LVMi was significantly higher in the athlete groups; the hypertrophy, however, was even more prominent in water polo athletes . To the best of our knowledge, this is the first study to characterize female athlete's heart of IFBB Bikini Fitness competitors. The predominantly static exercise regime induced a mild, concentric-type LV hypertrophy, while in water polo athletes higher ventricular volumes and eccentric LV hypertrophy developed.We aimed to characterize female athlete's heart in elite competitors in the International Federation of Bodybuilding and Fitness (IFBB) Bikini Fitness category and compare them to athletes of a more dynamic sport discipline and healthy, sedentary volunteers using 3D echocardiography. Fifteen elite female fitness athletes were recruited and compared to 15 elite, age-matched female water polo athletes and 15 age-matched healthy, nontrained controls. Using 3D echocardiography, left ventricular (LV) and right ventricular (RV) end-diastolic volume index (EDVi) and LV mass index (LVMi) were measured. Fitness athletes presented similar LV and RV EDVi compared to healthy, sedentary volunteers. Water polo athletes, however, had higher LV and also RV EDVi (fitness versus water polo versus control; LVEDVi: 76 ± 13 versus 84 ± 8 versus 73 ± 8 ml/m Athlete's heart is a general term for complex adaptive changes of all four cardiac chambers induced by regular vigorous exercise –3. WhileTraditionally, the various sport disciplines can be divided by their exercise nature to dynamic or static groups . While mAccordingly, we aimed to characterize female athlete's heart in elite competitors in International Federation of Bodybuilding and Fitness (IFBB) Bikini Fitness category and compare them to athletes of a more dynamic sport discipline and healthy, sedentary volunteers using 3D echocardiography.Fifteen elite female athletes competing in IFBB Bikini Fitness category were recruited. Furthermore, 15 elite age-matched female water polo athletes  and 15 age-matched healthy, nontrained  women were investigated. Study participants gave prior written informed consent for the examinations . All of the measurements were performed at least 12 hours after last athletic training of the athletes. Detailed medical history and training regime were obtained along with standard physical examination, blood pressure measurement, and 12-lead ECG. Body composition assessment and conventional and also 3D echocardiography were performed. Subjects with uncommon echocardiographic and/or ECG changes or suboptimal echocardiographic image quality or athletes who suspended regular training in the last 6 months were excluded and did not enter into further statistical analysis.2).Weight and height were measured using validated standard equipment. All participants wore light clothing and were barefoot. Body mass index (BMI) was calculated by dividing the body weight by the squared height. Body surface area (BSA) was calculated using the Mosteller formula . Body coEchocardiographic examinations were performed on a commercially available ultrasound system . Standard acquisition protocol consisting of loops from parasternal, apical, and subxiphoid views was used according to current guidelines , 9. In p3D datasets focused on the LV were processed by a single experienced operator using semiautomated, commercially available software . We determined end-diastolic (EDVi), end-systolic (ESVi), stroke volumes (SVi), and mass (LVMi) indices. Parameters were normalized to BSA. To characterize LV function, ejection fraction (EF) and deformation parameters such as global longitudinal (GLS) and circumferential strain (GCS) were also assessed.Offline analysis of the datasets focused on the RV were performed by the same operator using commercially available software . The algorithm automatically generates RV endocardial contour which was manually corrected on multiple short- and long-axis planes throughout the entire cardiac cycle. We quantified RV EDVi, ESVi, and SVi normalized to BSA and EF. Furthermore, the software automatically measures fractional area change (FAC) and free wall longitudinal strain derived from the 3D dataset.p values < 0.05 were considered significant.Statistical analysis was performed using dedicated software . Data are presented as mean ± SD. Shapiro-Wilk test was used to test normal distribution. One-way ANOVA followed by Fisher post hoc test was used to compare groups, and Pearson or Spearman test was performed for correlation analysis as appropriate. Basic characteristics of the study groups are presented in Interventricular septal thickness, posterior wall thickness, and left ventricular internal diameter were higher in water polo athletes compared to both fitness athletes and controls . RelativFitness athletes presented similar left ventricular end-diastolic, end-systolic, and stroke volumes compared to healthy, sedentary volunteers . Water pr = 0.607, p < 0.05), RV SV , and RV length ; in water polo athletes weekly training time correlated with LV mass  and the number of years spent with professional sport activity with LVMi .In fitness athletes, FFMI correlated with RV EDV  is a popular parameter among bodybuilders because it reflects better muscle mass gain than BMI , 28. MorLimitations. Firstly, the low number of investigated athletes represents a limitation. However, our approach was to select two distinct populations from two different sport disciplines representing the highest level possible. Water polo athletes had a longer training history and more extensive weekly training sessions compared to fitness athletes and their exercise nature is mixed rather than clearly dynamic. These factors may bias our comparison. Only resting echocardiographic measurements were performed in our current study. Further investigations are warranted to characterize cardiac function of female fitness athletes during exercise. Our study has a cross-sectional design, while the temporal changes in LV and RV volumes and mass, such as throughout a training season, or dynamics of deconditioning remain unknown. Although 3D echocardiographic solutions are commercially available, LA and RA volumes were calculated by a 2D method in our study. Despite the clear advantages of 3D echocardiography, still cardiac MRI is the gold standard method for the quantification of LV and RV volumes and mass.To the best of our knowledge, this is the first study to characterize female athlete's heart of IFBB Bikini Fitness competitors. The predominantly static exercise regime induced a mild, concentric-type hypertrophy, while in water polo athletes higher ventricular volumes and eccentric LV hypertrophy developed. Fitness athletes presented unchanged LV and RV systolic and diastolic function compared to sedentary volunteers. These findings highlight the applicability of Morganroth's classical hypothesis in the context of female athlete's heart.


Native T1 may be a sensitive, contrast-free, non-invasive cardiovascular magnetic resonance (CMR) marker of myocardial tissue changes in patients with pulmonary artery hypertension. However, the diagnostic and prognostic value of native T1 mapping in this patient group has not been fully explored. The aim of this work was to determine whether elevation of native T1 in myocardial tissue in pulmonary hypertension: (a) varies according to pulmonary hypertension subtype; (b) has prognostic value and (c) is associated with ventricular function and interaction.Data were retrospectively collected from a total of 490 consecutive patients during their clinical 1.5 T CMR assessment at a pulmonary hypertension referral centre in 2015. Three hundred sixty-nine patients had pulmonary hypertension , an additional 39 had pulmonary hypertension due to left heart disease , 82 patients did not have pulmonary hypertension . Twenty five healthy subjects were also recruited . T1 mapping was performed with a MOdified Look-Locker Inversion Recovery (MOLLI) sequence. T1 prognostic value in patients with pulmonary arterial hypertension was assessed using multivariate Cox proportional hazards regression analysis.p < 0.001; healthy subjects T1 = 940 ± 50 ms p < 0.001) with no significant difference between the major pulmonary hypertension subtypes. The RV insertion point was the most successful T1 region for discriminating patients with pulmonary hypertension from healthy subjects (area under the curve = 0.863) however it could not accurately discriminate between patients with and without pulmonary hypertension (area under the curve = 0.654). T1 metrics did not contribute to prediction of overall mortality . Systolic interventricular septal angle was a significant predictor of T1 in patients with pulmonary hypertension (p < 0.001).Patients with pulmonary artery hypertension had elevated T1 in the right ventricular (RV) insertion point  contains supplementary material, which is available to authorized users. Myocardial tissue changes have been visualised in patients with pulmonary hypertension using cardiovascular magnetic resonance (CMR) T1 mapping, T2 mapping and late gadolinium enhancement (LGE) CMR. Native myocardial changes measured using native T1 mapping have been shown across a range of cardiac diseases in clinical subjects –7.Patients with pulmonary hypertension have been shown to have worse prognosis in the presence of myocardial changes visualized by LGE at the RV insertion point  and in tPulmonary hypertension is a heterogeneous condition with 5 diagnostic subcategories: PAH; pulmonary hypertension due to left heart disease pulmonary hypertension due to lung disease and/or hypoxia; chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension with unclear or multifactorial causes. To date T1 mapping studies have been performed in relatively small populations, with only one report wherein diagnostic subcategories were considered separately  and therRV remodelling and failure occur as a result of prolonged elevations of RV afterload. Elevated mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) are characteristic features of the condition, however it is the failure of the RV that is the key determinant of adverse outcome , 12–16. In this work, we sought to determine whether elevation of the native T1 in myocardial tissue in pulmonary hypertension: (a) varies according to pulmonary hypertension subtype; (b) is related to adverse outcome independent of RV size and function, and (c) is associated with biventricular remodeling and function.Approval for analysis of imaging data was granted by the local research ethics committee and consent was waived for this retrospective database study. Consecutive patients with suspected pulmonary hypertension underwent CMR including a modified Look-Locker inversion recovery (MOLLI) sequence as part of their clinical assessment at a tertiary pulmonary hypertension referral centre between 01.01.2015 and 31.12.2015. Exclusion criteria were applied to all subjects according to standard criteria for undergoing CMR. A total of 490 patients were identified. Three hundred sixty-nine patients had a diagnosis of pulmonary hypertension without left heart disease as specified below, 39 patients were identified with pulmonary hypertension associated with left heart disease, and 82 did not have a diagnosis of pulmonary hypertension - mean PAP < 25 mmHg – and were used as a control group, see Fig. n = 83; PAH heritable, n = 5; PAH associated with connective tissue disease (PAH-CTD), n = 89; PAH associated with congenital heart disease (CHD), n = 31; PAH associated with portal hypertension, n = 9; PAH drug/toxin induced, n = 3; PAH other, n = 3. Group 2 left heart disease, n = 39  were treated with PAH therapy. Patients with PAH were strictly defined for this study as PCWP < 16 and no evidence of lung disease or left heart disease. Chronic thromboembolic pulmonary hypertension (CTEPH) patients and some aetiologies of Group 5 pulmonary hypertension were treated as appropriate. Patients with left heart disease were divided into two groups, firstly typical left heart disease (n = 35) and secondly, PAH with left heart disease comorbidity (n = 4). Patients in the PAH associated with lung disease were divided into severe PAH-lung disease (n = 13) and PAH with non-severe lung disease comorbidity (n = 28). A summary of all subject characteristics is shown in Table All patients with PAH , typically via the internal jugular vein using a Swan-Ganz catheter. PVR index (PVRI) was defined as (mPAP-PCWP)/CI, where CI is cardiac index, measured by thermodilution technique. Patients with right heart catheterisation within 30 days of their CMR were included in analysis of associations between right heart catheterisation metrics and myocardial T1.CMR was performed on a whole body 1.5 T scanner , using an 8-channel cardiac coil. Subjects were scanned in the supine position with electrocardiogram (ECG) gating. Short axis cine images were acquired using a multi-slice balanced steady state free precession (bSSFP) sequence with: temporal phases per cardiac cycle: 20; field of view: 480 