IDH mutation status in histologically LrGGs.The ratio of T1-weighted (T1W) to T2-weighted (T2W) signal intensity (T1W/T2W ratio: rT1/T2) derived from conventional MRI has been reported as quantitative imaging technique for detecting myelin integrity in the brainThe study was approved by the Institutional Review Boards of Asahikawa Medical University Hospital  and the Osaka International Cancer Institute (No. 1612065191). The requirement for written informed consent was waived for data collected retrospectively. Patients in prospectively recruited cohorts were provided with a detailed explanation and written informed consent was obtained from each patient or their family. The investigation was performed in accordance with all relevant local guidelines and regulations, and adhered to the tenets of the Declaration of Helsinki.16 and compared these T1- and T2-relaxometry data with rT1/T2 . Table The pathological diagnosis was based on the 2016 WHO Classification of Tumors of the Central Nervous SystemIDH1 mutation was performed for the exploratory cohort, and Sanger sequencing was performed to detect hotspot mutations of IDH1/2 (codon 132 of IDH1 and codon 172 of IDH2) for the validation cohort 13. The IDH mutation status of tumors in the TCIA/TCGA dataset were obtained from the report by Ceccarelli et al.23.Two laboratories performed genetic analyses of glioma tissues: the Department of Pathology, Asahikawa Medical University, Asahikawa, Japan, for the exploratory cohort; and the Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, Osaka, Japan, for the validation cohort 1. Immunobiological detection of https://ric.uthscsa.edu/mango/mango.html, accessed on March 6, 2022). We used an in-house imaging software incorporating an algorithm for reconstructing rT1/T2 images from T1WI and T2WI24. The algorithm and MATLAB codes for calculating rT1/T2 can be obtained as an open-source toolbox for SPM12 developed by Ganzetti et al. 18. Details of the reconstruction analysis are previously reported by Ganzetti et al.18. Reconstruction was performed by first applying a bias field correction to the original T1WI and T2WI using SPM12 . The intensity histograms were then adjusted based on intensities extracted from non-brain tissues such as cerebrospinal fluid, bone, and soft tissues. Finally, the processed T2WI was co-registered and divided by the processed T1WI to produce an rT1/T2 image using the NIfTI “scanner-anatomical” coordinate system . T1-relaxometry was performed by converting MP2RAGE images into T1-relaxation time maps. T2-relaxometry was performed by converting multi-echo T2-weighted images into T1-relaxation time maps. In both cases, relaxometry was performed via Bayesian inference modeling . Further technical details have been reported previouslyhttp://www.itksnap.org, accessed on March 6, 2022). VOIs were designed on T2WIs with visual identification of pathologically high-intensity areas, avoiding ambiguous and vaguely abnormal lesions as much as possible  in ITK-SNAP software , to ensure that further analysis will be performed using the NIfTI “general affine transformation” coordinate system  and Gray Level Run Length Matrix (GLRLM) analyses. In total, 49 imaging features were extracted from each image  curve analysis. A p-value of less than 0.05 was considered significant. t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis was used to investigate the difference in MRI qualities and characteristics among the three cohorts. Rtsne package version 0.15 for R with default parameters was used for this analysis . The relationship between mrT1/T2 and s Tables , and S52−0.0005T1-relax + 0.30 and rT1/T2 = 1.27exp−0.0081T2-relax + 0.48; R2 = 0.64 and 0.59, respectively)   and rT1/T2 within histologically LrGG tissues, voxel-wise analysis was performed for 114,465 voxels in total. T1- and T2-relax exhibited strong exponential correlations with rT1/T2 (rT1/T2 = 1.63expp < 0.05). ROC curve analysis revealed that the optimal cut-off value of mrT1/T2 for discriminating IDHmt was 0.666–0.677, with sensitivity of 58.8% and specificity of 87.5%   for differentiating IDHwt and IDHmt tumors. As shown in Fig. 05) Fig. B.Figure p = 0.02)  with sensitivity of 56.3% and specificity of 69.2%, using the previously obtained cut-off value for detecting IDHmt tumors  and an international public dataset (TCIA/TCGA cohort). The OICI cohort validated a statistically