Paranoia may be particularly prevalent during adolescence, building on theheightened social vulnerabilities at this age. Excessive mistrust may becorrosive for adolescent social relationships, especially in the context ofmental health disorders. We set out to examine the prevalence, symptomassociations, and persistence of paranoia in a cohort of young peopleattending child and adolescent mental health services.A total of 301 patients (11–17 years old) completed measures of paranoia,affect, peer difficulties and behavioural problems. Clinicians also ratedeach participant’s psychiatric symptoms. Patterns of association wereexamined using linear regressions and network analyses. In total, 105patients repeated the measures several months later.n = 195),self-harm/suicidality (n = 82), or neurodevelopmentalconditions (n = 125). Few had suspected psychosis(n = 7). Rates of paranoia were approximately doublecompared with previous reports from the general population. In this patientsample, 35% had at least elevated paranoia, 15% had at least moderateparanoia, and 6% had high paranoia. Paranoia had moderate associations withclinician-rated peer difficulties, self-harm, and trauma, and smallassociations with clinician-rated social anxiety, depression, generalisedanxiety, and educational problems. Network analyses showed paranoia had thestrongest unique relationship with peer difficulties. Paths from peerdifficulties to anxiety, self-harm, post-traumatic stress disorder symptoms,and behavioural problems were all via paranoia. Both self-harm andpost-traumatic stress disorder were solely associated with paranoia in thenetwork. Paranoia remained persistent for three-quarters and was associatedwith greater psychological problems over time.Most of the adolescents had affective disorders (Paranoia is relatively common and persistent across a range of clinicalpresentations in youth. When paranoia occurs alongside emotional problems,important peer interactions may be adversely affected. Wider considerationof paranoia in adolescent patients is needed. Paranoia – the unfounded idea that others deliberately intend harm – is one of themost prominent symptoms of psychotic disorders. Yet the clinical reality is thatparanoia is rarely specific to psychosis, with evidence it occurs across a range ofdisorders . Indeed,There is a substantial literature showing psychotic experiences in general are commonin adolescents accessing services, and, although transient for a number, thepresence of such symptoms indicates a pluripotent risk for multiple psychiatricdisorders and poor outcomes . HoweverIn recent years, significant advances have been made in the treatment of persecutorydelusions in adults by adopting a targeted focus on paranoia and its contributorycausal factors . Yet mucHere, we adopt a targeted approach: systematically assessing paranoia and potentialcorrelates in a cohort of adolescents accessing UK Child and Adolescent MentalHealth Services (CAMHS). We had three objectives. The first objective was todescribe the prevalence of paranoia in this cohort using a measure specificallyvalidated for adolescents and compare these rates to previous reports from thegeneral population . The secOver 15 months, adolescents (11–17 years) were recruited during routine clinicalappointments at a Tier 3 outpatient CAMHS team and a Tier 4 adolescent inpatientunit based in Oxfordshire, UK. Both services were part of Oxford Health NationalHealth Service (NHS) Foundation Trust. In the United Kingdom, Tier 3 CAMHSprovide specialist multidisciplinary assessment and treatment for adolescentsunder 18 years with complex mental health problems and Tier 4 units providehighly specialist care for under 18s requiring admission for severe psychiatricproblems and high levels of risk. Participants were invited to take partregardless of their reason for accessing services, clinical diagnosis, orcurrent treatment. The only exclusions were a moderate/severe learningdisability or inability to complete questionnaires in English. Informed parentalconsent and child assent (11–15 years) or consent (16–17 years) was obtainedprior to taking part. The study received approval by an NHS Research EthicsCommittee (Ref: 17/SC/0539).The Bird Checklist of Adolescent Paranoia B-CAP; , 2020 isThe Revised Child Anxiety and Depression Scale RCADS;  is a 47-The Strengths and Difficulties Questionnaire SDQ;  is a 25-The Current View  is a praParticipants completed the paranoia questionnaire alongside the routinelyadministered RCADS and SDQ. Clinicians involved in each participant’s care (i.e.care coordinator or psychiatrist) completed a routine measure of currentdifficulties (i.e. Current View). All three routine measures were completed aspart of participant’s standard care. Case note diagnoses/presenting problemswere obtained from the diagnosis section of participant’s electronic records,recent clinical assessment/review letters, and discussion with carecoordinators. The study involved an optional follow-up where the self-reportquestionnaires were repeated after at least 3 months for a subsample ofparticipants who were contactable and agreed to do so. Follow-up questionnaireswere completed at the clinic or online via a Qualtrics survey.All analyses were conducted in R, version 3.6.1 . For eact-test and thecorrelation between paranoia and age was examined.Paranoia prevalence was assessed with mean scores, item endorsement definedas a score of 2+ (i.e. ‘couple of times’ in past 2 weeks), and theproportion scoring above validated B-CAP thresholds . ParanoiPrevalence rates of paranoia in this sample were presented alongsidepreviously reported mean scores and item endorsements on the B-CAP from arepresentative dataset of 801 adolescents aged 11–15 years from a secondary school in the United Kingdom . Here, wThe bivariate relationships between paranoia and the presence ofclinician-rated difficulties were assessed using a series of linearregressions. We did not correct for non-normality in the residuals as linearregression models without normally distributed errors produce validestimates in large samples . For eignodes, andpairs of nodes may be connected by an edge that indicatesthe presence of an association after conditioning on all other variables for continuous variablesand the proportion of correct classification , oraccuracy, for binary variables   using the package ‘mgm’ . Missingariables . Wealso(CCmarg) .Once estimated, the unique relations among the variables were visualisedusing the package ‘qgraph’  in a weiFor all edges, 95% CIs were constructed using a non-parametric bootstrap with1000 iterations in the package ‘bootnet’ . ThebooMpre-Mpost/SDpreand a Wilcoxon signed-rank test. Individual change in paranoia was examinedusing the reliable change index  formula =dex RCI;  where andex RCI; , linearn = 184, 61%) than boys and most were White British. Participants included 271 community CAMHSpatients  and 30 inpatients. Adolescents were accessing services with a rangeof problems, although the most common were affective disturbances andneurodevelopmental conditions . There was ahigher proportion of girls , with 41% of girls reporting at least mildlyelevated levels compared to 24% of boys. There was no relationship between ageand paranoia . The 30inpatients had somewhat higher paranoia scores overall than the community patients , although this was notsignificant .Paranoia in the patient sample was significantly higher in girls than boys. Paranoia did not differ between those with andwithout Current View ratings . A total of 275participants completed either the RCADS or the SDQ . Paranoia wasslightly higher in those that completed either measure than those who did neither , although this differencewas not significant .The clinician-rated Current View was completed for 272 participants  and explained11% of the variance in paranoia scores. The second largest association wasfor self-harm which accounted for 7% of the variance in paranoia. Similar sized mediumassociations were also observed for post-traumatic stress symptoms and a history ofabuse/neglect ,although only 4% and 2% of the variance in paranoia was explained by thesefactors, respectively. It was notable that of the 104 patients with at leastelevated paranoia, 38 (37%) had clinician-rated trauma (post-traumaticstress or history of abuse/neglect). Depression and social anxiety showedsmall but significant associations with paranoia that each explained 6% ofthe variance. Small significant associations accounting for only 4% and 2%of the variance in paranoia were observed for educational difficulties andgeneralised anxiety, respectively. The presence of ADHD symptoms showed asmall negative association that explained 2% of the variance in paranoiascores.Bivariate associations between paranoia and the presence of eachclinician-rated problem are shown in p = 0.061, R2 = 0.01). Thiswas not statistically significant, most likely due to limited power withonly 17 patients rated as having these symptoms; notably, nine of these(53%) had at least mildly elevated paranoia. Small associations that werenot significant (p > 0.05) and each accounted for only1% of the variance in paranoia were observed for substance abuse, emergingpersonality disorder, separation anxiety, family relationship problems,panic, conduct problems and OCD (p > 0.05).There was a small-medium association between the presence of clinician-ratedpsychosis  and higher paranoia  but not self-harm or post-traumaticstress. None of the other edges with paranoia were significantly differentin size . A total of 56% of the variance inparanoia was explained by the direct edges with these seven variables . The absence of edges in Paranoia also demonstrated direct edges with self-harm , conduct problems , panic ,post-traumatic stress ,obsessive compulsiveness , andseparation anxiety . The edgewith peer difficulties was significantly larger than the edges with conductproblems, panic, obsessive-compulsiveness, and separation anxiety.Conversely, the edge with paranoia did not lead to any increase in accuracybeyond the intercept model for post-traumatic stress .Notably, paranoia was the only variable that both self-harm andpost-traumatic stress had a unique association with once all other variableswere controlled . The norn = 75, boys: n = 30) agreed to repeat thequestionnaires several months later . Thedifference in baseline paranoia between those with follow-up data  and those without  was small and notsignificant .A total of 105 participants . On an individual basis, however,18/105 participants had significant increases (RCI > 1.96) in paranoia and16/105 had significant decreases (RCI < −1.96). Of the 46 participants withat least mildly elevated baseline paranoia, 30 had consistently elevated orincreasing scores, 5 showed significant reductions that remained in the elevatedrange, and 11 had significant reductions into the average range.There was no overall difference in paranoia between baseline  and follow-up , across the two time points, participantswith persistent/increasing paranoia (n = 50) had consistentlyhigher levels of depression , panic , social anxiety , generalised anxiety , separation anxiety , peer difficulties , conduct problems , hyperactivity , and distress/social impairment, but not OCD.Linear mixed-effects models showed that, compared to those with low/transientparanoia (p = 0.043) and social anxiety , indicating those with persistent paranoiahad somewhat less improvement in these symptoms compared to those withlow/transient paranoia. Group by time interactions were negligible andnon-significant for all other domains .There were small paranoia group by time interactions at the threshold forsignificance for generalised anxiety . This relationship is consistent with findings from the adult literature and evidConsistent with a cognitive conceptualisation of paranoia as an unfounded threatbelief ,networkArguably one of the most important findings from the study is a close relationshipbetween paranoia and peer relationship difficulties. This association was thestrongest of all those assessed from both clinicians and patients, even aftercontrolling for the influence of all other variables in the network. Although therelationship will undoubtedly be bidirectional to a degree, our previous work usinga Bayesian approach to causal discovery found adolescent peer difficulties are morelikely to be influenced by paranoia than vice