mm; matrix: 256 × 256; bandwidth: 125KHz/pixel; TR: 3.7 ms; TE: 1.6 ms.T1 mapping was performed using a 2D 3–3-5 MOLLI sequence in a single short axis slice . A bSSFP3. Ventricular mass index was calculated as VMI = RV mass / LV mass. CMR volume and mass measurements were indexed for body surface area where appropriate. Interventricular septal angle was measured by determining the angle between the mid-point of the interventricular septum and the RV insertion points at RV end systole [Cine CMR analysis was performed prospectively on a GE Advantage Workstation 4.1 by a radiographer with 10 years’ experience, who was blinded to the patient’s clinical data. Right and left endocardial and epicardial surfaces were manually traced on the short axis cine images to obtain the volumetric indices; RV end diastolic volume (RVEDV), RV end systolic volume (RVESV), LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV). From the end diastolic and end systolic volumes, RV ejection fraction (RVEF) and LV ejection fraction (LVEF) were calculated. The interventricular septum was included in the LV mass. RV mass was estimated from the sum total of the myocardial slice volumes and an assumed myocardial density of 1.05 g/cm systole .RS was used to assess elevation of the T1 in the RV insertion points, normalised to septal T1. Regions of interest were compared across pulmonary hypertension subtypes -based non-rigid image registration algorithm , which wPatients with PAH were followed up with a census date of 30.01.2018 with a mean follow-up period of 27 ± 8 months and a median follow-up period of 30 months from CMR to death or census.p < 0.05 was considered statistically significant.Statistical analysis was performed and presented using SPSS 21 . Data are presented as mean ± standard deviation. Group comparisons were made using two-tailed ANOVA; post-hoc Bonferroni was used for multiple group corrections. Pearson’s correlation coefficient was used to assess the strength of correlations. Receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of T1 metrics with area under the curve. Intra and interobsever variability was assessed using the intraclass correlation coefficient (ICC); absolute values and 95% confidence intervals. To control for the heterogeneity of aetiology and therapy differences between the different subtypes of pulmonary hypertension, we elected to study the prognostic value of T1 metrics in patients with PAH alone. This controls for differences in outcome caused by factors such as severe lung disease in respiratory patients and chronic thromboembolic disease in patients undergoing pulmonary endarterectomy. Log-log plots were produced for T1 metrics to assess proportional hazards, with variables dichotomised by median values, and prognostic value was assessed using univariate Cox proportional hazards regression analysis. Variable scaling (Z-score) was performed to allow direct comparison of hazard ratios of all continuous variables by subtracting the mean from individual values and dividing by the standard deviation of the variable. Groups were compared using the log-rank (Mantel-Cox) test. Unless otherwise stated, a value of : Tables S1 and S2. Patients with PAH were not significantly different in age or sex than patients without PAH or healthy subjects. Figure Characteristics of the study populations are given in Table 1p < 0.001; patients PAH T1 = 1017 ± 69 ms, p < 0.001). Patients with PAH also had elevated T1 in the LV free wall and septum when compared to healthy subjects but not patients PAH, . See Table p = 0.182; RV insertion point: p = 0.977; LV free wall: p = 0.46). The standard deviation of T1 s within the RV insertion points was significantly higher in patients with PAH (SD = 62.2 ms) compared to healthy subjects (SD = 36.5 ms). The standard deviation of T1 s within the LV free wall and septum were not significantly different in healthy subjects when compared to patients  with PAH .In patients with PAH, T1 was significantly elevated at the RV insertion points when compared to healthy subjects and patients without PAH  in patients with CTD than patients with CHD. There were no other significant differences between groups, see Fig. Comparisons were made between PAH subgroups and there were no significant differences between subgroups. For PAH patients, LV free wall T1 was significantly higher p = 0.06 in patiR = 0.152), see Table Across the population of PAH patients scanned, the RV insertion point T1 had the strongest relationship with RV function. The mean insertion point T1 correlated significantly with RVEDV index, RVESV index and RVEF. Additionally, the RV insertion point T1 showed significant correlations with RV mass index, the VMI and the systolic and diastolic septal angle, see Table A multivariate forward linear regression showed that RVESVI and systolic septal angle were significant independent predictors of RV insertion point T1 in patients with PAH.RS correlated significantly with diastolic and systolic septal angle in patients with left heart disease, . Mean PAP for each patient group was as follows: patients with PAH: 44 ± 13; patients with PAH and left heart disease: 40 ± 12; patients without PAH 19 ± 3. Right heart catheter data is presented for patient subjects in Additional file 1The mean RV insertion point T1 correlated significantly with the functional parameters mean PAP, mean right atrial pressure, and CI but not PVR, see Table Patients with left heart disease showed significant correlations between RV insertion point T1 and mean PAP, mean right atrial pressure, and SvO2. Patients with left heart disease showed significant correlations with septal T1 and mPAP as well as SvO2. There were no correlations between LV free wall and right heart catheter parameters.Fifty-nine patients with PAH died during the follow up period of 29 months (standard deviation: 8 months), of which 43 had PAH.not associated with mortality , see Table Comparison of scaled Cox proportional hazard ratios are illustrated in Fig. T1 values in the septum, RV insertion point and LV free wall were tested for absolute agreement with a random two-way model. The intraclass correlation coefficients for the interventricular septum, RV insertion points and LV free wall T1 values respectively were: 0.841, 0.823 and 0.792 respectively. The interclass correlation coefficients for the septum, RV insertion point and LV free wall T1 values respectively were: 0.844, 0.742 and 0.618 respectively. Reproducibility was found to be excellent in all regions in healthy subjects, intraclass correlation coefficients for the interventricular septum, RV insertion points and LV free wall T1 values were: 0.898, 0.934 and 0.852 respectively. The interclass correlation coefficients for the septum, RV insertion point and LV free wall T1 values were: 0.972, 0.942 and 0.824 respectively.Despite the clinical heterogeneity found in subtypes of PAH in the patients in this study, there were no significant differences found in myocardial T1 between the subtypes of this population. In particular, patients with left heart disease who were considered separately (due to a different aetiology and cardiac phenotype) were found to have no significant differences from patients with other forms of PAH, this may be because the causal mechanism of T1 differences in PAH be present to some extent in all PAH subtypes. However, this may also be due to multiple casual mechanisms causing elevated T1 in PAHdue to the heterogeneity of the disease.Patients with CTD have been previously found to have elevated T1 when compared to controls , howeverTwo control groups were used to evaluate changes in the myocardium in patients with PAH: age matched healthy subjects and patients without PAH. Patients without PAH had significantly higher RV insertion point T1 when compared to healthy subjects. Although these patients do not meet the criteria for PAH diagnosis, they have a mean PAP of 19.4 ± 2.7, which is higher than seen in a healthy subject population. Additionally, T1 changes are not specific to PAH, and therefore raised T1 in this group may be due to other disease such as connective tissue disease or left heart disease in this patient population.RS were successful at differentiating healthy subjects from patients with PAH, they were not successful at differentiating control patients from patients with PAH. ΔT1RS was not significantly different between control groups, which suggests regional elevation of the insertion point T1 is characteristic of PAH rather than elevation of the whole myocardial T1. The lack of specificity of RV insertion point T1 indicates that processes responsible for the elevated RV insertion point T1 are not solely confined to patients with PAH.Though both RV insertion point T1 and ΔT1The RV insertion points were the myocardial regions with the highest T1 and they correlated significantly with loss of RV function and RV remodelling. Systolic septal angle and RVESVI were independent predictors of RV insertion point T1, however these variables only predicted 12.4% of the variance seen in RV insertion point T1 in patients with PAH. This may indicate that mechanisms which are not explicable solely through cardiac volume, mass and pressure changes are responsible for the tissue changes represented by T1.Animal models of PAH with increased native T1 and LGE present in the RV insertion points have been shown to have increased interstitial collagen associated with fibre disarray, and increased connective tissue density . It has RS correlated significantly with septal angle. The T1 value of the LV free wall, which would not experience stress/strain due to elevated ventricular pressure, was found to show no correlation between T1 and septal angle and was not elevated in patients with PAH when compared to patients without PAH. Therefore, our data suggests that the regional elevated native T1 in the insertion points is significantly related to the displacement of the interventricular septum in PAH. This supports the suggestions from histological studies that changes in myocardial T1 and the presence of LGE may be due to exaggerated fibre disarray in the RV insertion points of the myocardium due to stress on the septum and RV insertion points in PAH.Interventricular septal angle is a measure of deviation of the LV septum due to the high pressure in the RV, which correlated strongly with RV insertion point T1 in patients with PAH and was found to be an independent linear predictor of RV insertion point T1. Even in patients with left heart disease, who do not exhibit divergence of the LV septum to the same degree as other patients with PAH, ΔT1RV insertion point T1 was not an independent significant predictor of mortality in patients with PAH. Although LGE and elevated native T1 has been observed in the interventricular septum in PAH –5, elevaReproducibility data was found to be in line with that previously observed in patient T1 mapping studies . The RV Myocardial T1 did not provide additive diagnostic or prognostic information in this PAH cohort. It may be that myocardial changes are a secondary effect of cardiac remodelling and are therefore less relevant in this disease. However, it may also be that traditional region of interest based analysis of T1 is less suitable for this patient population due to heterogeneous T1 across the myocardium resulting in weaker reproducibility.In conclusion, the RV insertion points have been shown to be the region where T1 changes are most significantly related to cardiac function in PAH. Myocardial T1 did not differ significantly between PAH subtypes including LHD. The T1 in the RV insertion point was significantly associated with RV volume and function in the patients scanned. Interventricular septal angle independently predicted RV insertion point T1 in patients with PAH suggesting that regional elevation in the RV insertion point may be linked to increased stress on the interventricular septal wall. T1 in patients with PAH was not found to be prognostic independent of RV size and function. Overall, T1 mapping does not appear to predict the subtype of PAH, or provide additive value over RV volume, mass and geometry in the prognostic evaluation of patients with PAH.It is a limitation of this study that concurrent right heart catheter and CMR data were not present for all subjects. The follow up period for this study was relatively short, with 85% of patients alive at the follow-up date. Therefore, census at a later point may be required to provide more definitive evidence of whether RV insertion point T1 has independent prognostic value. Further work to evaluate regions of interest at the inferior and superior portions of the interventricular septum may clarify whether septal changes are present in these regions. The relationship between T1 and LGE in the RV insertion points was not evaluated here and further work may be warranted to evaluate this thoroughly in patients with PAH.Additional file 1Table S1. Subject characteristics for pulmonary artery sub groups. Table S2. Pulmonary artery hypertension subject. Table S3. Right heart catheterization characteristics of subjects. (DOCX 25 kb)