significant difference in mrT1/T2 between IDHwt and IDHmt tumors  Fig. A. ROC anp = 0.08)  , there was no significant difference in mrT1/T2 between IDHwt and IDHmt tumors (08) Fig. A. ROC an08) Fig. B.Figure We further investigated the impact of the image features in the original T1WI and T2WI for reconstructing rT1/T2 images. t-SNE analysis of the original T1WI and T2WI revealed clusters of image features in the exploratory cohort (the AMUH cohort) and the validation cohort (the OICI cohort), whereas those in the validation cohort 2 (the TCIA/TCGA cohort) were scattered across both the t-SNE1 and t-SNE axes Fig. A. ReconsIDH mutation status  can partially represent the relaxation properties of a tissue following radiofrequency-induced nuclear magnetic resonance spin polarization. For example, the T2-FLAIR mismatch sign utilizes the qualitative imaging features represented on conventional structural MRI derived from quantitative tissue relaxation properties, which enable detection of IDH-mutant 1p/19q intact tumors16.Along with others, we have reported that the T1- and T2-relaxation properties of tumor tissue tightly correlate with the 17. Although the exact pathological mechanism is unknown32, the relatively high sensitivity of rT1/T2 for detecting multiple sclerosis suggests that it might be suitable for characterizing tissue microstructure within the brain33. As shown in Fig. IDH mutation status in histologically LrGGs, without performing direct measurement of the tissue relaxation properties.The present study aimed to explore the possibility of retrieving quantitative data from qualitative conventional structural MRI by utilizing rT1/T2, a method initially proposed as an imaging surrogate of myelin content within the brain34. Table 35. Thus, to use rT1/T2 for predicting IDH mutation status, it might be necessary to use a preset MRI acquisition protocol or an institution-dependent cut-off value.However, the results obtained in the domestic cohorts  were not reproduced in the TCIA/TCGA cohort  Fig. . AlthougIDH mutation status is necessary to validate our findings. Second, the overall sensitivity and specificity were not high enough to be acceptable in routine clinical use. The present retrospective study was unable to integrate other imaging modalities for analysis due to insufficient data; however, combining rT1/T2 with diffusion and perfusion MRI might increase diagnostic accuracy, and such research should be pursued in the future. For example, a recent study proposed the concept of combining diffusion and perfusion MRI for IDH mutation detection, but requires external validation36. Third, some of the procedures performed during rT1/T2 reconstruction are highly complicated, as mentioned by Ganzetti et al.18, especially image intensity normalization. The normalization method used in the present study calibrated image intensity using non-brain tissues, including cerebrospinal fluid, bone, and soft tissues; however, other methods such as deep learning could offer potential solutions to improve rT1/T2 analysis37. Finally, recent rapid developments in deep learning and artificial intelligence have augmented the diagnostic precision of IDH mutation status in glioma, with reported pooled sensitivity and specificity of 0.88 and 0.8612, which are much higher than those in the present study12. The most appropriate machine learning algorithm is yet to be determined. Therefore, the simplicity of rT1/T2 reconstructed by T1WI and T2WI alone remains appealing, withstanding the need for further improvements and validations.Several limitations of the present study must be addressed. First, the sample sizes of the two domestic cohorts were relatively small, and the distributions of IDHwt and IDHmt differed among the three cohorts. This distribution difference might be responsible for the failure to validate the cut-off value in the TCIA/TCGA cohort. Ideally, a cohort with a larger sample size and an even distribution of tumors with The findings of the present study showed that rT1/T2 strongly correlates with T1- and T2-relaxation times in histologically LrGGs. The mean value of rT1/T2 was able to discriminate IDHwt and IDHmt tumors in two domestic cohorts, with statistical significance. However, this result was not validated in the original TCIA/TCGA cohort due to the wide variety of imaging characteristics in the cohort.Supplementary Tables.Supplementary Figures.