Delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging requires novel and time-efficient approaches to characterize the myocardial substrate associated with ventricular arrhythmia in patients with ischemic cardiomyopathy. Using a translational approach in pigs and patients with established myocardial infarction, we tested and validated a novel 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar maps in ventricular models reconstructed from both 3D-acquired and 3D-upsampled-2D-acquired LGE-CMR images. The results showed that 3D-upsampled models from 2D LGE-CMR images provided a time-efficient alternative to 3D-acquired sequences to assess the myocardial substrate associated with ischemic cardiomyopathy. Scar assessment from 2D-LGE-CMR sequences using 3D-upsampled models was superior to conventional 2D assessment to identify scar sizes associated with the cycle length of spontaneous ventricular tachycardia episodes and long-term ventricular tachycardia recurrences after catheter ablation. This novel methodology may represent an efficient approach in clinical practice after manual or automatic segmentation of myocardial borders in a small number of conventional 2D LGE-CMR slices and automatic scar detection. Several studies have shown that scar tissue quantification using LGE-CMR may increase the predictive performance of ventricular arrhythmic events in patients with established myocardial infarction3. Nonetheless, scar characterization remains controversial and has not been incorporated as a standard stratification tool for ventricular arrhythmic events or ventricular tachycardia (VT) characterization in patients with ischemic cardiomyopathy (ICM)4.Delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging represents a well-established method to identify infarct-related scar tissue based on signal intensity criteria after gadolinium administration5. Conversely, 3D sequences with higher and isotropic resolution are substantially less common in daily clinical practice, although frequently performed in research studies6. State-of-art 3D LGE-CMR sequences require larger acquisition time, appropriate patient collaboration, and time-consuming manual or semiautomatic processing for accurate myocardial segmentation7. Altogether, these drawbacks make 3D LGE-CMR sequences potentially inefficient in highly demanding agendas during regular clinical practice. The common alternative using 2D sequences provides sufficient information for assessing ventricular function. However, 2D-derived scar reconstructions may have limitations to properly assess the myocardial substrate compared to isotropic high-resolution 3D data. Moreover, these differences might have implications on accurate characterization of the ventricular substrate associated with VT episodes in patients with ICM.Two-dimensional LGE-CMR sequences with large slice thickness  are the most common images in the clinic8. This approach can be also implemented in upsampled 3D reconstructions9 obtained from conventional 2D LGE-CMR sequences. This methodology might provide an intermediate and time-efficient approach to improve performance of 2D LGE-CMR sequences to characterize the myocardial substrate particularly associated with clinical presentation of ICM-related VT episodes and potential recurrences after ablation. This may be especially relevant in patients without primary prevention indication for implantable cardioverter defibrillator (ICD).Recently, we have developed a 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar mapsWe hypothesize that transmural scar assessment using 3D-upsampled data from 2D-LGE-CMR sequences will be sufficient and superior to conventional analysis from 2D-LGE images to identify myocardial regions relevant for infarct-related substrate characterization in patients with ICM and VT episodes. Patient-specific scar reconstructions from isotropic 3D-acquired sequences were used as benchmark comparisons.8. The validation and clinical impact of the method were tested in the patients’ cohort undergoing 3D and 2D LGE-CMR studies within the same protocol. Figure . The data that support the findings of this study are available from the corresponding authors upon reasonable request.Experimental and clinical study including 10 pigs with established myocardial infarction and 15 patients admitted to hospital with spontaneous VT episodes and underlying infarct-related ventricular scar. All procedures in pigs were approved by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) Committee on Use and Care of Animals and by the Comunidad de Madrid (Ref#PROEX097/17). Animal experiments comply with Spanish , European (2010/63/EU) and Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. The ethical committees of the Hospital Clínico San Carlos and Hospital Universitario La Paz approved the protocol in patients . The study in patients was performed in accordance with the standards of the 2013 revision of the Declaration of Helsinki. Patients were prospectively included from two tertiary hospitals from May 2013 to December 2016. All patients signed the informed consent before inclusion in the study. Pigs underwent 3D LGE-CMR sequences to test and optimize the performance of a 3D transmural-based methodology that takes into account individual-specific myocardial