Early detection of subclinical myocardial dysfunction in patients with diabetes mellitus (DM) is essential for recommending therapeutic interventions that can prevent or reverse heart failure, thereby improving the prognosis in such patients. This study aims to quantitatively evaluate left ventricular (LV) myocardial deformation and perfusion using cardiovascular magnetic resonance (CMR) imaging in patients with type 2 diabetes mellitus (T2DM), and to investigate the association between LV subclinical myocardial dysfunction and coronary microvascular perfusion.n = 31, patients with diabetes for ≤ 5 years) and longer-term DM group . LV deformation parameters, including global peak strain (PS), peak systolic strain rate, and peak diastolic strain rate (PSDR), and myocardial perfusion parameters such as upslope, time to maximum signal intensity (TTM), and max signal intensity . Multivariable linear regression analysis showed that T2DM was independently associated with statistically significant CMR parameters, except for TTM . Further, longitudinal PDSR was significantly associated with upslope  and TTM .Pooled data from T2DM patients showed a decrease in global longitudinal, circumferential, and radial PDSR compared to healthy individuals, apart from lower upslope. In addition, increased TTM and reduced Max SI were found in the longer-term diabetics compared to the normal subjects  contains supplementary material, which is available to authorized users. Diabetes mellitus (DM), characterized by hyperglycemia, is one of the most common metabolic diseases worldwide with continuously increasing prevalence , 2. A maHowever, a substantial proportion of DM patients who do not yet satisfy DCM criteria may be at risk for progressing to DCM or heart failure. A previous research have found that impaired global longitudinal strain was associated with cardiovascular events in T2DM patients . TherefoCardiac magnetic resonance (CMR) imaging can provide a detailed and non-invasive picture of the myocardium, allowing simultaneous assessment of cardiac structure and function, and myocardial perfusion, in a single examination. Recently, feature tracking CMR (FT-CMR) imaging has emerged as a more sensitive technology for measuring myocardial deformation as an indicator of subclinical myocardial dysfunction . There aThe study complied with the mandate of the Declaration of Helsinki and was approved by the Institutional Review Board of our hospital with written informed consent obtained from all study participants. From April 2016 to November 2017, we prospectively recruited 78 patients with T2DM from outpatients attending the Department of Endocrinology at our institution. T2DM was diagnosed according to the current American Diabetes Association guidelines [The height and weight of all participants were recorded and BMI was calculated as weight (kg) divided by the square of height (m). The duration of diabetes was recorded as reported by the patient. Blood pressure was recorded as an average of three measurements in the right arm in a sitting position that were obtained after a 10 min resting period. Before CMR imaging, fasting (8 h) blood samples were obtained from patients and controls for standard laboratory analysis, including plasma glucose, glycosylated hemoglobin, and blood lipids, according to standard procedures of the central clinical laboratory in our hospital.2; matrix size = 184 × 256).CMR imaging was performed with patients in the supine position and on a 3.0-T whole-body scanner  with a dedicated two-element cardiac-phased array coil. A standard ECG-triggering device was also simultaneously used, and data was acquired during the breath-holding period. After the cardiac axes were determined using localizers, a balanced steady-state free-precession (bSSFP) sequence  was used to obtain cine images of the long-axis and the short-axis views and to achieve complete LV coverage from the mitral valve to the apex. For perfusion imaging, a contrast dose of 0.2 ml/kg gadobenate dimeglumine  was administered using an automated injector  at a flow rate of 2.5–3.0 ml/s, followed by a 20 ml saline flush at a rate of 3.0 ml/s. Rest perfusion images were acquired concurrently with intravenous contrast agents in three standard short-axis slices  and in one 4-chamber view slice using an inversion-recovery echo-planar imaging sequence . To exclude myocardial infarction, late gadolinium enhancement (LGE) imaging , the measurements were analyzed by a investigator who was blinded to the status  of the subjects. Left ventricular function parameters, namely, LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) were calculated by manually tracing the endocardial and epicardial contours in serial short-axis slices at the end-diastolic and end-systolic phases. For analysis of LV myocardial strain, long-axis 2-chamber, 4-chamber, and short-axis slices were loaded into the 3-dimensional (3D) tissue tracking module . The endTo determine intraobserver variability, LV global deformation and perfusion parameters in 30 random cases that included 22 T2DM patients and 8 normal controls were measured twice in 2-week intervals by a radiologist. Then, a second investigator, who was blinded to the first investigator’s results, reanalyzed the measurements. Finally, the interobserver variability was assessed on the basis of the two investigators’ results.All statistical analyses were performed with SPSS statistics for Windows . All data were evaluated for normality using the Kolmogorov–Smirnov test and are presented as mean ± standard deviation. Homogeneity of variance was evaluated using the Levene’s test. One-way analysis of variance (one-way ANOVA) was used to compare LV function, deformation, and perfusion parameters among controls, newly diagnosed diabetics, and longer-term diabetics, while, Least-Significant-Difference was used to analyze the difference between pooled data of the diabetes and normal groups, and the Student–Newman–Keuls or Least—Significant Difference test was used to evaluate the difference within the diabetes groups when the p-value of one-way ANOVA was less than 0.05. The Kruskal–Wallis rank test was used to analyze parameters that did not conform to normality or show homogeneity of variance. Binary variables were analyzed using the cross tabs Chi square test. Pearson’s correlation was used to examine the correlation between LV strain and perfusion parameters. The intraclass correlation coefficient (ICC) was used to evaluate both inter- and intra-observer variability.p-value of < 0.05 was considered statistically significant.Univariable analyses were performed to demonstrate the relationship between strain and perfusion or statistically significant CMR parameters and the presence of DM as well as other risk factors. Variables with a probability value of 0.1 in the univariable analyses were then included in a stepwise multivariable analysis based on a linear regression model. A p = 0.92; mean age 53.99 ± 11.15 vs. 53.23 ± 8.59 years, p = 0.74). Based on the duration of diabetes [n = 31) or longer-term DM . The baseline characteristics of the T2DM patients and healthy volunteers are presented in Table p < 0.05). Fasting plasma glucose, glycated hemoglobin, and triglyceride levels were higher in patients with T2DM compared to healthy subjects but were not different between the two subgroups of T2DM patients. As expected, diabetic patients had lower high-density lipoprotein (HDL) and lower low-density lipoprotein compared to healthy controls. Total cholesterol was also significantly lower in newly diagnosed DM patients than in control subjects, which might be due to the fact that a significant proportion of diabetics were also on statin therapy.We recruited 109 subjects (78 patients and 31 controls) for the study and acquired CMR imaging data for all subjects. However, data from five subjects had to be excluded because of poor image quality  and from three patients because the inferior quality of the perfusion data sets prevented quantitative analysis. Thus, the final study cohort comprised 71 T2DM patients and 30 healthy controls . Within the T2DM patient subgroups, the global longitudinal PSSR was significantly lower in the longer-term DM group than the newly diagnosed group (p < 0.017). Additionally, T2DM patients showed lower global radial, circumferential, and longitudinal PDSR compared to control subjects , except for radial PDSR in the newly diagnosed diabetics (p > 0.017). Within the two subgroups of T2DM patients, the global radial, circumferential, and longitudinal PDSR were also significantly lower in the longer-term group compared to the newly diagnosed group . Next, the TTM was higher in the longer-term DM group than the normal subjects . Additionally, Max SI was significantly reduced in the longer-term diabetics compared to the newly diagnosed diabetics and the normal subjects , the PSSR , and all three directions  of the PSSR . T2DM was also found to be independently associated with first-pass perfusion parameters , except for TTM .Multivariable linear regression analysis revealed that considering covariates , T2DM was independently associated with longitudinal PS (p = 0.01). LV global radial PS and PSSR, and circumferential PDSR were inversely correlated to TTM  in patients with T2DM. In contrast, longitudinal PS, circumferential PSSR, and radial PDSR were positively associated with TTM . Further, longitudinal PSSR was significantly associated with upslope  and TTM  and PSSR . In addition, the upslope was independently associated with the longitudinal PSSR  can measure subclinical myocardial dysfunction in patients with T2DM at the preclinical stage; importantly, these subtle alterations are considered to be early signs of DCM –26. MoreOur results show that there is no significant difference in LVEF between the healthy individuals and uncomplicated T2DM patients, regardless of the duration of T2DM. However, a previous study used Doppler echocardiography to demonstrate LV diastolic dysfunction in asymptomatic type 2 diabetic patients with good glycemic control and normal EF , indicatNext, we find reduced longitudinal PS but preserved circumferential and radial PS in longer-term diabetics compared to normal subjects. This is probably because the longitudinal myocardial fibers are predominantly located in the sub-endocardium and this wall layer is most susceptible to microvascular ischemia; thus change can lead to a reduction in longitudinal LV mechanics in the early stages of T2DM , 33. FurOur observations of upslope, Max SI and TTM confirm impaired coronary microcirculation in T2DM patients and suggest that myocardial microvascular dysfunction begins in the early stages of T2DM and accumulates as disease duration increases; this is consistent with previously reported pathological results from animal experiments , 35. FurA previous study has identified an association between impaired myocardial perfusion reserve and diastolic dysfunction in patients with T2DM using echocardiography and myocardial perfusion scintigraphy . In contThere are several limitations to our study. First, the patient population comprised uncomplicated T2DM patients in stable condition with no other significant co-morbidities; this has reduced the applicability of our results to “real world” populations with high incidence of co-morbidities. However, we recruited such participants as this design excluded the effects of confounding factors, such as other co-morbidities that affect cardiac function, and helped better explore the influence of T2DM on the myocardium. Second, due to the likely selection bias, the values of eGFR were normal in most T2DM patients. Therefore, we did not discuss the effect of eGFR on LV deformation and myocardial perfusion. Third, not all DM patients underwent coronary computed tomographic angiography (CCTA) because of the radiation dose. However, patients suspected of CAD  underwent CCTA examination. Finally, as this was a cross-sectional study, there are inherent design limitations and our results remain to be verified by longitudinal studies in T2DM patients. We aim to accomplish this in our future research endeavors.We show that 3.0T CE-CMR can simultaneously detect subclinical myocardial dysfunction and impaired myocardial microvascular perfusion in a single examination in the early stages of T2DM, and that these changes accumulate gradually over time. Further, we confirmed the correlation between impaired microvascular perfusion and subclinical myocardial dysfunction, suggesting that impaired coronary microcirculation may lead to cardiac dysfunction; this implies that future therapeutic strategies should focus on preserving or increasing coronary microvascular perfusion to prevent myocardial dysfunction in T2DM patients.Additional file 1. The short-axis and four-chamber long-axis LGE images showed no delayed enhancement, demonstrating that the T2DM patient (corresponding to Fig.