versa . This paThe study has several limitations. First, the sample was not a fullyrepresentative cohort. It was not possible to invite all patients accessingparticipating services to take part, since services could not be covered by theresearch team all the time. However, attempts were made to minimise samplingbias by inviting patients to take part regardless of their reason for accessingservices or clinical diagnosis. The cohort also included a higher proportion ofgirls than boys, although this may be representative of CAMHS given the higherrates of common mental health problems in adolescent girls .NeverthA strength of this study was the ability to compare the prevalence of paranoia inCAMHS patients with a representative general population sample of adolescentsusing the same measure. This was not a perfect comparison, however, as thegeneral population sample were slightly younger than the patients in this study.But as age was not associated with paranoia in either sample, the effect of thisdifference on the comparison is likely to be minimal. Another limitation wasthat aside from the B-CAP, our other measures were missing for approximately 10%of participants. This reflected the reality of routine measurement in CAMHSwhere clinical pressures could prevent clinicians from completing the CurrentView and patients sometimes left before completing all questionnaires. Notably,as follow-up questionnaires were collected as an optional second stage of thestudy, only a third of the sample provided longitudinal data. Plannedprospective studies examining paranoia in representative clinical samples willbe needed to understand fully the relationship over time with other mentalhealth problems.It must also be acknowledged that a degree of measurement error is likely inself-report measures of paranoia. It is not possible in self-reportquestionnaires to determine if concerns about intended harm from others areunfounded. However, the B-CAP has shown good construct validity as a measure ofunfounded ideation, with evidence that scores are distinct from bullying and areassociated with adolescents’ ratings that their fears of others are excessive, 2020.EOverall, this study highlights paranoia as a common, potentially clinicallyimportant, and overlooked problem in young people who are accessing mentalhealth services. Greater awareness by clinicians of paranoia in patientsattending CAMHS may be required. The use of validated tools such as the B-CAPmay be helpful for clinicians to identify paranoia within young people’s broaderclinical presentation and monitor change. Targeted intervention for paranoia,suitably adapted for this age group, may then be appropriate to help youngpeople feel safer in their daily lives.Click here for additional data file.Supplemental material, sj-pdf-1-anp-10.1177_0004867420981416 for Paranoia inpatients attending child and adolescent mental health services by Jessica CBird, Emma C Fergusson, Miriam Kirkham, Christina Shearn, Ashley-Louise Teale,Lydia Carr, Hannah J Stratford, Antony C James, Felicity Waite and DanielFreeman in Australian & New Zealand Journal of Psychiatry


P = 0.015), brachial-ankle pulse-wave velocity , cystatin C , and E/e’ . Ocular RI was significantly higher in the ACS group than in the control group in male in their 40 s  and 50 s . We found that the ocular RI was associated with systemic atherosclerosis, early renal dysfunction, and diastolic cardiac dysfunction in ACS patients, suggesting that it could be a useful non-invasive comprehensive arteriosclerotic marker.This study aimed to investigate the relationship between ocular vascular resistance parameters, evaluated by laser speckle flowgraphy (LSFG), and systemic atherosclerosis, renal parameters and cardiac function in acute coronary syndrome (ACS) patients. We evaluated 53 ACS patients between April 2019 and September 2020. LSFG measured the mean blur rate (MBR) and ocular blowout time (BOT) and resistivity index (RI). 110 consequent patients without a history of coronary artery disease who visited ophthalmology as a control group. Significant positive correlations were observed between ocular RI and systemic parameters in ACS patients, including intima-media thickness (r = 0.34,  Atherosclerosis is generally found in large blood vessels, such as the carotid and lower limb arteries, arteriosclerosis is known to occur in small vessels of the kidneys and retina3 . Nonetheless, the possible association between atherosclerosis and other-region arteriosclerosis and retinal microvessels remains unclear. The laser speckle flowgraphy (LSFG) technique has made it possible to non-invasively detect impairment of the ocular microcirculation by measuring blood flow velocity4. Among various parameters measured by LSFG, ocular blowout time (BOT) and resistivity index (RI) were used as indicators of vascular resistance or arteriosclerosis of microvessels6.Atherosclerotic diseases have dramatically increased in Japan with the westernization of diet and rapid aging of the population. The risk factors for atherosclerotic disease systemically affect all vasculature regions, as evidenced by coronary artery disease, cerebrovascular disease, and peripheral artery disease, all linked to one another7. HFpEF increases the left ventricular and systemic arterial stiffness, and promotes diastolic dysfunction8. Diastolic dysfunction was associated with coronary artery calcium score, indicating an association with atherosclerosis9. Moreover, it has been reported that transient retinopathy (soft exudate) occurred in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), suggesting that ACS might be involved in ocular circulation impairment11. Despite a high systemic atherosclerotic burden in ACS patients, there are few data that investigate whether systemic arteriosclerosis and diastolic function are linked to the ocular RI and BOT values. This study aimed to investigate the association between systemic atherosclerotic parameters , renal biomarkers, and cardiac function assessed by transthoracic echocardiography, and ocular RI and BOT evaluated by LSFG in ACS patients.Acute coronary syndrome (ACS) or heart failure with preserved ejection fraction (HFpEF) are associated with old age, hypertension, and type II diabetes mellitus, all strongly related to systemic arteriosclerosisTable P = 0.015; Fig. P = 0.002; Fig. P = 0.001; Fig. Table P = 0.047; Fig. P = 0.020; Fig. P = 0.029; Fig. P = 0.046; Fig. Table P = 0.013; Fig. P = 0.051; Table Table n = 32) and without (n = 21) retinopathy, diagnosed by the existence of soft exudate in the retina, were similar in systemic atherosclerosis, renal, and cardiac parameters. They were also similar in the ocular parameters .ACS patients with (n = 110). We compared the RI and BOT values between the ACS and control groups in each age category of 40–49 years, 50–59 years, 60–69 years, and ≥ 70 years, respectively, divided by sex  vascular changes or both remains to be elucidated3. This study sheds some light on this question and presents several important findings. The ocular RI correlated positively with systemic (IMT and baPWV), renal , and cardiac (E/e’) parameters, with BOT showing a much weaker association, suggesting that ocular RI may be more appropriate index to systemic parameters than BOT, at least in ACS patients.Retinal blood flow is adequately regulated by ocular perfusion pressure and vascular resistance in response to various physiological stimuli14. Increased mean IMT is a major cardiovascular risk factor15. baPWV, the most widely used measure of arterial stiffness, was shown to be a strong predictor of future cardiovascular events such as ACS16. Previous studies showed that the BOT on LSFG was associated with baPWV and IMT thickening17, but the relation between ocular RI and baPWV or IMT was not assessed before. Our results suggest that ocular RI, rather than BOT, could help identify the progression of systemic atherosclerosis in such high burden atherosclerotic patients as ACS patients.Carotid artery assessment by ultrasonography effectively detected the presence of carotid and other atherosclerotic diseases19. The cardiorenal syndrome is a disorder of the heart and kidney, in which one organ reportedly causes dysfunction of the other. The presence of renal disorder in ACS patients was reported to affect their prognosis20. Cystatin C, U-β2MG, and L-FABP are known to be better biomarkers for diagnosing acute kidney disease, which could transition to CKD, than creatinine and eGFR21. BOT obtained by LSFG in previous studies was correlated with renal function, and patients with CKD were found to experience an ocular circulatory disorder22.Renal dysfunction is associated with an increased risk of cardiovascular morbidity and mortality. Renal diseases such as chronic kidney disease (CKD) reportedly progress with arteriosclerosis24. The E/e’ ratio is an echocardiographic index used to assess left ventricular diastolic function. It was associated with left ventricular diastolic pressure (and mean pulmonary artery wedge pressure) earlier in the diastole25. Previous studies have stated that optic disc BOT obtained by LSFG is significantly correlated with left ventricular diastolic function (E/e’ ratio) in healthy persons27. Our data showed a similar finding, but the correlation coefficient was higher for RI than for BOT, suggesting that ocular RI assessment after ACS might be useful for determining the presence of diastolic dysfunction.Evaluation of diastolic function after ACS is important because it correlates with infarct size. Diastolic dysfunction has a high risk of death and is associated with poor prognosis independently of left ventricular systolic function28 reported that cotton wool spots developed within two months in more than half of the patients with AMI undergoing PCI and then tended to become quiescent without treatment. We found no difference in systemic atherosclerosis, renal, or cardiac parameters between patients with and without soft exudate in our study. Although the patient characteristics in the two studies were different, the results are comparable; the occurrence of soft exudate was unrelated to any ocular parameters measured by LSFG. The soft exudate is known as the representative of ischemic disorders in the local site of the ocular artery. Therefore, our findings and those of this previous study suggest that it may not always directly reflect systemic vascular resistance or atherosclerosis, especially for ACS patients in the subacute phase.We found that 21 (40%) ACS patients had mild and transient retinopathy with soft exudate. Kinoshita et al.Our results indicated a clinical importance that the non-invasive evaluation of ocular blood flow may be a robust marker for promoting the comprehensive evaluations for not only retinal but also systemic arteriosclerosis in ACS patients. Also, the high RI value in middle age patients of 40–60 years can be a potential to predict the vulnerability to cardiovascular disease.n = 17 vs. control n = 44) might have been statistically acceptable. Second, because most of our ACS patients were male, sex differences could have had some influence on our results, as reported previously29. We at least indicated a descriptive result of comparing the male and female RI and BOT values between the ACS and control groups  once their general conditions were stable. The dates for comprehensive assessment by LSFG, ultrasonographic imaging of the carotid artery, brachial-ankle pulse-wave velocity, and transthoracic echocardiography were set within 1 week between the 4 modalities. Patients were excluded from this study if they had glaucoma, uveitis, optic neuropathy, or retinal or choroidal vascular disease, left ventricular (LV) ejection fraction < 30%, or underwent hemodialysis, assisted circulation apparatus or previous intraocular surgery or if they were unable to visit the Department of Ophthalmology on foot. After filtering, 53 patients met the study criteria. LSFG control data were collected from 110 consecutive healthy subjects without any ocular diseases in the examined eye and no history of cardiovascular disease, from whom informed consent was obtained for the evaluation of LSFG. Control subjects were chosen among normal subjects aged 40 years or older who visited the Division of Ophthalmology in our hospital. The institutional review board of Nihon University Itabashi Hospital approved this cross-sectional