geometry7.Pigs  underwent percutaneous catheterization of the left anterior descending coronary artery using femoral access and fluoroscopic guidance under general anesthesia. An angioplasty balloon was inflated in the coronary artery for 60 min to generate myocardial infarction. Then, the balloon was deflated and a coronary angiogram was recorded to confirm patency of the coronary artery and reperfusion as described elsewhere see also 7.Ten-to-twelve weeks after myocardial infarction pigs underwent substrate characterization using a Philips Achieva 3T-Tx whole-body scanner equipped with a 32-element and phased-array cardiac coil . Seven minutes after intravenous contrast injection  3D LGE-CMR sequences were acquired using an inversion-recovery spoiled turbo field echo (IR-T1TFE) with isotropic resolution of 1.5 × 1.5 × 1.5 mm (reconstruction resolution 0.57 × 0.57 × 0.75 mm). Segmented and ECG-gated cine steady-state free precession was also performed to acquire 11–13 contiguous short-axis slices covering the ventricles from the base to the apex to evaluate left ventricular ejection fraction (LVEF) .CMR scans in patients were performed 24-to-48 h prior to invasive electrophysiological procedures for VT mapping and ablation. LVEF was assessed by multiphase-multislice acquisition with a balanced TFE sequence (1.8 × 1.8 × 8.0 mm). Three-dimensional LGE-CMR sequences  were obtained based on IR-TFE, seven minutes after intravenous contrast administration. The entire sequence was triggered with a respiratory navigator to compensate for minor volume displacements. The multislice IR-TFE delayed-enhanced 2D sequences  were acquired after completion of the 3D sequence. Good scar definition was ensured using a Look-Locker sequence before each acquisition and phase sensitive reconstruction for 3D acquisitions to select correct inversion time for proper healthy myocardium signal nulling.1. In patients, maximum signal intensity in 3D isotropic acquisitions was calculated using a slice thickness of ≈ 8-mm (i.e. average of 12 neighbouring voxels in the through-plane direction) to prevent any potential signal-to-noise effect from smaller pixel sizes compared to calculations in lower resolution 2D sequences . First, we obtained a region of interest, which roughly contained the heart and minimized surrounding tissue from other intrathoracic structures. Second, we automatically delineated the endocardial and epicardial contours using an automatic algorithm with an active contour method. Third, this initial myocardial segmentation was subsequently complemented with fine manual segmentation by one single operator and further reviewed by a second expert operator Fig. A,B. This9. Three-dimensional transmurality maps of the left ventricle  were represented on the epicardial surface and computed as reported elsewhere8. This method also provides point-wise correspondences between the endocardium and the epicardium (as other authors have done in the past)13 by finding a function s(x) for which s(x) = 0 at the endocardium, s(x) = 1 at the epicardium, and its intermediate values which define different myocardial layers  and then reconstructed with different slice thicknesses. For each slice thickness reconstruction, scar segmentations were created by averaging the high-resolution 3D scar segmentations to the new reconstructed slice thickness  were targeted using substrate ablation based on late and fragmented potentials. Local abnormal ventricular activities (LAVA) were not specifically ablated15. However, during data analysis, LAVA quantification was performed to further describe the electrophysiological substrate specially in the regions with higher density mapping during baseline sinus rhythm.The invasive electrophysiology study was performed using percutaneous venous and arterial femoral access to reach the right and left ventricles, respectively. Additional epicardial access, if necessary, was achieved using a percutaneous subxiphoid approach. Ventricular geometries were generated using the Carto3  or the Ensite NavX  electroanatomic mapping system. VT induction was attempted using programmed ventricular stimulation from the right ventricular apex. All stimuli were synchronized with the intrinsic QRS complex. The protocol consisted of two sequential basic drive cycle lengths (CLs) of 10 beats each (S1) at 600 or 400 ms. Each basic drive CL was followed by up to 3 extrastimuli  decremented in CL until reaching refractoriness or a minimum coupling interval of 200 ms. If the arising VT was hemodynamically stable, activation maps and entrainment maneuvers were performed with the ablation catheter or a 20-pole steerable mapping catheter  to localize the protected isthmus of the reentrant circuit. Ablation was performed with an open-irrigated-tip catheter . Direct current defibrillation was delivered to restore sinus rhythm in case of ventricular fibrillation or hemodynamic collapse. In the case of hemodynamic instability during mapping of VT morphologies documented on admission , deductive reconstruction of the reentrant circuit and ablation was performed using pace-mapping as described by de Chillou et al.Ventricular tachycardia CL was measured on VT tracings documented at the time of hospital admission before attempting pharmacological or electrical cardioversion. The