OHSS) is a serious iatrogenic condition, predominantly related to the hormone used to induce oocyte maturation during IVF treatment. Kisspeptin is a hypothalamic neuropeptide that has recently been demonstrated to safely trigger final oocyte maturation during IVF treatment even in women at high risk of OHSS. However, to date, the safety of kisspeptin has not been compared to current hormonal triggers of oocyte maturation.Ovarian hyperstimulation syndrome  triggered with human chorionic gonadotrophin (hCG) (n = 40), GnRH agonist  or kisspeptin (n = 122) at Hammersmith Hospital IVF unit, London, UK (2013‐2016).We conducted a retrospective single‐centre cohort study investigating symptoms and clinical parameters of early OHSSClinical Parameters of : Median ovarian volume was larger following hCG (138 ml) than GnRHa , and in turn kisspeptin . Median ovarian volume remained enlarged 20‐fold following hCG, 8‐fold following GnRHa and 5‐fold following kisspeptin compared to prestimulation ovarian volumes. Mean (±SD) ascitic volumes were lesser following GnRHa (9 ± 44 ml) and kisspeptin (5 ± 8 ml) than hCG . Symptoms of OHSS were most frequent following hCG and least frequent following kisspeptin. OHSS:Diagnosis of  The odds ratio for OHSS diagnosis was 33.6 (CI 12.6‐89.5) following hCG and 3.6 (CI 1.8‐7.1) following GnRHa, when compared to kisspeptin.hCG in women at high risk of OHSS.Triggering oocyte maturation by inducing endogenous gonadotrophin release is preferable to the use of exogenous  In women at high risk of OHSS, gonadotrophin‐releasing hormone agonist (GnRHa), which has a shorter duration of action than hCG, can be used as an alternative trigger of oocyte maturation. More recently, kisspeptin has been evaluated as a novel trigger of oocyte maturation. days. InSeveral classifications have been proposed for the diagnosis of OHSS based on symptoms, sonographic and laboratory parameters. The most widely used criteria are those devised by Golan et al in 1989 with the updated classification by Navot et al in 1992.Whilst severe OHSS occurs in 2%‐6% of patients in an unselected population,Therefore, we sought to characterise clinical parameters of OHSS  and symptoms of OHSS following different triggers of oocyte maturation  in women at high risk of early OHSS .22.1Data from patients who received kisspeptin to trigger oocyte maturation were obtained from randomised clinical trials approved by the Hammersmith and Queen Charlotte's Research Ethics Committee, London, UK (reference: 10/H0707/2).2.2The protocol for patients undergoing kisspeptin triggering has been previously described.2.3Women undergoing IVF treatment for infertility at Hammersmith Hospital, London, UK, between 2013 and 2016 were included in the study (n = 261). We selected patients at high risk of OHSS as defined by a total antral follicle count (AFC) or total follicle count on day of trigger ≥23.2.4Normal—Patients without any symptoms consistent with OHSS. Mild OHSS—Patients with at least one symptom consistent with OHSS and maximal ovarian volume (either left or right ovary) of between 65 and 903 ml (approximated to 5‐12 cm diameter). Moderate OHSS—Patients met the criteria for mild OHSS and additionally had at least 50 ml of total ascitic fluid in the pouch of Douglas, adnexae and abdomen. Severe OHSS—If patients met the above criteria for moderate OHSS, but additionally had at least 50 ml of fluid in the pleural space.Patients were assessed for parameters of early OHSS between days 2 and 6 following oocyte retrieval. For hCG and GnRHa groups, the Hammersmith IVF Unit policy is to screen all patients with at least 18 follicles ≥11 mm on the day of trigger for OHSS . Patients triggered with kisspeptin at high risk of OHSS (AFC ≥23) were part of a clincial trial and thus also screened for OHSS. In all patients, OHSS screening is usually conducted just prior to embryo transfer , although it may be conducted between days 2 and 6 following oocyte retrieval to avoid out‐of‐hours scheduling. During OHSS screening, patients were asked as to the presence of the following symptoms consistent with OHSS  and underwent transvaginal ultrasound screening to record parameters of OHSS such as ovarian size and the presence of ascites. Ovarian volumes were measured using transvaginal ultrasound  by experienced IVF physicians/ultrasonographers at Hammersmith IVF unit, London, UK during 2013‐2016 and converted electronically to ovarian volume values using the prolate ellipsoid formula (height × width × depth × 0.523). Patients were objectively graded for OHSS based on modified criteria of Golan et al 19892.5Statistical analysis was conducted by TWK and AA using Graphpad Prism version 7.0 and Stata version 14.0 statistical software. Baseline characteristics were compared using the Kruskal‐Wallis test for continuous variables and the Chi squared test for binary variables. Adjusted logistic regression analysis was used to derive odds ratios for experiencing symptoms of OHSS following hCG or GnRHa when compared to kisspeptin. Variables examined as potential confounders included age, body mass index (BMI), AFC, recombinant FSH dose, use of long IVF protocol, number of follicles ≥11 mm on day of trigger and number of oocytes retrieved. Univariate analyses were conducted to determine variables independently associated with both trigger and symptom and adjusted for in the logistic regression model. Odd ratios for abdominal pain and “self‐reported reduction in urine output” were adjusted for “use of long IVF protocol.” Odd ratios for abdominal bloating were adjusted for “use of long IVF protocol” and “number of oocytes” retrieved. Odd ratios for diarrhoea were adjusted for AFC and “use of long IVF protocol.” Odds ratios for nausea were adjusted for AFC, “total dose of recombinant FSH during stimulation” and “use of long IVF protocol.” No confounders significantly influenced the likelihood of diagnosis of OHSS and thus unadjusted odds ratios are presented. As no patient with kisspeptin triggering had “self‐reported reduction in urine output” or moderate OHSS, Laplace smoothing was applied.33.1Two hundred and sixty‐one women at high risk of OHSS received either hCG (n = 40), GnRHa (n = 99), or kisspeptin (n = 122) to trigger oocyte maturation. A further 16 patients in the hCG group, 24 patients in the GnRHa group and 3 patients in the kisspeptin groups were identified who met the criteria for inclusion in the study, but did not have data available and were thus excluded from further analyses. The cohort studied was at high risk of OHSS with a median of 38 antral follicles, 24 follicles ≥11 mm on the day of trigger and 19 oocytes retrieved. There were significant imbalances between the treatment groups as clinicians are more likely to recommend GnRHa trigger rather than hCG trigger for patients deemed at higher risk of OHSS (“Table 3.2P < .0001), than following kisspeptin   following hCG and 29 ml  following GnRHa when compared to kisspeptin. Mean total ascitic volume was 62 ml following hCG, 9 ml following GnRHa and 5 ml following kisspeptin  of ascitic fluid when compared to kisspeptin.Median ovarian volume at 2‐6 days following oocyte retrieval was higher following hCG 138 ml) than following GnRHa , and ~2‐fold more likely following GnRHa (P = .048) when compared to kisspeptin (Table P < .001), and ~4‐fold more likely following GnRHa (P = .005) when compared to kisspeptin (Table P = .001), and ~8‐fold more likely following GnRHa (P = .007) when compared to kisspeptin  and ~3‐fold following GnRHa (P < .0001) when compared to kisspeptin   leading to an increased risk of OHSS.0 days leData from previous studies have suggested that the observed rates of OHSS following different triggers may not be entirely explained by their relative durations of stimulation and could additionally be due to direct ovarian actions. In this context, hCG has been shown to directly increase VEGF expression and raise VEGF levels in human granulosa cells to increase the risk of OHSS,3 at 5 days after oocyte retrieval following hCG trigger in the short IVF protocol (~9‐fold prestimulation volumes)3 at 6 days after oocyte retrieval following a GnRHa trigger in women with normal ovarian reserve.Ovarian volume is dramatically enlarged following controlled ovarian stimulation in IVF treatment. The normal range for ovarian volume outside the context of IVF treatment in premenopausal women aged 23‐38 years is ~4‐10 ml.Due to the frequency of segmentation in patients treated with hCG (51%) or GnRHa (13%) as compared to kisspeptin triggering (3%), it was not possible to reliably assess parameters of late OHSS. Whilst processess for vitrification of embryos have improved significantly in recent years, segmentation has been associated with an increased risk of pre‐eclampsia in women with polycystic ovarian syndrome.Preventing premature ovulation during controlled ovarian stimulation prior to trigger using a GnRH agonist to downregulate the GnRH receptor (long IVF protocol) can be associated with a higher risk of OHSS than when this is achieved using a GnRH antagonist (short IVF protocol). Therefore, clinicians are more likely to treat patients at higher risk of OHSS with a GnRH agonist trigger in the short IVF protocol rather than to use an hCG trigger in the long IVF protocol. In patients triggered with hCG in the present study, 55% (22 of 40) had controlled ovarian stimulation using the long IVF protocol and 45% the short IVF protocol. Nevertheless, rates of moderate to severe OHSS were similar to those triggered with hCG in the context of the long protocol (40.9%) as in the short protocol (33.3%). Toftager and colleagues reported the frequency of OHSS symptoms at 5 days postoocyte retrieval using hCG trigger in the short IVF protocol in an unselected population to be: abdominal discomfort 67%, abdominal pain 44%, abdominal distension 31%, nausea 17%, vomiting 1% and shortness of breath 7%.All patients in this study were treated and assessed at the same centre and no more than 9 different IVF physicians/ultrasonographers conducted ultrasounds over the 3‐year study period. Limitations of the study include that insufficient data on blood results were available to assess for haemoconcentration and thus rates of severe OHSS may be underestimated. Indeed, patients in all three groups were at markedly increased risk of OHSS  and the rate of severe OHSS encountered in the hCG group 15%) was consistent with the published literature for women with PCOS.% was conThere were some differences in baseline characteristics between the treatment groups in this retrospective cohort study Table ; howeverIn summary, we observe that the likelihood of clinical parameters of early OHSS was higher when triggering oocyte maturation with hCG than following GnRHa or kisspeptin. These results suggest that triggering oocyte maturation by the induction of endogenous gonadotrophin release is preferable to the use of hCG in women at high risk of OHSS.All authors declare that they have no competing interests.All authors provided contributions to study conception and design, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version to be published. Here are the most important contributions of each author: AA and WSD designed the study. Data were collected by AA, SC and RI. Analysis was carried out by TWK and AA. WSD takes final responsibility for this article. Click here for additional data file. Click here for additional data file.