study, and all participants provided their informed consent for participating in the study. The study was conducted following the tenets of the Declaration of Helsinki.30 was used as the mean IMT for data analysis.One to two weeks after admission for ACS, we performed high-resolution ultrasonographic imaging of the carotid artery with an EUB-8500 device , using B-scan mode and a probe frequency of 7.5 MHz. Measurements were performed with the participants in the supine position, and their head slightly turned away from the sonographer. The procedures involved scanning the near and far walls of the carotid artery 1 cm proximally and distally to the carotid bulb in the longitudinal view, and the average of the maximum values on both sidesThe baPWV was measured 1–2 weeks after admission for ACS, using a volume-plethysmographic device  that simultaneously recorded heart sounds, electrocardiograms, and blood pressure at the left and right brachia and ankles. After the patients rested for a minimum of 5 min and while lying supine, pulse volume waveforms were recorded non-invasively from over the brachial and tibial arteries, and the two waveforms time delay (T) between the feet was measured. The distance (D) covered by the waves was estimated as the distance measured between the two recording sites. baPWV was calculated as follows: baPWV = D (cm)/T(s).2), LDL-C (mg/dL), high-density lipoprotein cholesterol (mg/dL), triglycerides (mg/dL), HbA1c (%), N-terminal pro-brain natriuretic peptide (pg/mL), cystatin C (mg/L), U-NAG (U/L), U-β2MG (µg/L), urinary creatinine , U-Alb (mg/L), and L-FABP (ng/mL).The following values were measured during the transport to our emergency department: BUN (mg/dL), creatinine (mg/dL), eGFR , LV systolic diameter (LVDs), and left atrial diameter were measured on the parasternal long-axis view. LV ejection fraction was measured using the modified Simpson’s method in apical 4- and 2-chamber views. The LV mass was calculated with the formula derived from the data of the American Society of Echocardiography32. The LV mass index was calculated as the ratio of the LV mass-to-body surface area. Transmitral flow velocity curves were recorded to measure the peak early (E) and late (A) diastolic velocities. Tissue Doppler imaging at the mitral annulus level was obtained in the septal position to measure the early (e’) and late (A’) diastolic myocardial velocities, as previously described28.Echocardiographic parameters were obtained during the stable phase . Echocardiography was performed with the patient in the supine position, using Vivid 7 or Vivid E9 cardiovascular ultrasonographic systems , operated by experienced sonographers who were blinded to patient data. Echocardiographic measurements were performed following the American Society of Echocardiography guidelineAll patients underwent a baseline ophthalmic evaluation by a well-trained ophthalmologist (HY) before the ocular blood flow measurement. All patients had good visual acuity (VA > 20/20) and normal intraocular pressure (IOP < 20 mmHg). IOP was monitored by applanation tonometry .12. Briefly, the LSFG images were obtained from a 21° section centered on the optic disc. This observation field comprised 750 pixels (width) × 360 pixels (height). The mean blur rate (MBR) was calculated from the moving erythrocytes illuminated by an 830-nm wavelength diode laser beam. The MBRs were expressed in arbitrary units and were considered an indicator of the relative erythrocyte velocity. A total of 118 MBR images were recorded from the ONH area over 4 s. Using accompanying analysis software 22, a grayscale map of the still images was automatically created by averaging the MBR images  was used to measure ocular circulation at the ONH. The principles of LSFG were previously described in detail13. Briefly, the RI was calculated as the ratio of the difference between the maximum and minimum MBR (labeled A) to the maximum MBR. The number of frames showing one-half the value of A was designated B, and the number of frames showing one cardiac cycle was labeled C. The following formula: BOT = 100 × (B)/(C) was used to analyze the pulse wave in the optic nerve head circulation33. We measured MBR, RI, and BOT of the ONH area twice in each eye, and the average values calculated by the LSFG software were used for statistical analysis. All pulse wave analyses in this study were based on the pulse waveform obtained from the MV .The changing MBR pulse wave corresponding to each cardiac cycle was obtained on the analysis screen and displayed after being normalized to one pulse Fig. b. The put-test or Mann–Whitney U test. Categorical data are expressed as numbers and percentages and were compared using the chi-squared test or Fisher’s exact test. Linear regression analysis with Spearman rank-order correlation coefficients was used to assess the correlations between the variable, including systemic atherosclerosis, renal, and transthoracic echocardiography cardiac parameters with the LSFG parameters. Statistical significance was defined as a 2-tailed P-value < 0.05. Statistical analyses were performed using JMP Version 14.0 .Continuous data are expressed as mean ± standard deviation if normally distributed or as median (interquartile range) if otherwise. Comparisons were performed using Student’s


Left bundle branch area pacing (LBBAP) is a novel form of conduction system pacing which can reverse left bundle branch block and deliver cardiac resynchronization therapy (CRT). The WiSE-CRT system delivers leadless endocardial pacing with symptomatic and left ventricular (LV) remodelling improvements following intervention. We report the technical feasibility of delivering leadless LBBAP using the WiSE-CRT system.In Case 1, a 57-year-old male with ischaemic cardiomyopathy and complete heart block underwent implantation of the WiSE-CRT system, using a retrograde transaortic approach, after failed conventional CRT. Temporary left bundle stimulation from the LV septum achieved superior electrical resynchronization and equivalent haemodynamic response compared to endocardial pacing at the lateral LV wall. In Case 2, an 82-year-old gentleman with tachyarrhythmia-induced cardiomyopathy underwent WiSE-CRT implantation via a trans-septal inter-atrial approach, with the endocardial electrode successfully deployed in the LV septum.Here we report the first case of deployment of the WiSE-CRT endocardial electrode in the LV septum and demonstrate the technical feasibility of leadless LBBAP. Entirely leadless CRT is an attractive option for patients with venous access issues or recurrent lead complications and has previously been successful using the WiSE-CRT system and a leadless pacemaker in the right ventricle. Further studies are required to assess long-term efficacy and safety of leadless LBBAP. Learning pointsLeft bundle branch area pacing (LBBAP) from the left ventricular (LV) aspect of the septum achieves excellent electrical resynchronization and haemodynamic response.Deployment of the WiSE-CRT endocardial electrode in the LV septum is feasible.This demonstrates the technical feasibility of leadless LBBAP using the WiSE-CRT system.,Figure  1. After pre-procedural acoustic screening to identify an appropriate intercostal space, patients undergo implantation of the transmitter over the intercostal muscle and implantation of the generator placed in the adjacent mid-axillary line. The endocardial electrode is implanted either on the same sitting or as a separate procedure in a two-stage technique. Implantation can be performed via a retrograde aortic approach using femoral arterial access or via an inter-atrial trans-septal approach using femoral venous access. The system requires the presence of a co-implant capable of delivering continuous right ventricular (RV) pacing. After identification of the RV pacing signal, the transmitter delivers a focused beam of ultrasound energy to the endocardial electrode, which converts this into electrical energy to capture to the LV myocardium and achieve biventricular pacing. We describe two cases of patients undergoing leadless LV endocardial pacing following failed conventional CRT. In the first case, temporary stimulation of the LV septum achieved optimal electrical and haemodynamic indices. In the second case, the endocardial electrode was successfully deployed in the LV septum. These cases demonstrate the feasibility of conduction system pacing by leadless stimulation of the left bundle branch.Left bundle branch area pacing (LBBAP) has been proposed as an alternative to His bundle pacing (HBP), and has been shown to reverse left bundle branch block (LBBB) and deliver cardiac resynchronization therapy (CRT) in observational studies.A 57-year-old male with ischaemic cardiomyopathy, prior anterior myocardial infarction, and a dual-chamber pacemaker for complete heart block underwent upgrade to a CRT-defibrillator. He had New York Heart Association (NYHA) Class III symptoms and severe LV systolic impairment (ejection fraction 32%) despite optimal medical therapy. Physical examination findings were in keeping with chronic heart failure. The upgrade procedure was difficult due to small calibre coronary sinus (CS) tributaries. The LV lead was placed in a lateral branch of the CS, however, during routine follow-up the lead threshold increased with eventual loss of capture. Further transvenous attempts were unlikely to be successful given the difficulty of the original procedure and so the patient underwent leadless endocardial pacing using the WiSE-CRT system.max) was performed with a pressure wire in the LV cavity using a previously described protocol.max measurements were recorded using CoroFlow  and AHR was expressed as percentage improvement from baseline dual-chamber RV pacing to biventricular pacing at different LV endocardial sites. Left bundle branch area pacing was achieved by pacing the LV aspect of the interventricular septum  at the site of a left bundle potential . The greatest AHR was seen when pacing the left bundle (34% increase from baseline) and was equivalent to endocardial stimulation at the mid-lateral wall (34%) as shown in Table 1. However, LBBAP showed greater electrical resynchronization (QRS duration 106 ms) compared to pacing at the mid-lateral LV wall (QRS 132 ms) and baseline RV pacing (172 ms) as shown in Figure  3. The endocardial electrode was deployed in the mid-lateral wall of the LV as the current WiSE-CRT system is not designed to target the septum when a retrograde aortic approach is used .The WiSE-CRT system was implanted using a previously described technique with a retrograde transaortic approach.Figure  4A). Four years later the patient was re-admitted with syncope associated with RV lead dysfunction and a high LV lead threshold with intermittent loss of capture. The left subclavian vein was occluded, and so a new RV lead was implanted via the right subclavian vein. It was not possible to transfer the previously tunnelled LV lead to the right side, and so the existing LV lead was extracted. Re-implantation of a new LV lead failed due to thrombosis of the posterolateral branch of the CS. Without biventricular pacing, the patient deteriorated with worsening LV systolic function (ejection fraction 30%) and heart failure symptoms (NYHA Class III) despite optimal medical therapy. Physical examination findings were in keeping with chronic heart failure. The patient subsequently underwent implantation of the WiSE-CRT system, which was performed via a trans-septal inter-atrial approach using the FlexCath Advance Steerable Sheath . Sensing and pacing threshold measurements in the LV lateral wall were not acceptable and so the endocardial electrode was implanted in the LV septum  with significantly improved electrical resynchronization on electrocardiogram . A stable LV capture threshold (1.5 V at 0.5 ms) and high biventricular pacing percentage (98%) were reported on the pre-discharge device check. At 6-month follow-up, device function was satisfactory and the patient reported significant symptomatic improvement (NYHA Class II).An 82-year-old gentleman with tachyarrhythmia-induced cardiomyopathy required upgrade to a CRT-pacemaker prior to undergoing an atrioventricular node ablation for poorly controlled atrial fibrillation. He had an existing dual-chamber pacemaker which was implanted 4 years previously for sinus node disease, with leads placed via a