number of induced VT morphologies and the CL of each morphology were quantified for each patient. Twelve out of 15 patients underwent implantable cardioverter defibrillator (ICD) implantation before hospital discharge. Patients underwent annual clinical follow-up to detect VT recurrences of any morphology after new hospital admissions or any sustained VT (episode duration > 30 s or terminated by the ICD) detected on the ICD.Data are expressed as median and interquartile range for quantitative variables, and number and percentage for qualitative variables. Data normality was assessed with the Shapiro–Wilk test. The Mann–Whitney U test was used for two-group comparisons. The Pearson’s correlation coefficient (r) was used for correlation analysis between scar volumes or transmural-based scar areas and VT CLs. A p < 0.05 was considered statistically significant for differences in group comparisons and for a non-null Pearson correlation coefficient. The intraclass correlation coefficient was also used as a measure of concordance (ICC 2.1 version). All data were analyzed in Graphpad Prism6  and custom-made software in Matlab.Baseline patient and animal characteristics are shown in Table The maximum downsampling factor used for LGE-CMR 3D sequences in pigs reached 8.0 mm slice thickness on the longitudinal ventricular axis  were delivered in LAVA regions, although complete LAVA elimination was not pursued in any of the cases. The total ablation time during the procedure was 15.8  min. Non-inducibility of clinical VT morphologies was achieved in 13 out of 14 cases. In 3 patients, other non-clinical and non-mappable morphologies remained inducible on programmed ventricular stimulation after ablation. Epicardial mapping was only attempted in one patient, although severe pericardial adherences did not enable further mapping of the region of interest and radiofrequency energy was only delivered from the endocardium.2, respectively, for 3D-acquired models; p = 0.004, and 64.0  vs. 83.0  cm2, respectively, for 3D-upsampled models; p = 0.04, Fig. 3, respectively, for 3D-acquired LGE-CMR; p = 0.26, and 30.7  vs. 35.0  cm3, respectively, for 2D LGE-CMR; p = 0.27, Fig. At 5 years of follow-up VT recurrences of any morphology were documented in 5 out of 15 patients. Four patients were under class III antiarrhythmic drugs at the end of the follow-up. Patients with VT recurrences showed lower scar areas on 3D-acquired and 3D-upsampled models using < 0.1 and < 0.2 transmurality criteria, respectively, than patients without VT recurrences  and < 0.2 (for 3D-upsampled models) was located in the endocardial layer  and < 0.2 (for 3D-upsampled models), mainly reflected endocardial scar Fig. C,D. Henc17. However, CMR-based scar characterization and quantification to predict ventricular arrhythmic events or VT features remains controversial18. Moreover, these associations have not been consistent across studies20. Imaging resolution, myocardial and scar segmentation, and partial volume averaging represent important factors that may explain the lack of uniform results and variable scar identification criteria among series22. Partial volume averaging may also explain the differences we documented in myocardial wall thickness using 2D and 3D LGE-CMR images. Larger scar extension is expected to be present in lower resolution images21, which might substantially affect the predictive performance of scar assessment from LGE-CMR sequences. In fact, our results are consistent with larger scar volumes in patient-specific 3D models obtained from 2D LGE-CMR sequences compared to those from 3D LGE-CMR studies .Our data provide new insights into the role of scar characterization in clinical presentation and long-term follow-up of patients with infarct-related VT episodes undergoing catheter-based ablation, especially in patients without primary ICD indication (14 out of 15 patients in this series). Lower scar areas in patients with VT recurrences at 5 years of follow-up might reflect more viable myocytes within scar regions21. Data from one representative patient undergoing sequential 3D-2D-3D LGE-CMR acquisitions also supported the notion that lower resolution images show larger scar regions  will provide more insight into this specific question. Statistical association of scar areas derived from transmurality analysis with VT recurrences might have been affected by individual specific substrate modification during the ablation procedure. Further series are warranted to confirm these descriptive results in relatively limited ablation strategies without extensive scar homogenization.Clinical implications of transmural scar assessment in spontaneous VT features were only studied in patients with established myocardial infarction. Other ventricular events as ventricular fibrillation and polymorphic VT episodes have not been studied in this series, which mainly included patients with mild to moderate decrease in LVEF, without ICD at the time of hospital admissionThree-dimensional transmural scar assessment in ventricular models reconstructed from 3D-upsampled or 3D-acquired LGE sequences may provide relevant scar characterization for clinical presentation and long-term ablation outcomes in patients with infarct-related spontaneous VT episodes.Supplementary Information.