Left ventricular outflow tract (LVOT) obstruction is a relatively common consequence of transcatheter mitral valve replacement (TMVR). Although LVOT obstruction is associated with heart failure and adverse remodelling, its effects upon left ventricular hemodynamics remain poorly characterised. This study uses validated computational models to identify the LVOT obstruction degree that causes significant changes in ventricular hemodynamics after TMVR. Seven TMVR patients underwent personalised flow simulations based on pre-procedural imaging data. Different virtual valve configurations were simulated in each case, for a total of 32 simulations, and the resulting obstruction degree was correlated with pressure gradients and flow residence times. These simulations identified a threshold LVOT obstruction degree of 35%, beyond which significant deterioration of systolic function was observed. The mean increase from baseline (pre-TMVR) in the peak systolic pressure gradient rose from 5.7% to 30.1% above this threshold value. The average blood volume staying inside the ventricle for more than two cycles also increased from 4.4% to 57.5% for obstruction degrees above 35%, while the flow entering and leaving the ventricle within one cycle decreased by 13.9%. These results demonstrate the unique ability of modelling to predict the hemodynamic consequences of TMVR and to assist in the clinical decision-making process. These techniques vary from balloon and self-expanding AV used in the mitral position, to newer devices specific to the MV, to Valve-in-Valve interventions for failed bioprosthetic devices4. Irrespective of the approach, it is clear that transcatheter mitral valve replacement (TMVR) poses a distinct set of challenges compared to AV implantation. The geometry of the mitral apparatus and its relationship to atrial and ventricular structures introduce significant concerns pertaining to device stability. Specifically, TMVR devices need to be oversized to ensure adequate anchoring while accommodating deformational changes of the valve annulus during the cardiac cycle. This, in conjunction with the displacement of the anterior MV leaflet towards the AV, introduces a risk of left ventricular outflow tract (LVOT) obstruction as it involves a taller frame protruding inside the left ventricle (LV)6.With the success of transcatheter aortic valve (AV) implantation for patients at high surgical risk, attention has now been cast on transcatheter therapies for the mitral valve (MV)7. Outflow obstruction can in turn increase left ventricular afterload and introduce adverse hypertrophic LV remodeling, which correlates with high risks of ventricular failure especially in patients with underlying dysfunction8. Evidence also exists that TMVR is associated with risks of blood stagnation inside the ventricle, with elevated pressure gradients and less effective ejection after MV implantation identified as predisposing factors for early postoperative thrombi11.The interplay between the protruding device, the septal wall, and the anterior leaflet results in the formation of a neo-LVOT with reduced cross-sectional area compared to the original outflow tract15. In the current study we sought to evaluate the utility of combining this technique with computer models to simulate blood flow dynamics in TMVR patients and to predict the ventricular response to LVOT obstruction.Although pre-procedural planning aims to predict the likelihood of LVOT obstruction, existing techniques are largely based on standard geometric evaluation of pre-procedural imaging datasets and there is consensus on neither the effect of the cardiac phase at which measurements are taken, nor the procedural canting of the device on the prediction. It also remains unknown as to what threshold of LVOT obstruction is clinically significant in these patients. To enable a successful introduction of TMVR devices, it is clear that careful patient selection and advanced quantitative evaluation of both anatomy and hemodynamics will be vital. Advanced imaging evaluation can provide valuable insight into the patient pathophysiologySeven patients were included in the study Tables  and 2: sMultiphase contrast-enhanced computed tomography angiograms (CTA) were acquired in all patients using a Philips Brilliance iCT 256-slice MDCT scanner . Intravenous metoprolol was used to achieve a heart rate of <65 beats/min . Intravenous contrast  was subsequently injected into the antecubital vein . Ascending aorta contrast triggered, retrospectively ECG-gated scanning with no dose modulation was performed in a single breath hold after 10–12 seconds with a heart rate-dependent pitch of 0.2–0.45, a gantry rotation time of 270 ms, a tube voltage of 100 or 120 kVp (depending on the patient’s body mass index) and a tube current of 125–300 mA (depending upon the thoracic circumference). Transthoracic and transesophageal echocardiography data were also acquired. The direction and maximum magnitude of blood velocity across the valves was evaluated from Color Doppler data, which was also used to estimate mean and peak LVOT and transaortic pressure gradients. For all Doppler measurements, the average of three signals was taken. The mitral valve annulus was defined as the hinge points between the left atrium and mitral valve leaflets. The area of the annulus was measured as an average of three estimates on a 3D volume acquisition of the left atrium and left ventricle in mid systole by multiplanar reformatted imaging.LV/DLV) were measured as shown in Fig. The valve dimensions, the angle between the MV and AV planes (α), the distance between the MV coaptation point and the interventricular septum (C-sept), and LV aspect ratio (AR = LLV) is given by:Although the valve dimensions in the models were informed from specific devices, our results can be applied to any stent-based valve design within these size ranges. This study aims at identifying the degree of obstruction that causes significant changes in hemodynamic function, and not at investigating the valve design itself: therefore we chose a simplistic representation of the bioprostheses, with a rigid cylinder of diameter D and height H, respectively equal to the inner diameter and frame height of the commercial valve under consideration for implantation Fig. . A tetraLA is the portion of the valve frame in the left atrium relative to the mitral sewing cuff  was then calculated as the normal projection of the valve frame on the AV plane, divided by the total outflow area : gradient between the mean pressures within a sphere of radius 4 mm in the apical region and on the AV plane : gradient between the mean pressures within a sphere of radius 1 mm placed 6 mm below the AV plane and on the AV plane : percentage of blood entering and exiting the LV within the same cardiac cycle.Retained inflow : percentage of blood that enters the LV during diastole and is not ejected in the following systole.Residual volume : percentage of blood that spends more than two cycles in the LV before being ejected.RVU, RVL(%): residual volume of blood in the upper and lower LV respectively .The pressure gradients in the LV were calculated at peak systole in each model. In addition to pressure calculations, a functional flow analysis was performed by splitting the blood flow into different components depending on the time spent inside the LV Fig. , with eaIn each patient, all hemodynamic parameters from the predictive models were normalised based on the corresponding value from the baseline model.C, %) at which a change in the slope of the regression line occurred.Descriptive statistics are presented as mean ± SD. A simple regression model was used to predict the variations of each normalised hemodynamic parameter with OF. Pair-wise comparisons between predictive and baseline models were performed using a Wilcoxon test and differences were considered significant for p < 0.05. A piecewise linear regression of the hemodynamic parameter on OF was also applied to the data to detect the change point  included comprehensive imaging data acquired immediately before and after implantation, allowing us to create two independent models pre- and post-TMVR. When in its predictive capacity, the pre-TMVR model included a rigid cylinder with the same internal diameter, frame height and atrial positioning of the implanted valve, a 29-mm Medtronic Intrepid device. The mean and peak PG and obstruction fraction from this predictive model were validated against the values derived from both the post-TMVR imaging data and model Table . A diffeSimple linear regression was performed to predict the effect of LVOT obstruction on PG-AV and PG-LVOT Fig. .Figure 32 = 0.74, p < 0.05) compared to the baseline values . Piecewise regression analysis identified a critical value OFC = 35%, which corresponded to an increase in PG-AV of 21%. Specifically, the mean increase in PG-AV from the baseline was 5.7% for OF <35% and 30.1% for OF >35% . A polynomial fitting analysis showed that the value OFC = 35% identified a switch from a linear to an exponential growth of PG-AV with OF (r2 = 0.91).The normalised peak systolic PG-AV increased monotonically with OF in Fig. 2 = 0.53, p < 0.05) over the range of OF tested . A mean decrease of 6.6% for OF <35% and 23.5% for OF >35% was observed .Contrary to the trend identified for PG-AV, in Fig. Pressure isocontours from the baseline and predictive models for Case 1 typify the disrupting effect of the obstruction on the PG-LVOT Fig. . The corIn Case 2 and 6, where no obstruction was observed due to anatomical features, both peak systolic PG-AV and PG-LVOT after implantation were close to the baseline values.Figure C the slope of the regression line increased significantly by 46.8% and 37.5% for RV and RI when respectively compared to the corresponding slope of the overall linear regression, while a moderate increase of 3.5% was reported for DF. For OF <30% the mean increase from the baseline in the RV component was 4.4%, but this value raised significantly to 57.5% for OF >30% . Mean increases from the baseline of 8.9% for OF <30% and of 14.1% for OF >30% were recorded for the RI component .For all flow components a change point was identified for OF values of approximately 29–30%. Above this OFC = 34%, which corresponded to a decrease of 31%. The mean decrease was 17.4% for OF <34% and 46.2% for OF >34% .Overall the R ratio in the post-TMVR models decreased from the baseline by 36.7% with increasing OF  Fig. . PiecewiU component increased on averaged by 27.1% from the baseline in the range of obstructions tested , while RVL component did not show any statistically significant variation  resulted in a 33% increase in transaortic pressure gradients, which increased exponentially with EOA decreasing below a threshold valueted Fig. . Since o28.Outflow obstruction also resulted in a localised decrease in the systolic pressure gradient in the LVOT that was not present in the baseline models, where the pressure changes occurred gradually in space Fig. . The prein-vitro models, which showed blood accumulation sites near the valve structure and between the valve frame and the myocardium, creating potential sites for thrombus formation29. Such a conclusion is also supported by our finding of an increase in the number of RVU particles post-TMVR, which was not accompanied by a consistent decrease in the number of RVL particles. In the predictive models, these extra RVU particles accumulate in the sites between the myocardial wall and the valve or inside the valve frame itself  