persistent left-sided superior vena cava (SVC). LV lead placement in the CS was difficult due to the left-sided SVC, and was ultimately implanted via right subclavian access and tunnelled across to the left-sided generator  and endocardial CRT deliver two non-physiological wavefronts which merge to resynchronize the myocardium. Conduction system pacing can recruit the intrinsic His–Purkinje system and reverse LBBB. His bundle pacing is feasible in delivering CRT in heart failure patients, with electrical resynchronization and AHR superior to conventional CRT.In Case 1, temporary LBBAP was associated with excellent electrical resynchronization (QRS duration 106 ms) and haemodynamic indices (AHR 34%). However, the endocardial electrode was ultimately deployed in the LV lateral wall as the current WiSE-CRT delivery system is not designed to target the septum when a retrograde transaortic approach is used, and rotation of the delivery catheter to reach the septum is technically challenging. In Case 2, a trans-septal inter-atrial approach to the LV was used, which allowed successful deployment of the endocardial electrode in the septum. This is the first reported case of LBBAP delivered via the WiSE-CRT system and, to the best of our knowledge, this is the first reported case of permanent LBBAP from the LV aspect of the interventricular septum. Left ventricular septal mapping was not performed to identify the specific location of a left bundle branch potential in Case 2, and therefore selective stimulation of the left bundle branch cannot be guaranteed, however, the marked reduction in QRS duration (from 207 ms during RV pacing to 142 ms during biventricular pacing) suggests that at least non-selective stimulation of the left bundle branch was achieved. Comparison of the QRS morphology during LBBAP via the WiSE-CRT system with that of previously reported lead-based LBBAPEntirely leadless CRT systems are an attractive option in patients with vascular access issues, such as haemodialysis patients, and in those with recurrent lead complications. While the majority of WiSE-CRT systems are implanted in patients with standard right-sided pacing systems, there have been reports of entirely leadless systems using the WiSE-CRT system in conjunction with a leadless pacemaker in the RV.In conclusion, in the first case, electrical resynchronization appeared superior during temporary LBBAP, compared to endocardial pacing in the lateral LV wall, with similar haemodynamic responses. In the second case, the endocardial electrode was successfully deployed in the LV septum and is the first reported case of LBBAP via the WiSE-CRT system. Together, these cases demonstrate the feasibility of leadless LBBAP. Further studies are required to assess long-term safety and performance.Mark Elliott is a cardiology trainee in the North East Thames deanery and a PhD research fellow working in the school of Biomedical Engineering and Imaging Sciences at King’s College London. His research interests include cardiac resynchronization therapy, endocardial left ventricular pacing, conduction system pacing and electrocardiographic imaging.European Heart Journal - Case Reports online.ytab379_Supplementary_DataClick here for additional data file.


We determined the 123I-BMIPP/201TlCl ratio and grouped the patients according to presence or absence of a mismatch. We evaluated the relationship between mismatch and the laboratory and echocardiographic findings.We performed a retrospective study of 26 patients diagnosed with new-onset active PM/DM who underwent P =  < .01 and 29.5 mm vs 25.0 mm, P < .01). Left ventricular ejection fraction was significantly lower in the mismatch group . Significant inverse correlation  was observed between left ventricular ejection fraction and mismatch ratio.Mismatch was found in 13 (50%) patients. There was no statistically significant difference in age, cardiac troponin T, myoglobin, myosin light chain, aldolase levels, E wave/A wave ratio, right ventricular systolic pressure between the mismatch and non-mismatch groups. Left ventricular end-diastolic and end-systolic dimensions were significantly greater in the mismatch group (45.0 vs 42.5 mm, 123I-BMIPP/ 201TlCl scintigraphy may be considered for evaluating myocarditis in patients with PM/DM.The use of  Cardiac involvement is an important risk factor for death in patients with PM/DM due to increased risk of cardiovascular events such as myocardial infarction.–4 The incidence of cardiac involvement has been reported to be between 9% and 72%. Therefore, evaluation of myocardial function in patients with PM/DM is important.Polymyositis (PM) and dermatomyositis (DM) are inflammatory autoimmune disease. Left ventricular diastolic dysfunction can also occur in patients with cardiac involvement. Echocardiography is used for serial monitoring of global and regional left ventricular function after ischemia,but, there are limitation for ischemic memory.In PM/DM, myocardial function is assessed by echocardiography, which evaluates for cardiac abnormality; more specifically for left ventricular and right ventricular systolic dysfunctions that have been reported in new onset PM/DM patients.123I-BMIPP (which reflects fatty acid metabolism) and 201TlCl .123I-BMIPP accumulates in ischemic areas are few, with delayed recovery. Therefore, 123I-BMIPP single photon emission computed tomography will identify ischemic areas as low accumulation (defect) area and can be used to evaluate ischemic memory. In contrast, in the ischemic environment created by vascular spasm, coronary blood flow is preserved and 201TlCl accumulation does not change. The utility of 123I-BMIPP/201TlCl mismatch for the diagnosis of coronary artery disease and as a predictor of cardiac events. And the utility of 123I-BMIPP/201TlCl scintigraphy was reported in patients with dilated cardiomyopathy. Despite the increased risk of myocardial damage in patients with PM/DM, there are few reports on the use of myocardial scintigraphy to identify ischemic memory in this group of patients. We hypothesize that a mismatch between 123I-BMIPP and 201TlCl uptake will be observed in patients with PM/DM. We therefore undertook a retrospective study to evaluate the hypothesis that a mismatch between 123I-BMIPP and 201TlCl uptake is seen in PM/DM, and to evaluate its usefulness in detecting myocarditis in these patients.Myocardial damage from past ischemic events (ischemic memory) can be evaluated using nuclear cardiac imaging that incorporates 22.1123I-BMIPP and 201TlCl between April 2010 and March 2015. And we selected a total of 26 consecutive patients with PM or DM who had undergone double-nuclide myocardial scintigraphy with 123I-BMIPP and 201TlCl between April 2010 and March 2015. In all cases, the diagnosis was new-onset active PM or DM, and had not received treatment prior to the study period.We checked the collagen disease patients who received the double-nuclide myocardial scintigraphy with 2.2123I-BMIPP/201TlCl myocardial scintigraphy. Intravenous administration of 111 to 148 MBq of 123I-BMIPP was followed by 74 MBq of 201TlCl. Accumulation of the 2 tracers was measured simultaneously during imaging: 123I-BMIPP with an ECAM  scintillation camera, and 201TlCl with a GXA-7200  scintillation camera. Risk estimation software  was then used to quantify the radioactivity and degree of mismatch. Mismatch was reported as the ratio of 123I-BMIPP to 201TlCl. Patients were grouped according to the presence or absence of mismatch. Representative images of absence and presence of mismatch are shown in Figures All patients underwent 2.3Of the 26 patients, 24 underwent echocardiography, and scintigraphy was performed at a median of 4.5 days  later. The information collected include left ventricular end-diastolic dimension, left ventricular end-systolic dimension, left ventricular ejection fraction, E wave (early diastole)/A wave  ratio, and right ventricular systolic pressure.2.4The laboratory tests of serum samples and the median interval between scintigraphy and each test were as follows: cardiac troponin T assay (n = 19), 7 days ; myoglobin assay (n = 17), 7 days ; myosin light-chain assay (n = 23), 7 days ; aldolase assay (n = 21), 7 days .2.5U test. The relation between left ventricular ejection fraction and mismatch ratio was determined by Spearman rank order correlation coefficient. All statistical analyses were performed with EZR software, which was developed by Jichi Medical University Saitama Medical Center  as an evolution of the R statistical software . A P value (2 tail) of .05 was considered to be significant.Continuous data were presented as the mean ± SD or median values. Between-group differences were analyzed by Mann–Whitney 2.6This study was conducted with the approval of the Ethics Committee of St. Marianna University School of Medicine (2976) and used opt out.33.1The patient group comprised 23 women and 3 men aged 53.3 ± 15.3 years  patients. The mismatch ratio was 2.6 ± 5.9%. Upon visual inspection of the images, the distributions of 3.3The mean left ventricular end-diastolic dimension was 43.9 ± 3.5 mm, end-systolic dimension was 27.3 ± 3.2 mm, and ejection fraction was 67.8 ± 5.7%. The E/A ratio was 0.9 ± 0.4, and right ventricular systolic pressure was 26.2 ± 7.3 mm Hg. The mean deceleration time (DCT) was 210 ± 56.4 ms.3.4The mean values of the laboratory tests and the number of patients showing above-normal values were as follows: cardiac troponin T concentration = 0.09 ± 0.11 ng/mL ; myoglobin concentration = 469.7 ± 595.4 ng/mL ; myosin light-chain concentration = 46.0 ± 66.6 ng/mL ; aldolase concentration = 22.3 ± 20.9 IU/L .3.5P = .01 and 29.5 mm vs 25.0 mm; P < .01)   was found between left ventricular ejection fraction and the mismatch ratio . The left ventricular end-diastolic and end-systolic dimensions were significantly greater in the mismatch group  of the patients, the left ventricular end-diastolic and end-systolic dimensions were significantly greater in the mismatch group, and the left ventricular ejection fraction was significantly lower in the mismatch group. The mean left ventricular end-diastolic dimension of 43.9 ± 3.5 mm, end-systolic dimension of 27.3 ± 3.2 mm, and ejection fraction of 67.8 ± 5.7% are similar to that of previous reports  in our study showed abnormal cardiac troponin T level, which is lower than that in a previous report (41%). Elevated cardiac troponin T level suggests cardiac ischemic damage and ischemic memory, which reduces cardiac function. However, the cardiac damages was small, accounting for the echocardiography and cardiac troponin T change.In this study,  So the cardiac damage evaluation is important. In this study, we used 123I-BMIPP/201TlCl scintigraphy as a screening, there are some abnormal value about cardiac troponin T, myoglobin, myosin light chain. But, our results should be interpreted in light of the limitations of our study, which include its retrospective design and the small number of patients, Further, we did not evaluate for myocardial function using cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging is useful, but, there are side effect-especially, allergy, kidney damage. Moreover, there are sudden change risk by the load. One hand, 123I-BMIPP/201TlCl scintigraphy do not need the motion or drug load. 2D echocardiography is useful, but there are skill variation between the physician. Other hand, 123I-BMIPP/201TlCl scintigraphy do not depend on the physician skill and have the high quality of objectivity. So we used the 123I-BMIPP/201TlCl scintigraphy. But we did not identify the mismatch site. Additional research is needed in this regard. From these results, the cardiac damage evaluation is necessary.The cardiac involvement in PM/DM-myocradial inflammation, degenerative change, necrosis. 46.4% patients died by heart disease in PM/DM.123I-BMIPP and 201TlCl uptake was useful for early detection of PM/DM-associated cardiomyopathy. A prospective clinical trial involving a large number of patients is needed to confirm the mismatch phenomenon in patients with PM/DM.In conclusion, we found that mismatch between Data curation: Yukinori Okada, Yukiko Takakuwa.Data analysis: Yukinori Okada, Yukiko Takakuwa.Formal and result check: Seido Ooka, Yukihisa Ogawa.Initial idea: Yukinori Okada, Yukiko Takakuwa.Project administration: Yasuyuki Kobayashi, Keiichiro Yamaguchi, Yoshihiro Akashi, Kimito Kawahata.