In phantom, for T1/T2 values in a physiologically relevant range , scanners had strong correlation (R2 > 0.999) with average absolute percent difference of 8.1% and 10.1%, respectively. Comparison of the two trajectories on the newer scanner showed differences of 2.6% (T1) and 10.9% (T2), suggesting a partial explanation of the observed inter-scanner bias. Inter-scanner agreement was better when the same trajectory was used, with differences of 6.0% (T1) and 4.0% (T2). Intra-scanner coefficient of variation (CV) of T1 and T2 estimates in phantom were <2.0% and in vivo were ≤3.5%. In vivo inter-scanner white matter CV was 4.8% (T1) and 5.1% (T2). White matter measurements on the aging scanner after two months were consistent, with differences of 1.9% (T1) and 3.9% (T2). In conclusion, MRF is feasible on an aging MRI scanner and required only changes to the gradient trajectory.The purpose of this work is to evaluate the feasibility of performing magnetic resonance fingerprinting (MRF) on older and lower-performance MRI hardware as a means to bring advanced imaging to the aging MRI install base. Phantom and in vivo experiments were performed on a 1.5T Siemens Aera  and 1.5T Siemens Symphony . A 2D spiral MRF sequence for simultaneous T Recent advances in MRI data acquisition and reconstruction methods enable rapid scanning and multiparametric quantitative imaging ,2. Such 0 field considerations [0 [1 inhomogeneities [1 field shaping; and has the potential to eventually simplify protocols by enabling retrospective contrast synthesis from an MRF acquisition [1 and T2 measurements in phantom and in the brain [0 homogeneity, and gradient imperfections  is a flexible framework that may enable advanced imaging on aging MRI scanners. While initially developed for simultaneous quantification of multiple tissue properties using the highest-end scanner hardware, MRF has features that may enable quantitative imaging on older or less-refined scanners. MRF does not require specific gradient trajectories beyond specified spatial resolution, field of view, and Berations ,8, thus erations , thus entions [0  and B1 ieneities , and thuuisition . Howeverhe brain . While t, delays ) can res1 and T2 maps in phantoms and in vivo across scanner platforms. To this end, the capabilities of the older scanner were first assessed, and the MRF sequence was modified according to scanner hardware constraints. Phantom and in vivo experiments were performed to assess inter-scanner agreement, repeatability, and reproducibility. While this work is a demonstration that MRF can be used on an older MRI system after modest adjustments of an implementation originally designed for a modern MRI system, our goal is to show that it may be possible to deploy MRF for high-value imaging on scanners designed to have more modest performance and a lower cost.In this work, we explore the feasibility of performing MRF on aging MRI hardware  as a step towards implementing this advanced technology on older and less powerful scanner platforms to democratize the deployment of this advanced technology. Our hypothesis is that, when modified to function on this system, MRF will provide comparable TData were collected on two different clinical MRI scanners. The more recently manufactured ‘modern’ scanner, located at the main campus of the institution and on which research MRF scans are routinely performed, is a 1.5T MAGNETOM Aera . This scanner, installed in 2015, will be referred to as the comparatively ‘new’ scanner. This scanner has a gradient system with maximum strength of 43 mT/m and maximum slew rate of 180 T/m/s. A 24-channel head coil available at the scanner was used. The ‘aging’ MRI scanner is located at a satellite site and used only for routine outpatient clinical scans prior to this study. This scanner, from here on referred to as the ‘old’ scanner, is a 1.5T MAGNETOM Symphony (Siemens). While this scanner was installed in 2002, it received a total imaging matrix (TIM) upgrade in 2015 (affecting only the receive coil system). The gradient system is weaker than on the ‘newer’ scanner, with a maximum strength of 30 mT/m and maximum slew rate of 100 T/m/s. A four-channel head coil available at the scanner was used in this study.3 with a 400 × 400 mm2 field-of-view and duration of 26 s (3000 MRF frames) per imaging slice. Reconstruction is performed using the non-uniform fast Fourier transform [1 and T2 maps. The MRF dictionary included slice profile correction [1 values ranging from 10 to 4500 ms and T2 values ranging from 2 to 1000 ms . Proton density (M0) maps were computed based on the scaling of the measured signals relative to best-matched dictionary entries and normalized between 0 and 1.The MRF sequence used for this study is based on fast imaging with steady state precession with spiral-out readout . This seransform , adaptivransform , and innrrection  and contIn order to meet the hardware constraints of the ‘older’ scanner, modifications were made to the MRF acquisition. Due to the weaker gradients available on this system, either the trajectory from the new scanner could be used with a slower readout, or the trajectory could be modified such that the TR series could be kept the same. The latter approach was adopted so that the excitation scheme and MRF dictionary could be used without modification. This ‘weak gradient’ spiral trajectory designed for the old scanner, in contrast to the ‘strong gradient’ spiral described previously, uses a more uniform sampling density, requiring 48 interleaves to fully sample k-space and 40 interleaves to sample the inner 50% of k-space . The spiral trajectories are shown in 1 and T2 values are used to describe the phantom in following sections, whereas the measured T1 and T2 values on the new scanner were used for comparisons with the old scanner. The phantom was scanned five times on each of the scanners at a fixed position. Average T1 and T2 values in reference objects were measured and compared across scanners using Pearson’s correlation, Bland–Altman analyses, and inter-scanner coefficient of variation (CV). Additionally, the phantom was scanned on the new scanner using the ‘weak gradient’ spiral trajectory employed on the old scanner, and a Bland–Altman analysis was used to assess any differences in measurements made using the two different spiral trajectories with all other sequence parameters fixed. Bland–Altman analysis was used to also assess agreement between the new and old scanners using the same ‘weak gradient’ spiral. To assess intra-scanner measurement repeatability, CV was computed for each reference object. A test–retest experiment for the old scanner was performed on two different days to assess the reproducibility of T1 and T2 quantification.The ISMRM/NIST MRI system phantom  was used1 and T2 values were recorded for each ROI. To assess intra-scanner repeatability, CV was computed using repeated scans on each scanner. The average and standard deviation of subjects’ intra-scanner CV was evaluated. To assess inter-scanner variability, CV was computed for each subject across scanners using the averaged T1 and T2 values from each scanner’s repeated measurements. The average and standard deviation of subjects’ inter-scanner CV is reported. To assess reproducibility on the old scanner, a test–retest scan was performed for one subject with two months between scans. White matter T1 and T2 values were compared for each subject between scanners and for one subject in a test–retest experiment using an unpaired, two-tailed Welch’s t-test with significance level of p = 0.05.Three healthy volunteers were recruited under an institutional review board approved protocol. Brain scans were obtained on both scanners. Five MRF scan repetitions were collected for each subject on each scanner at a fixed position. The ‘strong gradient’ spiral trajectory was used on the new scanner. Regions of interest (ROIs) were manually drawn by a biomedical engineer (B.E.) in the genu of the corpus callosum (white matter). ROI sizes were recorded. Average T1, T2, M0) from both scanners are shown in 1 and T2 maps are qualitatively similar across scanners and spiral trajectories, whereas M0 maps exhibit different levels of spatial variation. The correlation and repeatability analyses are shown in 1 and T2 values within the physiologically relevant range of 195–1539 ms (T1) and 19.8–267.0 ms (T2) were analyzed. Measured values for vials outside this range were observed to be unstable on both scanners. Within the relevant range, the correlation between scanners for both T1 and T2 measurements was strong . The intra-scanner CV was <1.0% for T1 and <2.0% for T2 in both scanners for vials with physiologically relevant values. Bland–Altman plots are shown in 1 differed by an average absolute percent difference of 2.6% and T2 by 10.9%. Comparison of the old and new scanners both with the ‘weak gradient’ spiral showed average absolute percent differences of 6.0% in T1 and 4.0% in T2. However, when comparing the old scanner to the new scanner with the ‘strong gradient’ spiral, T1 differed by an average of 8.1% and T2 by 10.1%. The average inter-scanner coefficients of variation between the old scanner and the new scanner with the ‘strong gradient’ spiral were 5.8% (T1) and 7.1% (T2). The results of the test–retest analysis on the old scanner showed strong correlation of T1 and T2  with an average T1 difference of 3.0% and T2 difference of 4.3%.Representative MRF maps  for T1 and +2.5 ms (+7.7%) for T2. Differences between the test–retest values on the old scanner were: +11 ms (+1.9%) for T1 and −1.5 ms (−3.9%) for T2. The intra-scanner coefficients of variation for the old and new scanners, respectively, were 2.9% and 2.1% for T1, and 2.6% to 3.5% for T2. The inter-scanner CV was 4.8% for T1 and 5.1% for T2.Representative MRF maps for the three subjects are shown in 1 and T2 maps obtained by MRF on