and do not account for specific manufacturing characteristics. This approximation allows the models to be consistent across implants and thus does not limit the generalisability of the results. The simplified valve represents the bulk of frame and leaflets without distinguishing between each structure: while such representation is an approximation of the real system, this is what eventually causes obstruction in the LVOT, whose prediction is the main goal of the study. However, further modelling work on a larger number of patients will be necessary to investigate how anatomical parameters such as the size of the LV cavity may affect the threshold OF for haemodynamics deterioration, since LVOT obstruction can impact the behaviour of the LV differently in small ventricular cavities. Similarly, future modelling studies with more realistic shapes of implanted device should also be performed to analyse the effect of the bioprosthesis geometry on ventricular haemodynamics. This will be highly relevant to the topic of LVOT obstruction, as new dedicated D-shaped MV bioprostheses that are able to mimic the original shape of the mitral annulus, and thus avoid high transvalvular gradients by maximising the inflow area, are also likely to protrude into the LVOT causing obstruction due to their large size. While smaller devices like the AV bioprostheses deployed in the mitral position may circumvent this risk, they are also prone to stability issues and patient-prosthesis mismatch, underscoring the need for robust means to match device model and size to the individual patient’s pathophysiology.in-vivo measurement of pressure were not available, we used experimentally measured velocity profiles at the valve planes that account for both preload, afterload, and potential altered blood flow dynamics such as aortic stenosis or concomitant mixed valve disease. While the present study only provides a proof of concept of the potential of this modelling approach, the impact of contraction patterns, ventricular loading, and geometries of the subvalvular apparatus on LV function post-TMVR can be investigated in further work using this methodology by modelling a cohort of patients of sufficient sample size to represent significant variations in all these factors.Finally, the ventricular geometry in our models did not include trabeculations, chordae and papillary muscles and thus the respective effects on the blood flow could not be investigated. However, the tracked wall motion from the CTA data incorporates the effects of these structures on the global and segmental wall motion, as well as those due to wall thickness, potential prior myocardial infarction or any other contraction defect, which would also result in an alteration of the motion pattern derived from the imaging data. Similarly, as direct By combining imaging and computer modeling we have provided a tool to predict LVOT obstruction post-TMVR and to quantify the impact of varying degrees of obstruction on ventricular afterload and blood residence times, providing a link between anatomical and hemodynamics parameters. This approach overcomes some of the limitations of current methods for LVOT obstruction predictions, which largely rely on anecdotal experience and standard anatomical evaluation. The goal of our modelling technique is to create impact on patient care and procedural skills by informing the device choice and placement to lower the possibility of reinterventions. This is particularly relevant in TMVR, where reintervention is associated with high morbidity and mortality rates. Despite the small size and heterogeneity of the cohort analysed, these results show a clear correlation between the degree of LVOT obstruction and changes in ventricular afterload and blood residence times following TMVR. A LVOT obstruction between 30% and 35% has been identified as a threshold for hemodynamic deterioration, providing a quantitative criterion for intervention that has been lacking so far. The next step for an effective clinical translation of this technology will be to apply it to a large number of patients to generate detailed response maps, which could be used in the future to design and test new devices.


In addition to fractional shortening (FS) and ejection fraction (EF), LV function was quantified by tissue Doppler imaging of the mitral annulus. Aortic strain/distensibility and arterial compliance were derived from echocardiography and simultaneously recorded pulse pressure. Despite similar FS and EF, peak mitral annular systolic velocity (median (interquartile range): 9.0 (7.5–10.0) vs. 10.0 (8.8–11.5) cm/s, p = 0.05), and early diastolic velocity (13.8 (13.0–14.8) vs. 15.5 (14.0–17.3), p = 0.01) were decreased after chemotherapy combined with CRT compared to chemotherapy without CRT. Systemic arterial compliance was lower in post-CRT subjects (1.0 (0.8–1.2 vs. 1.4 (1.1–1.7) mL/mmHg, p = 0.002). Aortic strain and distensibility were similar regardless of prior CRT. In conclusion, lower arterial compliance and subclinical LV dysfunction may be possible late consequences of past CRT in adult survivors of childhood ALL. Whether arterial stiffening is associated with future HF development in CRT-exposed ALL survivors remains to be investigated.Long-term survivors of acute lymphoblastic leukemia (ALL), the most common childhood malignancy, are at remarkably increased risk of heart failure (HF) in middle age, most likely due anthracycline cardiotoxicity. The role of cranial radiation therapy (CRT) in the development of left ventricular (LV) dysfunction, a predecessor of overt HF, remains unclear. Our aim was to compare LV function and systemic arterial properties according to past CRT in young adult survivors of anthracycline-treated ALL. We studied young adult survivors of childhood ALL at a median of 16 years from diagnosis treated with anthracycline-based chemotherapy, with ( Adult long-term survivors of childhood acute lymphoblastic leukemia (ALL), the most common childhood malignancy, are at risk of chronic health conditions, including atherosclerotic cardiovascular disease and heart failure (HF) ,2,3. NotThe predictors of adult-onset HF in CCSS participants included younger age at malignancy diagnosis, cumulative anthracycline dose, concomitant cardiac irradiation, and female sex . In anotAlthough the use of cranial radiation therapy (CRT) has considerably decreased over time, there are still many ALL survivors who have received prophylactic CRT based on the previous treatment protocols. In contrast to anthracyclines (initiating progressive loss of cardiomyocytes) and mediastinal irradiation , CRT induces hypothalamic-pituitary dysfunction with consequent growth hormone (GH) deficiency and enhanced development of metabolic syndrome ,15,16,17Thus, we hypothesized that CRT can contribute to large artery stiffening in anthracycline-treated childhood-onset ALL subjects, thereby possibly potentiating associated risk of HF development in adulthood. Our aim was to compare estimates of LV function and systemic arterial properties according to past CRT in young adult survivors of childhood ALL.Study participants included Polish adult childhood ALL survivors of Caucasian origin, diagnosed between the year 1994 and 2009. The survivor population was recruited from consecutive patients seen at the outpatient clinic at the University Hospital in Cracow from 2017 until 2018. We used medical records to obtain data on demographics, date of ALL diagnosis, the end of therapy, and treatment protocol including anthracycline exposure, CRT, and radiation dose (dose range: 12–18 Gy). Treatment regimens were based on protocols used in the treating institution at different time periods between the years 1994 and 2009.Eligibility criteria included the following: Diagnosis of ALL before 18 years of age, five or more years since completion of cancer treatment, and exposure to anthracycline-based chemotherapy with or without CRT. Exclusion criteria encompassed the following: Time from the end of therapy for ALL shorter than 5 years, relapse or secondary cancer at the time of the study or during 5 preceding years, HF symptoms or HF-related medical therapy, any other self-reported cardioactive medication, coexisting diseases, or relevant abnormalities in routine blood and urine assays. ALL survivors treated with chemotherapy only were compared with those who had received the combination of chemotherapy with CRT.The study was approved by the Bioethics Committee at the Jagiellonian University . In agreement with the principles outlined in the 1975 Declaration of Helsinki, all participants provided written informed consent prior to the inclusion in the study. Study participants underwent a complex clinical evaluation including physical examination accompanied by anthropometric assessments, echocardiography, and blood sampling for future biochemical assays.Transthoracic echocardiography was performed by a well-trained experienced sonographer with Vivid 8 ultrasound equipment . The sonographer was blinded regarding clinical data, including CRT exposure. Standard 2D-guided M-mode measurements of LV chamber dimensions and wall thickness were done in agreement with practice recommendations . LV massAdditionally, LV systolic and diastolic functions were estimated by tissue Doppler imaging, as follows: Mitral annular velocities were averaged from peak recordings taken at the lateral and septal region of the mitral annulus in systole (S’) and early diastole (e’) . The peastrain) was calculated as the percent difference between systolic (Aos) and diastolic (Aod) internal diameter (cm) of the ascending aorta, imaged 3 cm above the aortic valve in the left parasternal long-axis view, as follows: Aostrain (%) = ((Aos − Aod)/Aod) × 100 [s and Aod were measured at the maximal anterior motion of the aortic wall and at the R-wave peak on the simultaneous ECG tracing, respectively [dist) was defined according to the following formula: Aodist (cm2 dyne−1) = 2 × (Aos − Aod)/(Aod × (pulse pressure)) [2. Finally, systemic arterial compliance (mL/mm Hg) was computed as stroke volume (derived from volumetric LV measurements) divided by the simultaneously recorded pulse pressure [Aortic strain (Aod) × 100 ,30. Aos essure)) ,30. Pulsessure)) ,30, and pressure .Fasting venous blood samples for biochemical assays were collected on the day of the echocardiographic assessment. Serum levels of glucose, high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides were measured . Low-density lipoprotein (LDL) cholesterol concentrations were calculated using the Friedewald formula. N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) was measured using a chemiluminescence immunoassay .