Fibrose cardíaca difusa é fator importante na avaliação prognóstica dos pacientes com disfunção ventricular. Mapeamento T1 nativo pela ressonância magnética cardíaca (RMC) apresenta elevada sensibilidade e é considerado preditor independente de mortalidade por todas as causas e desenvolvimento de insuficiência cardíaca (IC) nos pacientes com cardiomiopatia.Avaliar aplicabilidade da avaliação com mapa T1 nativo em pacientes com IC em um hospital de referência de cardiologia e sua associação com parâmetros estruturais e perfil funcional.Estudo transversal com pacientes adultos com IC classes funcionais NYHA I e II, isquêmicos e não isquêmicos, acompanhados em hospital de referência, que realizaram RMC. Os valores de T1 nativo foram analisados em relação a parâmetros estruturais, comorbidades, etiologia e categorização da IC pela fração de ejeção do ventrículo esquerdo (FEVE). Análises foram realizadas com nível de significância de 5%.Analisados 134 pacientes. Valores de T1 nativo elevados foram encontrados em pacientes com maior dilatação , volume  e disfunção ventricular , mesmo quando analisados isoladamente os não isquêmicos. Pacientes classificados com IC com fração de ejeção reduzida apresentaram maiores valores T1 em relação aos com IC e fração de ejeção preservada (ICFEP) . Dos com ICFEP, 55,2% apresentavam T1 elevado.Mapeamento T1 por RMC é factível para avaliação da IC clínica. Houve associação direta entre maior valor nativo de T1 e menor fração de ejeção, maiores diâmetros e volumes do VE, independentemente da etiologia da IC. Fibrose cardíaca tornou-se fator importante na avaliação prognóstica dos pacientes com disfunção ventricular, sendo considerada como uma das consequências do remodelamento patológico do ventrículo esquerdo (VE),–,–Ressonância magnética cardíaca (RMC), considerada ferramenta eficaz para avaliar a morfologia e função miocárdica, bem como alterações teciduais,,Estudo observacional multicêntrico evidenciou que o T1 nativo mostrou ser melhor preditor expressivo de piores desfechos na cardiomiopatia dilatada (CMD) do que os parâmetros clínicos clássicos, mostrando que T1 nativo foi o mais forte preditor independente de mortalidade por todas as causas e desenvolvimento de IC.Nosso estudo objetiva avaliar a aplicabilidade da avaliação com mapa T1 nativo em pacientes com IC em um hospital de referência de cardiologia e sua associação com parâmetros estruturais e perfil funcional destes pacientes.Foram incluídos pacientes acompanhados no ambulatório de IC do Hospital Ana Nery, Salvador, Bahia, que consecutivamente foram encaminhados para realização de RMC como parte do cuidado clínico e diagnóstico no período compreendido entre os anos de 2012 e 2016.New York Heart Association (NYHA), com ao menos IC diastólica tipo II definida pelo ecocardiograma transtorácico, de diversas etiologias, divididas em isquêmicas ou não isquêmicas, definição essa baseada na documentação de infarto do miocárdio (IM) prévio, pela presença de realce tardio pelo gadolínio (RTG) subendocárdico ou transmural (respeitando território coronariano) na RMC e/ou presença de isquemia por algum método diagnóstico. Em relação à cardiomiopatia chagásica, foi considerado o diagnóstico na presença de sorologia positiva e após exclusão de isquemia.Foram selecionados, de forma consecutiva, pacientes com idade ≥ 18 anos com diagnóstico de IC, de acordo com critérios de Framingham e/ou Boston, conforme Diretriz Brasileira de Insuficiência Cardíaca Crônica e Aguda, com classes funcionais I e II pela Todos os pacientes realizavam exames de rotina no ambulatório de IC, como radiografia de tórax, teste de caminhada e eletrocardiograma, associado a avaliação de uma equipe multiprofissional. Todos pacientes eram acompanhados no serviço de IC da unidade e faziam uso de terapia medicamentosa otimizada, associada ou não à reabilitação cardíaca pela equipe multidisciplinar, conforme critério clínico do médico assistente.O trabalho foi aprovado pelo Comitê de Ética e Pesquisa da instituição, como subprojeto do trabalho principal: “Características dos pacientes submetidos à ressonância magnética cardiovascular em um hospital de referência”.Todos os exames de RMC foram realizados em um scanner de corpo inteiro Avanto de 1,5 T  usando uma bobina cardíaca de 8 canais. Imagens em varredura foram realizadas para obter sequências cine SSFP em duas, três e quatro câmaras, além do eixo curto. As imagens de cine foram adquiridas durante apneia expiratória . Para análise da função do VE, o eixo curto foi composto de um mínimo de 8 e um máximo de 12 cortes, com 8 mm de espessura e 2 mm de intervalo.Modified Look-Locker Inversion recovery (MOLLI), com acoplamento eletrocardiográfico, 250 a 360 mm de FOV; 192 × 122 a 192 × 183 de tamanho da matriz. Espessura do corte de 6-8 mm; 2,2 / 1,1ms ≈ TR / TE, ângulo de viragem de 35 °; Fator GRAPPA = 2; 17 batimentos cardíacos (que coletam 3 + 3 + 5 amostras). Como a utilização de contraste nos estudos não fazia parte do protocolo e esteve reservado a critério clínico, não foi realizado o cálculo de volume extracelular (VEC) e mapa T1 pós contraste.Imagens de mapa T1 nativo foram realizadas sem injeção de contraste através de corte em porção média do VE através da sequência O valor de normalidade do T1 nativo, para nossa amostra, foi obtido previamente através de um estudo piloto com pacientes sem comorbidades e coração estruturalmente normal da mesma instituição/scanner, como recomendado pela Society for Cardiovascular Magnetic Resonance (SCMR).Circle Cardiovascular Imaging Inc., Calgary, Canada) por especialista em imagem cardiovascular com mais de 5 anos de experiência. Após delineamento de bordos endocárdicos e epicárdicos no eixo curto do VE, em sístole e diástole máximas, foram quantificadas variáveis funcionais como fração de ejeção do ventrículo esquerdo (FEVE), diâmetro diastólico final do ventrículo esquerdo (DDFVE), volume diastólico final do ventrículo esquerdo (VDFVE), massa cardíaca (indexados para superfície corpórea), avaliados conforme valores de referência em RMC recomendados.Todos os exames foram analisados através do software cvi42  FEVE reduzida (IC de fração de ejeção reduzida – ICFER: < 40%); 2) FEVE limítrofe (IC de fração de ejeção limítrofe – ICFEL: 40 a 49%); e 3) FEVE preservada (IC de fração de ejeção preservada – ICFEP: ≥ 50%) .t de Student não pareado, teste de Mann Whitney e teste do qui-quadrado. Valores de p inferiores a 0,05 foram considerados estatisticamente significativos. A análise estatística foi realizada utilizando o software SSPS (versão 22.0).Os dados coletados foram descritos através de médias e desvio padrão para as variáveis contínuas de distribuição normal; e medianas e intervalo interquartílico para as de distribuição não normal. As variáveis categóricas foram descritas em números absolutos e porcentagens. A normalidade das variáveis foi testada através do teste de Kolmogorov-Smirnov. Foram realizados testes estatísticos, conforme o tipo de variável e a normalidade da distribuição: teste Foram incluídos 134 pacientes no período de janeiro de 2014 a dezembro de 2016. Houve uma predominância de pacientes do sexo masculino, FEVE reduzida e diâmetros/volumes cavitários aumentados . PacientValores de T1 miocárdico nativo elevados, quando analisado em relação ao VE, foram encontrados em pacientes com maior dilatação , maiores volumes ventriculares  e disfunção ventricular  . Numa avQuando analisado o T1 miocárdico nativo em relação ao perfil da IC, classificada conforme a FEVE, observou-se um maior valor T1 nos pacientes com FEVE < 35%  . Houve d2) e VSFVE indexado .Quanto à etiologia da IC, foi observado que, independente da etiologia, há alta porcentagem de pacientes com T1 nativo elevado , com um maior valor T1 nos isquêmicos em relação aos não isquêmicos . Analisando especificamente o grupo de não isquêmicos, 13 pacientes tinham diagnóstico de cardiomiopatia chagásica, todos apresentam T1 nativo elevado  associado a FEVE reduzida , elevados DDFVE , DSFVE , VDFVE indexado . O presente estudo demonstra que, além de o Mapeamento T1 ser factível na prática clínica, existe associação do T1 miocárdico nativo com disfunção miocárdica, expressa por uma menor FEVE e maiores volumes e diâmetros intracavitários, independentemente da etiologia da cardiomiopatia.A RMC permite a detecção de fibrose miocárdica difusa através do mapeamento T1 nativo e com alta concordância com a biópsia miocárdica.,,Entre as etiologias, no Brasil, há uma característica distinta em relação à prevalência e importância da doença de Chagas.Há limitações que devem ser destacadas principalmente relacionadas ao modelo transversal do estudo. O tamanho da amostra foi limitado, o que impede a validação adequada das conclusões encontradas. Algumas patologias adicionais podem levar a alterações do T1, incluindo fibrose miocárdica difusa por outras causas, edema, inflamação e doenças infiltrativas. Como não foi realizado estudo de mapa T1 pós-contraste, o cálculo e avaliação do VEC não foi possível, o que