both new and old scanners were of comparable appearance despite differences in gradient systems, number of receive channels, and software versions. Quantitative T1 and T2 measurements were repeatable, with intra-scanner CV of <2.0% for physiologically relevant phantom values (T2 between 20–267 ms) and CV of ≤6% for all subjects. Inter-scanner correlation of T1 and T2 was strong in phantom experiments (R2 > 0.999) with inter-scanner CV of 4.8% (T1) and 5.1% (T2). Reproducibility of in vivo T1 and T2 values in a single subject after two months was also good, with measurements within 4%.These findings demonstrate the feasibility of collecting tissue property maps using MRF on aging, lower performance MRI scanners. T1 and T2 values except T2 < 13 ms [1 and T2 were all similarly <5%. A multi-site study by Buonincontri et al. examined reproducibility in phantom and in vivo brain at 1.5T and 3T for scanners with 8–12 receive coil channels, 33–50 mT/m maximum gradient strengths, 120–200 T/m/s maximum slew rates, and four different software versions [1) and 2.9–4.7% (T2), comparable to the CV of 2.1–2.9% (T1) and 2.6–3.5% (T2) observed in this work. However, the inter-scanner CV in the NIST phantom presented in this work, with averages of 5.8% (T1) and 7.1% (T2), was greater than that found by Buonincontri et al., 0.9% (T1) and 2.7% (T2).MRF repeatability and reproducibility on the aging scanner were within the ranges anticipated based on previous reports. A study of MRF repeatability across 34 days for the ISMRM/NIST phantom showed CV <5% for all reference T < 13 ms . In the 1 and T2 maps similar in appearance to those collected on the new scanner. While there were statistically significant differences in white matter measurements between scanners for each subject, overall inter-scanner white matter CV in this work, 4.8% (T1) and 5.1% (T2), was within the inter-site variability reported by Buonincontri et al., 6.6% (T1) and 9.7% (T2). T1 values were lower than the overall white matter values reported by Buonincontri et al., but in agreement with previously reported T1 for genu of the corpus callosum at 1.5T . T2 wasure 5 of ), which ure 5 of ,25. Alth2 relaxation times compared to spiral MRF [2 varied by approximately 10% when using the ‘weak’ spiral, comparable to the T2 differences observed when comparing the old scanner to the new scanner with the ‘strong gradient’ spiral. Furthermore, the comparison between scanners with the same ‘weak gradient’ spiral showed a smaller average absolute percent difference in the measured T2 values, below that observed in the old scanner test–retest comparison (4.0% vs. 4.3%). The difference between T1 measurements made on different scanners with the same ‘weak gradient’ spiral trajectory was smaller than inter-scanner T1 measurements made with different spirals (6% vs. 8%), although the remaining bias was larger than that observed in the test–retest experiment (6% vs. 3%). Differences in the undersampling patterns for the tested spiral trajectories may have contributed to these observed differences. It has been reported that T1 and T2 maps can have mean relative differences of up to 16.9% (T1) and 19.9% (T2) in the brain [1 and T2 relaxation times.Although MRF sequences were purposely designed to be as similar as possible when considering system limitations, factors in sequence design can influence parameter measurements. For example, it has been suggested that measured parameter values are affected by gradient trajectory. In cardiac MRF, a rosette trajectory with inherent fat suppression was shown to yield 2–3 ms higher Tiral MRF . Differehe brain , and thahe brain . FInallyComputation time and cost of computing is a consideration for deployment of MRF on aging MR hardware. Image reconstructions in this study were performed offline using a research workstation with an 18-core Intel i9-9980XE processor and 64 GB of RAM, although these specifications were well beyond the minimum resources necessary for reconstruction. Reconstruction times were within 1–2 min using non-optimized, in-house developed reconstruction code with a pre-computed MRF dictionary. Reports have shown that similar MRF reconstructions can be performed online using open-source Gadgetron tools . Thus, t1 mapping has been demonstrated to improve imaging in the presence of metallic objects [Although this work focused on implementation of MRF on aging hardware, MRF could potentially enable robust advanced imaging to be performed on MRI scanners designed to be less powerful and thus less expensive. As suggested from this work, reduced gradient specifications do not significantly alter the measurements made using MRF; designing a modern MRI scanner with weaker and slower gradients could consequently lead to cost savings both in scanner construction, as well as in electrical power and cooling infrastructure . Similar objects  and grad objects . The fle0 maps were not quantitatively analyzed in this