−6 cm2 dyne−1 for Aodist, and 0.5 mL/mm Hg for arterial compliance) with a power of 80% at a type I error rate of 0.05. A p-value below 0.05 was inferred significant.We report data as means and SD, medians and interquartile range, or numbers. Patients’ characteristics were compared according to a history of past CRT by the Mann–Whitney U test, and Fisher’s exact test for continuous and categorical data, respectively. By a post-hoc analysis, the study design allowed the detection of intergroup differences of 0.95 SD  in those with a history of CRT .p = 0.05; early diastolic velocity: 13.8 (13.0–14.8) vs. 15.5 (14.0–17.3) cm/s, p = 0.01). Additionally, in patients with a history of past CRT, we observed a higher mitral peak E-to-e’ ratio, albeit within the normal range, while traditional diastolic estimates, including mitral inflow-based parameters and LA size, were unchanged  vs. 10.0 (8.8–11.5) cm/s, nchanged . p = 0.002), whereas neither aortic strain (12.9 (5.9–19.0) vs. 9.3 (7.5–13.3) %), nor distensibility (3.1 (1.8–4.9) vs. 3.0 (2.0–4.5) (10−6 cm2 dyne−1)) differed by prior CRT  vs. 1.4 (1.1–1.7) mL/mmHg, rior CRT .Our principal finding was lower large artery compliance, with unchanged aortic strain and distensibility, and subclinical LV dysfunction revealed on tissue Doppler imaging in young adult survivors of childhood-onset ALL treated with both CRT and anthracycline-based chemotherapy in comparison with those who had received only chemotherapy. NT-proBNP levels did not differ significantly by prior CRT, which is in agreement with an improved ability of novel echocardiographic methods to better detect late subclinical LV dysfunction in asymptomatic childhood cancer survivors than natriuretic peptides assays ,33,34. MAs to earlier studies focused on arterial properties in anthracycline-treated childhood cancer survivors, none of those reports has linked elevated arterial stiffness to prior CRT ,25,26. TAdmittedly, on the basis of our small cross-sectional study, we can only speculate on the potential causal mechanisms of these observations. However, there is some evidence that the interference of CRT with the hypothalamic-pituitary function with subsequent GH deficiency and insulin resistance can underlie our findings because a history of past CRT was associated with marginally higher fasting glycaemia and shorter stature in the ALL survivors participating in the present study. Firstly, the prevalence of metabolic syndrome was over 3-fold higher (23% vs. 7%) in ALL survivors treated with CRT and chemotherapy compared to those who had received only chemotherapy . SimilarTherefore, our results may be suggestive of site-specific vascular effects of CRT-dependent GH deficiency and consequent insulin resistance. In 518 asymptomatic young adults participating in the Bogalusa Heart Study, the magnitude of insulin resistance (by the homeostasis model assessment) was associated with lower large artery but not small artery compliance, also including the arteriolar bed . MoreoveThat large-artery compliance reflects distinct vascular properties, not covered by investigations focused on the distal part of circulation or endothelial function, may translate into different pathogenic relevance of respective parameters derived from various techniques of vascular studies. In particular, in young adult ALL survivors, endothelial dysfunction, reported previously by several research groups, including ours ,39,40,41As the pressure wave propagates faster in the stiffened arteries, it returns earlier to the heart, thereby elevating central systolic blood pressure, despite unchanged peripheral blood pressure, as in our study subjects. This results in increased LV afterload and a prolonged LV ejection period with concomitant reduction of LV filling time and diastolic pressure, governing coronary blood supply to the LV myocardium. Aortic compliance increases during the first decade of life and reaches a peak around puberty . ConsequAn increased pressure load on the LV myocardium in combination with compromised coronary flow predominantly affects longitudinally oriented subendocardial myocardial fibers, which translates into a selective impairment of LV long-axis function despite unchanged global LV systolic performance, a feature of HF with preserved ejection fraction . EstimatOur findings should be interpreted with caution in terms of their potential clinical significance. We may only hypothesize that subclinical late LV dysfunction after anthracycline-based chemotherapy could possibly be enhanced by slowly-developing arterial stiffening attributable to past CRT. Curiously, in an animal model of late-occurring anthracycline-induced cardiac dysfunction, prior doxorubicin exposure abolished LV hypertrophy in response to angiotensin II-induced hypertension . Since LFirstly, our study is limited by a small number of patients and a retrospective design, thus the preliminary results require confirmation in large cohorts of ALL survivors. Secondly, longitudinal LV systolic function was estimated only by tissue Doppler imaging of the mitral annulus, while longitudinal strain analysis by speckle-tracking echocardiography has been considered the best method to detect subtle chemotherapy-related LV dysfunction ,50. NeveOur preliminary study appears to suggest decreased large artery compliance and subclinical LV dysfunction as possible late consequences of concomitant past CRT in young adult survivors of childhood-onset anthracycline-treated ALL. Whether arterial stiffening can contribute to LV dysfunction and late development of overt HF in CRT-exposed ALL survivors, remains to be investigated.


Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs. Microvascular and vasospastic angina are relevant but may not be diagnosed without measuring coronary vascular function. The relationship between cardiovascular magnetic resonance (CMR)-derived myocardial blood flow (MBF) and reference invasive coronary function tests is uncertain. We hypothesise that multiparametric CMR assessment will be clinically useful in the ANOCA diagnostic pathway.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) trial is a prospective, blinded, randomised, sham-controlled study comparing two management approaches in patients with ANOCA. We aim to recruit consecutive patients with stable angina undergoing elective invasive coronary angiography. Eligible patients with ANOCA (n=150) will be randomised to invasive coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Based on these test results, patients will be stratified into disease endotypes: microvascular angina, vasospastic angina, mixed microvascular/vasospastic angina, obstructive epicardial coronary artery disease and non-cardiac chest pain. After randomisation in CorMicA, subjects will be invited to participate in the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) substudy. Patients will undergo multiparametric CMR and have assessments of MBF (using a novel pixel-wise fully quantitative method), left ventricular function and mass, and tissue characterisation (T1 mapping and late gadolinium enhancement imaging). Abnormalities of myocardial perfusion and associations between MBF and invasive coronary artery function tests will be assessed. The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests.The CorMicA trial and CorCMR substudy have UK REC approval (ref.16/WS/0192).NCT03193294. Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs.A significant proportion of these patients may suffer from microvascular and vasospastic angina.Diagnosis in this patients may be challending, are there are uncertain associations between the results of reference invasive diagnostic tests and the non-invasive ischaemia test results.Novel CMR methods for measuring myocardial blood flow have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina.The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests. CorCMR will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in patients with ANOCA.In contrast to the reference standard invasive tests of coronary artery function, non-invasive imaging is safer and more acceptable to patients.The CorCMR sub-study presents a unique opportunity to assess and validate the diagnostic accuracy of fully-quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.Ischaemic heart disease is the leading cause of mortality standardised by age and sex.Patients with angina and no obstructive coronary artery disease (ANOCA) present a diagnostic conundrum.The underlying pathogenesis in patients with ANOCA is unclear, as specific disease endotypes are not routinely tested for. CMD may result from coronary structural abnormalities, whereby decreased capillary luminal size and number result in increased microvascular resistance to myocardial blood flow (MBF) and reduced vasodilatory capacity.Abnormalities of coronary vascular function portend a worse prognosis in patients with both obstructive epicardial CAD and ANOCA.Diagnosis of coronary microvascular and vasomotor dysfunction is challenging due to the heterogeneity of underlying disease mechanisms, the potentially patchy distribution of disease throughout the myocardium, and limited spatial resolution of existing diagnostic tests.There is no accepted guideline-directed diagnostic algorithm for coronary vascular dysfunction in routine clinical practice.The available non-invasive ischaemia tests were all validated for the detection of obstructive epicardial CAD. There has been a low yield of inducible myocardial ischaemia in ANOCA patients with traditional non-invasive ischaemia tests .Coronary microvascular disease may be revealed by a deficit in MBF during stress CMR. The spatial distribution of this abnormality typically involves the subendocardium, which is the location of the microvascular plexus.There are uncertain associations between the results of invasive diagnostic tests and the non-invasive ischaemia test results in patients with ANOCA. There is no accepted objective diagnostic threshold for the diagnosis of coronary vascular dysfunction , with either PET or perfusion CMR. Recent studies have investigated the relationships between invasive tests of coronary artery function and semiquantitative perfusion CMR analysis.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) clinical trial is a proof-of-concept, prospective, blinded, randomised, sham-controlled study comparing two management approaches to the clinical problem of patients with ANOCA.The IDP consists of coronary artery function testing using a dual pressure-sensitive and temperature-sensitive guidewire and adenosine followed by intracoronary acetylcholine provocation testing. Assessment of microvascular resistance (IMR), microvascular vasodilatory capacity (resistance reserve ratio (RRR)), epicardial and microvascular vasodilatory capacity (CFR), endothelial function (acetylcholine provocation testing) and epicardial CAD ) will be performed. Following these invasive tests of coronary artery function, patients will be classified into the following ANOCA disease endotypes : (1) micPatients in the control group will receive standard care based on the interpretation of the invasive coronary angiogram alone. Patients in the intervention group will have care based on the disease endotypes disclosed by invasive tests of artery function, and pharmacotherapy linked to the underlying disease endotype will be commenced.Novel CMR methods for measuring MBF have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina. The CorCMR substudy of the CorMicA clinical trial presents a unique opportunity to assess and validate the diagnostic accuracy of fully quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.We hypothesise that abnormal myocardial perfusion, as revealed by a novel fully quantitative pixel-wise CMR perfusion sequence, will be prevalent in a contemporary UK cohort of patients presenting with ANOCA and that multiparametric CMR imaging will be clinically useful in the diagnostic pathway of patients with ANOCA.We aim to assess the diagnostic validity of quantitative stress perfusion CMR in patients with ANOCA and specific disease endotypes of coronary vascular dysfunction. Our specific aims are to assess:The proportion of ANOCA patients with abnormal myocardial perfusion. There is no accepted threshold for abnormal MPR. Thresholds for reduced CFR of 1.5–2.6 have been described, however <2.0 is