não reduz a importância dos achados, uma vez que o T1 nativo demonstrou na literatura ser comparável ao VEC na quantificação de colágeno demonstrado histologicamente.A utilização do mapa T1 miocárdico nativo é factível para avaliação da IC clínica, com correlação significativa a um pior perfil funcional. Houve associação direta entre maior valor nativo de T1 e piores parâmetros clínicos e funcionais, dentre eles uma menor fração de ejeção, diâmetros e volumes maiores do VE, independentemente da etiologia da cardiomiopatia. É importante ressaltar que, em pacientes com cardiopatia chagásica, patologia prevalente no Brasil, a mesma associação foi observada. Cardiac fibrosis has become an important factor in the prognostic evaluation of patients with ventricular dysfunction, considered as one of the consequences of left ventricular (LV) pathological remodeling,–,–Cardiovascular magnetic resonance imaging (CMR), considered an effective tool for evaluating myocardial morphology and function, as well as tissue changes,,A multicenter observational study showed that native T1 was a better predictor of worse outcomes in dilated cardiomyopathy (DCM) than the classic clinical parameters, showing that native T1 was the strongest independent predictor of all-cause mortality and development of HF.The severity of diffuse disease, assessed by the T1 map, maybe a pathophysiologically relevant parameter, since it is directly related to the progression of the disease and to the functional capacity of the remaining myocardium. The continuous nature of T1 values corresponds accurately to the rate of clinical events: the higher the native T1, the greater the risk of adverse events. These findings allow us to refine the current approach to risk stratification in patients with cardiomyopathies, especially DCM.Our study aims to evaluate the feasibility of native T1 mapping assessment in patients with HF in a cardiology referral hospital and its association with structural parameters and the functional profile of these patients.Patients were included in the period between 2012 and 2016. They were followed up at the HF outpatient clinic at Hospital Ana Nery, Salvador, Bahia, who were consecutively referred for CMR as part of the clinical care and diagnosis.Patients aged ≥ 18 years with a diagnosis of HF, according to Framingham and/or Boston criteria, according to the Brazilian Guideline for Chronic and Acute Heart Failure, with functional classes I and II by the New York Heart Association (NYHA), with at least type II diastolic HF defined by transthoracic echocardiogram were consecutively selected. Multiple HF etiologies were divided into ischemic or non-ischemic groups, based on the documentation of myocardial infarction (MI), ischemia by some diagnostic method or presence of ischemic  late gadolinium enhancement (LGE) in CMR. In relation to Chagas cardiomyopathy, the diagnosis was considered in the presence of positive serology and after exclusion of ischemia.All patients underwent routine examinations at the HF outpatient clinic, such as chest radiography, walking test and electrocardiogram, associated with the evaluation of a multidisciplinary team. All patients were followed up at the unit's Heart Failure service and used optimized drug therapy, associated or not with cardiac rehabilitation by the multidisciplinary team, according to the clinical criteria of the attending physician.The work was approved by the institution's Ethics and Research Committee, as a subproject of the main work entitled “Characteristics of patients submitted to cardiovascular magnetic resonance at a referral hospital”.All CMR examinations were performed on a 1.5T Avanto full body scanner  using an 8-channel heart coil. Acquired images were performed to obtain 2D cine balanced SSFP stacks in two, three and four chambers, in addition to the short axis. The cine images were acquired during expiratory apnea . For analysis of the left ventricular function, the short axis was composed of a minimum of 8 and a maximum of 12 cuts, 8 mm thick and 2 mm wide.Native T1 mapping images were performed without contrast injection in the mid-section of the LV through the Modified Look-Locker Inversion recovery (MOLLI) sequence, with electrocardiographic gating, 250 to 360 mm FOV; 192 × 122 to 192 × 183 matrix size. Slice thickness of 6-8 mm; 2.2 / 1.1ms ≈ TR / TE, flip angle 35°; Factor GRAPPA = 2; 17 heartbeats (collecting 3 + 3 + 5 samples). Due to the protocol used in the study, the calculation of extracellular volume (ECV) and post-contrast T1 mapping were not performed, since the use of contrast was optional and indicated only when necessary according to clinical evaluation.The normal native myocardial T1 value for our sample was previously obtained through a pilot study with patients without comorbidities and structurally normal hearts, of the same institution / scanner, as recommended by Society for Cardiovascular Magnetic Resonance (SCMR).All the exams were analyzed through the software cvi42  by a cardiovascular imaging specialist with more than 5 years of experience. After all the contours were drawn in the endocardial and epicardial borders of the LV short axis, in end systole and diastole, all functional variables were quantified, such as left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes and myocardial mass, all indexed to the body surface, according to recommended CMR reference values.,Native T1 values obtained were analyzed in relation to clinical comorbidities, structural parameters, etiology and HF categorization. HF was categorized into: 1) HFrEF (heart failure with reduced EF), EF<40%; 2) HFmrEF (heart failure with mid-range EF), EF 40-49% and; 3) HFpEF (heart failure with preserved EF), EF ≥ 50%.The collected data was described through averages and standard deviation for normal distribution variables; and median and interquartile range for the others. Categorical variables were described in absolute numbers and percentages. Variable normality was tested using the Kolmogorov-Smirnov. Statistical tests were performed according to the type of variable and distribution normality: unpaired Student's t-test, Mann Whitney test and chi-square test. P values less than 0.05 were considered statistically significant. Statistical analysis was performed using SSPS software (version 22.0).We included 134 patients from January 2014 to December 2016. There was a predominance of male patients, reduced LVEF, and increased cavity diameters/volumes . Non-iscElevated native myocardial T1 values, when analyzed in relation to the left ventricle, were found in patients with greater dilation (p = 0.007), larger ventricular volumes (p <0.01) and ventricular dysfunction (p <0.001) . In an aWhen analyzing native myocardial T1 in relation to the HF profile, classified according to LVEF, a higher T1 value was observed in patients with LVEF <35% (p <0.001) . There w2) and indexed LVESV (112.7 ± 54.1 ml/m2).Considering HF etiology, regardless of etiology, there was a high percentage of patients with elevated native T1 (89.7% in ischemic and 81.1% in non-ischemic), with a higher T1 value in ischemic patients compared to non-ischemic (p = 0.004). Specifically analyzing the non-ischemic group, 13 patients were diagnosed with Chagas cardiomyopathy, all presenting elevated native T1 (1077.1 ± 61.1ms) associated with reduced LVEF (27.6 ± 16.8%), high LVEDD (7.1 ± 1.5cm), LVESD (6.1 ± 1.7cm), indexed LVEDV . The present study demonstrates CMR native T1 mapping feasibility in clinical practice with an association with myocardial dysfunction, expressed by lower LVEF and larger ventricular volumes and diameters, regardless of the etiology of the cardiomyopathy.CMR allows the detection of diffuse myocardial fibrosis through T1 mapping, with high agreement with myocardial biopsy.,,Among the etiologies in Brazil, there is a distinct characteristic regarding the prevalence and importance of Chagas disease.There are some limitations worth noting, mainly related to the cross-sectional model of the study. The sample size was limited, which precludes proper validation of the results. Some additional pathologies may lead to T1 changes, including diffuse myocardial fibrosis from other causes, edema, inflammation, and infiltrative diseases. As no post-contrast T1 mapping study was performed, the calculation and evaluation of the ECV was not possible, which does not reduce the importance of the findings, since native T1 has been shown in the literature to be comparable to ECV in quantification of histologically demonstrated collagen.Native myocardial T1 mapping is feasible for clinical HF assessment, with significant correlation to worse functional profiles. There was a direct association between a higher native T1 value and worse clinical and functional parameters, including a lower ejection fraction, larger LV diameters and volumes, regardless of the etiology of cardiomyopathy. Importantly, in patients with Chagas heart disease, a pathology prevalent in Brazil, the same association was observed.


Nucleus pulposus (NP) regions-of-interest (ROI). T1, T2, and T2* mapping correlated with Pfirrmann grading and histological scoring (p < 0.05) except for the most ventral rectangular ROI on T2 maps. Correlations were excellent for all of the T1 ROIs and the T2* NP ROIs. Highly significant differences in T1 values were found between all Pfirrmann grades except between grades I/II and between grades III/IV. Significant differences were identified in the T2 and the T2* values between all grades except between grades I/III. T1, T2, and T2* relaxation times measurements of the NP are an accurate and time-efficient tool to assess lumbar IDD in sheep. Variable-flip-angle T1 mapping may be further considered as a valuable method to investigate IDD and to assess the efficacy of regenerative treatments in longitudinal studies.An easy, reliable, and time-efficient standardized approach for assessing lumbar intervertebral disc (IVD) degeneration with relaxation times measurements in pre-clinical and clinical studies is lacking. This prospective study aims to determine the most appropriate method for lumbar IVD degeneration (IDD) assessment in sheep by comparing three quantitative MRI sequences , correlating them with Pfirrmann grading and histology. Strong intra- and interrater agreements were found for  Numerous mechanisms have been studied, and lumbar intervertebral disc degeneration (IDD) has been identified as one of the main causes of non-specific LBP5. Biochemical changes occur early in the degenerated intervertebral disc (IVD) with proteoglycan loss, dehydration, and collagen fibers degradation especially in the Nucleus pulposus (NP)6. These modifications lead to morphologic changes as well as biomechanical and functional failures, some factors which may cause discogenic back pain.Low back pain (LBP) is a major health concern that affects a great part of the population7. Radiologic features of the IVD have been historically well-studied as being the first imaging modality widely accessible. But by its entire soft tissue opacity, the different parts of the IVD are not distinguishable, in particular in the early stages of the degeneration process. The radiographic signs of IDD are mainly the disc height loss with a narrowing of the IVD space. An increased radio-opacity may sometimes be observed on the projection area of the NP, representing intradiscal calcification. Sclerosis of the endplates and osteophytes can also be associated with the degenerative process8.Image-based assessment of the IVD is essential to determine the severity of IDD in vivo and to select the most suitable patient management. Numerous grading systems have been developed to score the degeneration of the IVD or the facet jointsAnnulus fibrosus (AF) in a healthy tissue. On the contrary, even if the IVD can be assessed in the three dimensions, computed tomography meets the same contrast restrictions as radiographs and is however less relevant than MRI to investigate the changes which occur in the IVD. MRI allows mainly qualitative evaluations of the IVD. Among these evaluations, the Pfirrmann grading system for T2-weighted MRI conventional sequences evaluates the signal intensity and homogeneity of the NP as well as its transition zone with the AF and the variation of the IVD height9. Although Pfirrmann grades are commonly used to assess IDD, there remains a degree of subjectivity and observer bias. This scoring system also fails to detect subtle degenerative changes that arise in the IVD, which can, however, be instrumental to assess the efficacy of a therapeutic strategy in longitudinal studies10.Over the past fifteen years, magnetic resonance imaging (MRI) has been recognized as the most useful imaging modality to investigate and characterize IDD. This non-invasive cross-sectional imaging technic has an important soft tissue contrast which allows a good distinction between the NP and the 13. IDD implies alterations of the biochemistry and the molecular environment and interactions which can be detected on MRI mapping sequences. These sequences aim to provide absolute values that may be useful for detecting subtle variations in the considered tissue or for longitudinal studies.Quantitative MRI, and in particular relaxation time measurements also called mapping, has been recently developed to characterize more precisely the variations in the tissue composition of the IVD, the cartilage, or the brain14. T2* mapping allows assessment of the ultrastructural tissue composition of the IVD by providing information regarding the spatial architecture of the macromolecules and the mobility of water molecules12, and it correlates with functional lumbar mechanics10. T1 mapping has been widely used in cartilage degeneration16, brain sclerosis17, or cardiovascular studies18 and has been shown to be correlated to the water content16. Nevertheless, its usefulness remains to be evaluated in IDD and particularly on the NP.T2 mapping reflects the network of proteoglycan fibers, the water content, as well as molecular interactions, which tend to decrease with IDD22. NP histological evaluation is the gold standard to assess the tissue changes in the lumbar IVD thus assessing the correlation between the two parameters appears to be particularly relevant. All of the studies which have correlated MRI relaxation sequences with histology used animal models. Surprisingly, whereas sheep is one of the most frequently used large animal models for assessing IDD26, only one study has been carried with this species to date19.Few studies have correlated the T1, T2, and T2* relaxation time values and the histological data27.Development of MR mapping sequences aims to evaluate their pertinence in order to apply them in routine clinical evaluation. Yet, some MRI sequences investigated in fundamental research projects are not available on standard clinical MR scanners or not feasible on patients because of their long time of acquisition. In routine, clinicians need MR sequences and measurement methods that are readily easy to use, reliable, repeatable, specific, and not time-consuming to assess IDD. The time dedicated to one patient depends mostly on (1) the time of acquisition of the different sequences which need to be as shorter as possible to get an image quality acceptable for the analysis and (2) the method initially chosen for image analysis. Various methods of region-of-interest (ROI) drawing have been described to define the NP, the AF, or the junctions and to measure the relaxation times of the studied parts of the IVD but no consensus has been found. Only one study has compared three different approaches to define the different parts of the human IVD on T2 and T1rho mapping sequences and no real differences have been found between the manual method and the 5 or 7-squares delimitations of the IVDThus, the objectives of this study were (1) to compare MRI T1, T2, and T2* mapping using two region-of-interest (ROI) drawing methods on lumbar ovine IVD to determine the most suitable approach to assess the changes occurring during the degeneration process and that could be used in preclinical and clinical investigations, and (2) to correlate the MR relaxation times with the histological scoring to establish whether MR mapping sequences may be useful in longitudinal studies for assessing therapeutic strategies in IDD.Fifty lumbar IVDs of 10 sexually mature healthy female sheep between 24 and 108 months of age (mean age: 50.4 months) were prospectively included. None of the animals exhibited musculoskeletal or neurological conditions or signs of low back pain. The cohort came from an accredited farm . This study was approved by the French Ministry of Agriculture . All of the animal experiments were carried out in accordance with EU Directive 2010/63/EU and ARRIVE guidelines.The animals were anesthetized prior to the imaging procedures. The anesthesia was maintained by inhalation of isoflurane (1–3%) after intravenous injection of diazepam (0.2–0.4 mg/kg), ketamine (2–5 mg/kg), and propofol (1–3 mg/kg).Frontal and mid-sagittal radiographs of the lumbar spine were performed using a collimator-to-film distance of 100 cm, exposure of 20–30 mAs, and penetration power of 70–85 kV .28, the images were systematically acquired in the morning.MR images were obtained on the lumbar spine of each sheep with a 1.5 T MR scanner  and a standard spine coil. Sagittal T1-weighted fast spin-echo images  and sagittal T2-weighted fast spin-echo images  were acquired. These sequences were followed by the acquisition of sagittal (1) variable flip-angle T1 mapping sequence , (2) multi-echo T2 mapping , and (3) multi-echo T2* mapping . The times of acquisition were 164 s for the T1-weighted fast spin-echo sequence, 231 s for the T2-weighted fast spin-echo sequence, 88 s for the T1 mapping sequence, 306 s for the T2 mapping sequence, and 101 s for the T2* mapping sequence. The nine elements of the spine coil were used to obtain the sequences. An example of the full FOV images for T1, T2, and T2* mapping is provided as Supplementary Data .The image data were analyzed with Horos software 3.0® . Radiographs were useful to determine the number of lumbar IVDs in each sheep, as they vary between 5 and 6 in this species9Each IVD was assigned a degenerative score on T2-weighted mid-sagittal images using a 5-point grading system as described by Pfirrmann et al.27. The size of each ROI varied according to the size of the IVD. In the 3-ROI method, on the T2-weighted images, an oval ROI was manually drawn around the NP (ROI B) and two other oval ROIs were drawn from either side representing the ventral AF (ROI A) and the dorsal AF (ROI C). Particular attention was paid to not include parts of the vertebral endplates in the ROI. The contrast of the images was changed manually in order to distinguish better the NP. In the 5-ROI method, a rectangular ROI was drawn on the T2-weighted images with these limits: between the cranial and the caudal endplates and between the dorsal and the ventral borders of the IVD. This rectangular region was subdivided into 5 equal rectangular ROIs with ROI 1 corresponding to the most ventral ROI and ROI 5 corresponding to the most dorsal ROI. For each IVD, those eight ROIs were copied on the T2 weighted images and pasted on the corresponding T1, T2 and T2* mapping images. The position of each square in the 5-ROI method was manually slightly readjusted in the craniocaudal axis in order not to include vertebral endplates in the ROI section. The mean T1, T2, and T2* relaxation time values of each ROI were collected. Each value was determined by the mapping method  and the corresponding letter (3-ROIs method) or number (5-ROIs method). For example, the value of the NP collected by the 3-ROIs method on the T1 mapping images was designated “T1ROIB”. The data of the time dedicated to each drawing method was collected by one observer on one IVD of each animal. The time dedicated was measured from the opening of the qualitative MRI image on which the ROIs were initially drawn to the end of the data collection on the three quantitative mapping sequences. The mean time of the ten measures was kept to compare the two drawing methods.To delineate the various parts of the IVD, ROIs were drawn following two previously described drawing methods: the 3-ROIs method and the 5-ROIs method Fig. 27. The s30, the IVDs were analyzed using modified Boos' scoring focusing only on the NP31. Cell density, mucous degeneration, tears and cleft formations, and granular changes were assessed to classify the IDD. The scores ranged from 0 (no degeneration) to 22 (complete degeneration). A blind evaluation of the histological samples was performed separately by two observers. If the scoring differed by less than two points, the median of the two values was used for the analysis. If the scoring differed by more than two points, the histological sample was examined once again by the two raters jointly to reach a consensus.The animals were euthanized after the MR exam by intravenous injection of 140 mg/kg pentobarbital. Fifty lumbar discs were harvested and fixed with 4% paraformaldehyde then placed in a Shandon TBD-2 decalcifier  and frozen in isopentane chilled with dry ice before being embedded in Super Cryoembedding Medium . The samples were cut at −30 °C in an axial orientation into 7-μm slices with a CryoStar NX70 . Following standard protocols, Hematoxylin–Eosin-Safran and Alcian-Blue stainings were performed. Because IVD degeneration is well acknowledged to initiate mainly in the NPIntra-rater reliability for the Pfirrmann grading and each ROI on the T1, T2, and T2* mapping sequences: a linear mixed-effects model was used. The intra-rater reliability was considered to be good if the value was < 15% and moderate if the value was between 16 and 50%.Inter-rater reliability for the Pfirrmann grading: the weighted kappa coefficient (κ) was used to determine the interobserver reliability