commonly used.The diagnostic accuracy of the perfusion CMR metrics for abnormal invasive tests of coronary artery function  and the associations between specific disease endotypes and myocardial perfusion in patients with ANOCA. We also aim to assess the correlation between abnormal CMR-derived perfusion and invasive tests of coronary artery function, of qualitative versus quantitative perfusion methods.The proportion of patients with ANOCA and abnormal myocardial tissue characterisation derived from CMR  imaging) and its association with abnormal myocardial perfusion.The associations between baseline patient characteristics and abnormal myocardial perfusion.The proportion of patients with a change in diagnosis based on quantitative CMR findings, as compared with the initial diagnosis by the attending cardiologist based on the coronary angiogram.Prespecified substudy of the CorMicA stratified medical therapy clinical trial.Patients referred from 14 acute hospitals to two large regional UK hospitals  providing invasive care to all patients in the West of Scotland (population 2.5 million). All CMR studies will be performed at the Golden Jubilee National Hospital.Consecutive outpatients undergoing clinically indicated elective diagnostic angiography for investigation of suspected angina will be screened and invited to participate in the CorMicA trial. Informed consent is obtained before the invasive coronary angiogram. A minimum of 400 consecutive patients undergoing elective invasive coronary angiography is expected to be screened to enrol 150 subjects with ANOCA within 24 months. Consenting patients who are not randomised  will enter a registry. Only patients randomised in the CorMicA trial (both in the intervention and control groups) are eligible to participate in the CorCMR substudy.Age ≥18 years, a clinically indicated plan for invasive coronary angiography and symptoms of angina (according to the Rose angina questionnaire).A non-coronary indication for invasive angiography , obstructive epicardial CAD disease evident in a main coronary artery (diameter >2.5 mm) (defined as diameter stenosis >50% or FFR ≤0.80) and contraindication to contrast-enhanced CMR .Patients will undergo perfusion CMR within 42 days of the CorMicA trial invasive coronary artery function testing. CMR studies will be performed at 1.5 Tesla , and patients will undergo a standardised CMR protocol. All patients will be asked to abstain from caffeine-containing beverages or foodstuffs for 24 hours and vasoactive medications for 48 hours prior to the CMR examination. All scan acquisitions will be spatially coregistered. All CMR analyses will be performed by analysts blinded to the invasive coronary artery function test results. The standardised CMR protocol is demonstrated in Stress and rest first-pass perfusion imaging will be performed using an echo planar imaging dual-sequence investigational perfusion method, which consists of a low resolution arterial input function image, followed by three short axis  myocardial images during each R–R interval.The raw stress and rest perfusion images will be qualitatively assessed for inducible or fixed perfusion defects. Perfusion defects will be reported on a segmental basis according to the American Heart Association 16-segment model.Pixel-wise perfusion maps will be generated and analysed to derive fully quantitative MBF estimates on a pixel-wise basis in mL/g/min of myocardium. The pixel-wise perfusion method uses a series of automated postprocessing steps on the raw Digital Imaging and Communications in Medicine images to generate fully quantitative pixel maps.2] and percentage coefficient of variation of time to maximum signal intensity upslope and time to peak myocardial signal intensity enhancement.The myocardial perfusion dyssynchrony index is a novel perfusion metric that assesses temporal differences in the distribution of gadolinium-based contrast media myocardial wash-in. This index has the potential to increase the diagnostic sensitivity and specificity of perfusion CMR for abnormalities of myocardial perfusion in patients with ANOCA.Fast gradient echo images in the axial, coronal and sagittal planes will be qualitatively assessed for extra cardiac anatomy and pathology and clinically relevant incidental findings.Steady-state free procession ‘cine’ imaging using a trueFISP sequence (multislice single-shot breath-hold true fast imaging) will be performed in the three long-axis and short-axis planes for assessment of LV volumes, function and mass.Native T1 mapping will be performed using a modified look-locker inversion recovery investigational prototype sequence. Images will be obtained in three short-axis images . T1 mapping will be performed pre- and post-gadolinium contrast to assess the myocardial native T1 relaxation time and estimate the myocardial extracellular volume (ECV) in both the mid-septum and globally.LGE imaging will be performed using a segmented phase-sensitive inversion recovery turbo fast low-angle shot imaging sequence.Abnormal myocardial perfusion reserve .A summary of the secondary outcomes is shown in Box 2.LV EFLVEDVLV EDV indexLV ESVLV ESV indexLV massLV mass indexLV COLV CO index2)Left atrial area (cmLeft atria dilated (Y/N)2)Right atrial area (cmRight atria dilated (Y/N)Abnormal perfusion (Y/N)Number of abnormal segments (n)Transmurality of perfusion defects (%)Pattern Global MPR <2.0 (Y/N)Segmental/AHA MPRGlobal stress and rest MBFSegmental/AHA territory stress and rest MBFGlobal stress endocardial:epicardial MPR ratioSegmental/AHA territory endocardial:epicardial MPR ratioMyocardial perfusion dyssynchrony index Splenic switch-off (Y/N)HR and BPchangeRate-pressure product at rest and stressAbnormal LGE (Y/N).Number of affected AHA segments (n)Pattern of abnormal LGE (ischaemic and non-ischaemic)Myocardial infarct scar burden Native T1 ECV Feature-tracking and DENSE (two methods)Longitudinal strain Circumferential strain Radial strain Present (Y/N)Clinically significant (Y/N)Sex, age and traditional CAD risk factorsCAD risk scores (JBS3 and ASSIGN)Gensini score of epicardial plaque burdenAssociation of myocardial perfusion with IMR, CFR, RRR and endothelial function testing (continuous and binary)Subset of patients with multivessel invasive coronary artery function measurementsAssociation with clinical diagnosis (ANOCA disease endotype)LV volumes and massMyocardial strainNative T1 relaxation time and ECVPresence of LGEDiagnostic accuracy of quantitative perfusion CMR to detect abnormal IMR, CFR, RRR and endothelial dysfunctionAHA, American Heart Association; ANOCA, angina with no obstructive coronary artery disease; BP, blood pressure; CFR, coronary flow reserve; CAD, coronary artery disease; CO, cardiac output; CorCMR, Coronary Microvascular Angina Cardiac MRI; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; ECV, extracellular volume; HR, heart rate; IMR, index of microcirculatory resistance; LV, left ventricular; LGE, late gadolinium enhancement; MBF, myocardial blood flow; MPR, myocardial perfusion reserve; RRR, relative resistance ratio,The CorMicA trial has a comprehensive statistical analysis plan that governs all statistical aspects of the study authored by the trial statistician. The statistical analysis plan includes the prespecified CorCMR substudy that is designed to assess for associations between CMR measures and invasive measures and endotypes (reference dataset). Continuous outcomes will be analysed using linear regression with adjustment for baseline levels where available. Where continuous data are clearly not normally distributed, standard transformations will be applied to achieve approximate normality prior to analysis. Appropriate alternative regression methods will be applied to other types of data .The primary outcome is the proportion of patients with an MPR<2.0. The proportion of patients with microvascular angina defined by invasive endotyping will be assessed. We will further assess the MPR ratio with the highest AUC for microvascular angina classified invasively.Considering the correlation between CFR measured invasively and MPR measured non-invasively within the common territory of a major epicardial coronary artery, then a sample size of 110 subjects would enable a minimum clinically significant correlation of 0.3 to be detected with 90% power at a 5% significance level. If only 60 subjects have available data, then 80% power would be available to detect a correlation of 0.37 at the 5% level.The British Heart Foundation CorMicA trial will assess a routine stratified medicine strategy in a large cohort of prospectively enrolled patients with ANOCA. The prespecified CorCMR substudy will involve comprehensive invasive tests of coronary artery function paired with multiparametric perfusion CMR studies. The analysis will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in this population.Contemporary guidelines recommend functional testing, including with CMR, to assess for myocardial ischaemia in patients in whom multidetector CT coronary angiography has shown CAD of uncertain functional significance or is non-diagnostic.The CorCMR substudy will be performed on a 1.5 Tesla MRI scanner. In comparison, 3.0 Tesla imaging permits improved signal-to-noise ratio and provides higher in-plane spatial resolution perfusion imaging.et alet alPatients with confirmed microvascular or vasospastic angina have a precise diagnosis of the underlying disease endotype, and pharmacotherapy may be commenced as appropriate. Conversely, patients with normal invasive coronary artery function tests may have antianginal therapy appropriately discontinued, and alternative causes of chest pain investigated. In comparison with invasive tests of coronary artery function, non-invasive CMR imaging may be more attractive to patients, but at present, the role of CMR in the diagnostic work-up of patients is uncertain. CorCMR will provide data on the role of CMR in the diagnosis of patients with ANOCA. Traditional non-invasive ischaemia testing in patients with ANOCA has provided mixed results. Panza et al compared semiquantitative perfusion CMR against IMR measurement in 50 patients with ANOCA and 20 age-matched healthy control subjects.et alCorCMR will inform the nascent evidence on the presence and magnitude of associations between invasive and non-invasive assessments of coronary vascular function. Liu et alCMR permits the reference-standard non-invasive assessment of myocardial tissue characterisation. CorCMR will provide data on diffuse interstitial fibrosis, ECV and myocardial scar. The role of T1 mapping and ECV analysis in patients with ANOCA is uncertain. In a substudy of the iPOWER natural history study, 54 women with ANOCA underwent native T1 mapping and ECV analysis, PET-derived MBF measurement, and transthoracic Doppler echocardiography CFR assessment.http://www.equator-network.org/reporting-guidelines/stard/) and Consolidated Standards of Reporting Trials (http://www.consort-statement.org/) guidelines.Progress in the trial will be monitored by the trial anager (KB) and sponsor. The study will be subject to internal and external audit that is routinely coordinated by the sponsor. An annual report will be submitted to the Research Ethics Committee on a 12-month basis. The flow diagram illustrates conservative estimates of patient enrolment and activity on a single site. The study will follow Standards for Reporting of Diagnostic Accuracy (STARD) (The CorCMR data will be presented at conferences and/or published in peer-reviewed journals.