for the Pfirrmann grading. The agreement was excellent for κ > 0.80, good for κ = 0.60–0.79, moderate for κ = 0.40–0.59, fair for κ = 0.20–0.39, and slight for κ < 0.2. The five readings were reviewed and the grade that was assigned the most to each IVD by each observer was retained for the determination of the inter-rater reliability.2 > 0.75, good if R2 = 0.6–0.75, moderate if R2 = 0.4–0.59, and poor if R2 < 0.4.Inter-rater reliability for each ROI on the T1, T2, and T2* mapping sequences: when the intra-rater reliability was < 15%, the mean of the five values was retained for the calculation of the inter-rater reliability. A coefficient of determination was used. Reliability was considered to be excellent if R32 for mixed-effects models.Correlations between the mapping data and the Pfirrmann and the modified Boos' scorings were analyzed using Spearman’s correlation. The correlations were considered significant if the p-value was < 0.05. For each MRI quantitative parameter, significant differences between the Pfirrmann grades were assessed using a linear mixed-effects model followed by comparisons between groups by a Wilcoxon-Mann–Whitney test. The differences were statistically significant when the p-value was < 0.05. For every linear mixed-effects model, the normality and the independence conditions of the residuals were validated according to the method described by Pinheiro and BatesThe statistical analyses were performed with R-software . Five measurements of the imaging data were collected for each MRI parameter with a 1-week interval between the measurements by two independent blinded observers.The intra-observer analysis revealed strong agreement for all of the parameters (< 15%) except for T2*ROI2. The T2* relaxation time measurement for ROI 2 had moderate intra-observer agreement for observer 1 (20%). Detailed data are provided in Table The inter-rater analysis revealed good agreement for the Pfirrmann grading (k = 0.64).2 > 0.75) for T1, T2, and T2* mapping for all of the NP ROIs (ROIs B and 3) and for the AF/NP junction ROIs (ROIs 2 and 4). The inter-observer agreement was variable for the AF ROIs . It was poor for T2 ROI 1 , T2 ROI 5 , and T2 ROI C , moderate to poor for T1 ROI A  and T2 ROI A , and good for T2* AF ROI . There was strong agreement between the two observers for the AF only for T1 ROIs 1, 5, and C (p < 0.001 and R2 > 0.75). Detailed data are provided in Table The inter-observer analysis showed strong agreement between the two observers .No animal was excluded because of major vertebral disease. Five IVDs were counted in five sheep and six IVDs were counted in the five other sheep.Regarding the Pfirrmann grading, 11 IVDs 22%) were classified as grade I, 17 (34%) as grade II, 16 (32%) as grade III, and 6 (12%) as grade IV. None were classified as grade V. The mean relaxation time values of the ten measurements for the different NP ROIs for each mapping method and for each Pfirrmann grade are summarized in Table 2% were cThe Spearman correlations showed that the Pfirrmann grading was negatively correlated with the NP values measured with ROIs 2, 3, 4, and B on the T1 mapping images , I and III (p < 0.05), I and IV (p < 0.05), and between II and IV (p < 0.05) for all of the NP ROIs. By contrast, there was not a significant difference between grades I and II and between grades III and IV for any of the four NP T1 ROIs Table a.Table 2Analysis of the T2 relaxation time measurements revealed statistically significant differences between all of the Pfirrmann grades except between grades I and III for T2 ROIs 2, 3, and B. Only T2 ROI 4 had significant differences between all of the Pfirrmann grades . These times do not take into account the selection of the two sequences and their correct display on the screen, which do not vary from one method to the other. The number of computer manipulations was much higher for the 5-ROIs method compared to the 3-ROIs approach (22 vs. 11).With an ordinal regression, the probability of the degenerative degree according to the relaxation time value was obtained for T1 ROI B, T2 ROI B, and T2* ROI B and are illustrated in Fig. Considering ROI B, the probability of a non-degenerated NP (Pfirrmann grade I) or an NP with few degenerative changes (Pfirrmann grade II) is higher than 80% if the T1, T2, and T2* relaxation times are greater than 1,320 ms, 164 ms, and 59 ms, respectively.33. The manually drawn oval ROI A and ROI C representing the ventral and the dorsal AF, respectively, were assessed subjectively. The position of the rectangular ROI 1 and ROI 5 representing the ventral and the dorsal AF, respectively, in the 5-ROI method were also adjusted manually. Although particular care was taken to draw an oval ROI of maximal size or to replace the rectangular ROIs without including the border of the NP and the vertebral endplates, a degree of variation may remain, and this could explain the lack of agreement between the two observers for this ROI. This result does not influence the assessment and the quantification of early degeneration of the NP, when MR qualitative grading systems fail to reach this goal with adequate precision7. Indeed, as the early events of IDD happen in the NP, it is crucial to find a non-invasive technique to detect the subtle changes that occur in this tissue. Normative values for healthy adult ovine lumbar IVD have only been established for the T2* mapping on 5 IVDs. Mean T2* relaxation time values for the ventral NP, the central NP, and the dorsal NP were 31.8, 44.1, and 37.3 ms, respectively19, which is coherent with the T2* values obtained in this study. Numerous studies have focused on the correlation between T2 and T2* times with various parameters to characterize IDD. A strong negative correlation has been found between T2 and T2* times and MR qualitative Pfirrmann grading of IDD, which is consistent with our results37. In contrast, T1 mapping has rarely been used to assess IDD, although it has been studied extensively for other tissues’ perfusion such as brain or myocardium38. Very few studies have applied T1 mapping sequences to the IVD, all of which used the multiple-inversion-recovery method40. Our study, to the best of our knowledge, is the first to utilize the variable-flip-angle method and to demonstrate the strong correlation between qualitative MR and histology. The main difference between the two acquisition methods is the time of acquisition of the sequences. The number of inversion-recuperation sequences varies between 5 and 16. Only one of those studies provides the actual time of acquisition of each sequence28, in which the total time of acquisition of the T1 mapping was 784 s, while our method only took 88 s, thus allowing for time savings in daily practice.This study investigated the effectiveness and the feasibility of MR T1, T2 and T2* mapping MRI using two drawing ROI methods on the ovine lumbar IVD. These sequences were correlated to qualitative MR Pfirrmann grade and histological scoring in order to find the most suitable approach that can readily be used in practice in veterinary and human medicine. In accordance with previous studies, most of the AF ROIs offer poor-to-moderate inter-agreement, contrary to the NP ROIs, irrespective of the MRI quantitative sequences42 and T1 mapping28 in healthy human lumbar IVD due to the decrease in water content that occurs during a diurnal cycle. One study has assessed this variation in the human IVD using T2* mapping but no significant differences have been identified 43. In sheep, a potential diurnal variation in mapping values has not been investigated yet but, for ethical considerations, we decided not to anesthetize our cohort twice in one day to explore this feature and realized all the MR exams in the morning. In in vivo studies, quantitative MRI is also sensible to motion artifacts induced by respiration and involuntary displacements of the specimen during the acquisition of the sequences39 but the fact that our study was conducted on anesthetized sheep put under mechanical ventilation limited the presence of these artifacts. Moreover, mapping sequences may be prone to artifacts. When selecting the FOV of each mapping sequence, particular care was taken to select not only the lumbar IVDs but to extend to the last thoracic IVDs and the lumbosacral junction. This allowed spatial warping at the border of the images to be avoided and thus limit such artifacts.Relaxation time measurement is a real challenge in terms of the risk of bias. In this study, great care was taken to reproduce the MR acquisitions under similar conditions. Diurnal significant variation has been highlighted previously in the NP using T227, our data confirm the moderate-to-poor inter-observer agreement for AF ROIs, unlike NP ROIs. No pertinent difference was found between the two approaches used in our study to define the NP and its junction with the AF. Although ROI 4 appears to be more precise at distinguishing the degenerative grade, especially on T2 images, the drawing method to obtain this ROI implies drawing the 5 ROIs together before isolating the mean value obtained with ROI 4. On the other hand, in the 3-ROIs method, the ROIs are independent and can be drawn individually. In clinical practice, the mean time required to obtain ROI 4 is then greater than for ROI B (150 vs. < 50 s). Moreover, the 5-ROIs method appears to be more complicated than the other method in terms of software manipulations and thus involves a steeper learning curve, especially for an untrained observer. Therefore, of the three mapping methods, ROI B appears to be the most suitable tool for evaluation of the NP, and it warrants being assessed for routine clinical practice in human medicine. ROI B has many benefits: ease of drawing, timeliness, and sensitivity.As there is no standardized method for ROI acquisition, comparison of mapping data is not straightforward. Numerous approaches are used to assess IVD degeneration that focus on various parts of the IVD. In accordance with the study that compared three ROI drawing methods26. In particular, ovine lumbar spine and discs present a lot of similarities with human tissues regarding the anatomy, biology, and biomechanics46. Preclinical investigations with intradiscal injections are essential to test the new therapeutics developed in vitro before clinical transposition to human patients. Surprisingly, if sheep have been well described in IVDD preclinical studies, very few investigations using quantitative MRI have been conducted on this species. T2* mapping and T2 mapping have been negatively correlated with disc degeneration using modified Boos19 and non-enzymatic glycation47, respectively. T2 reference values according to the sheep age have been established in a study that used MRI and CT to assess the spontaneous disc degeneration25. Our data indicated that T1, T2, and T2* mapping are applicable in sheep to estimate the changes occurring in the NP in preclinical regenerative studies focusing on this tissue.Even if a perfect match with human IVD degeneration can’t be found, animal models are crucial in studies related to degeneration or regeneration therapeutic strategies of this tissue, and, notably, spontaneous degenerative models19. Our study is the first, to our knowledge, to demonstrate the correlation between T1, T2, and T2* mapping and histology in an ovine model of lumbar IVD degeneration. Imaging may be a valuable substitute for histological analysis of the ovine IVD, by limiting the number of animals sacrificed in accordance with the 3R-ethics-rules. Moreover, longitudinal assessment of the IVD is likewise useful to study the changes that occur in early IDD. However, while T2 and T2* mapping have been correlated to the water content and molecular interactions14 and to the spatial architecture of the macromolecules, respectively, further studies are needed to establish which molecular changes the T1 value reflects in the IDD process.Finally, few studies have assessed the correlation between in vivo quantitative MR measurements and histology of the NP. Investigations using animal models facilitate the comparison of imaging modalities and histology. Boos’ scoring has been used in a T2* mapping study of the lumbar ovine NP of healthy IVDs, but not for correlationIn conclusion, quantitative T2, T2*, and T1 mapping using a single manual oval ROI focused on the NP are easy, reliable, time-efficient, and reproducible tools to evaluate lumbar IVD degenerative disease in sheep and they could be useful tools for routine clinical practice. Early detection and characterization of IVD degeneration will need such tools to assist with the diagnosis and to help with the therapeutic decision. In particular, variable-flip-angle T1 mapping appears to be a relevant modality for assessment of the pathological changes in the lumbar IVDs and it warrants particular consideration in further preclinical and clinical studies.Supplementary Information.