work and were observed to have visually apparent differences between systems , which likely contributed to observed differences. Last, system imperfections that might have contributed to the observed biases in T1 and T2, such as field inhomogeneity, as well as differences in sequence implementations across different hardware and software platforms such as TE in this work, should be further explored.There are notable limitations of this study. The sample size for in vivo experiments is small, with only three subjects. An expanded study of more volunteers should be performed to identify systematic bias or differences in precision when performing MRF on the aging MRI scanner. MRF scans should be performed in patients with pathology on the aging scanner to determine clinical translation potential. Additionally, the aging scanner that was used did receive a “TIM” upgrade which, although it did not affect the gradients or main magnetic field, may have improved receive system performance as compared to a true original model scanner. Mms e.g., . Given t1 and T2 was comparable to that previously observed in the literature; however, subtle differences in the MRF sequence or scanner characteristics may have contributed to bias in measured values. Findings suggest that newer data collection and processing approaches like MRF may enable older scanners to be used for state-of-the-art imaging, and may potentially drive the development of new, lower-cost MRI systems.In conclusion, MRF is feasible on older scanners with weaker gradient systems and a small number of receiver coils. Overall repeatability and reproducibility of quantitative T


The aims of this study were to assess whether there is a conceptual overlap between the questionnaires HIT-6 and EQ-5D and to develop a mapping algorithm allowing the conversion of HIT-6 to EQ-5D utility scores for Germany.This study used data from an ongoing randomised controlled trial for patients suffering from migraine. We assessed the conceptual overlap between the two instruments with correlation matrices and exploratory factor analysis. Linear regression, tobit, mixture, and two-part models were used for mapping, accounting for repeated measurements, tenfold cross-validation was conducted to validate the models.We included 1010 observations from 410 patients. The EQ-5D showed a substantial ceiling effect (47.3% had the highest score) but no floor effect, while the HIT-6 showed a very small ceiling effect (0.5%). The correlation between the instruments’ total scores was moderate (− 0.30), and low to moderate among each domain (0.021–0.227). The exploratory factor analysis showed insufficient conceptual overlap between the instruments, as they load on different factors. Thus, there is reason to believe that the instruments’ domains do not capture the same latent constructs. To facilitate future mapping, we provide coefficients and a variance–covariance matrix for the preferred model, a two-part model with the total HIT-6 score as the explanatory variable.This study showed that the German EQ-5D and the HIT-6 lack the conceptual overlap needed for appropriate mapping. Thus, the estimated mapping algorithms should only be used as a last resort for estimating utilities to be employed in economic evaluations.The online version contains supplementary material available at 10.1007/s10198-021-01342-9. Migraine is a common neurological condition affecting 10.6% of the German population  , 3.This condition also imposes an economic burden on health care systems due to increased demand for goods and services and work-related productivity losses , 5. As hClinical trials in migraine often use monthly migraine days as a primary endpoint and the International Headache Society actually recommends the use of monthly migraine days as the primary endpoint for HTAs involving preventive treatments . Where gNevertheless, several trials in the migraine field e.g. , 10) onl onl10]) One study by Gillard et al. has already mapped the EQ-5D to the HIT-6, but used quality weights for England in a Brazilian population . SeveralBased on these considerations, we will address the issue of whether there is enough conceptual overlap between the two instruments using not only correlation tables, but also exploratory factor analysis (EFA). Based on regression-type approaches we will develop a mapping function to predict EQ-5D utility values for Germany from HIT-6 values, including variables widely used in migraine trials, and validate them with tenfold cross-validation.This study is based on data from the SMARTGEM project. SMARTGEM is an ongoing national randomised controlled clinical trial, which seeks to assess if a digital intervention via the use of a headache app and online consultations leads to a decrease in migraine frequency. The intervention consists of a certified medical app where patients document trigger factors, attacks, and medication in an electronic calendar; the app analyses the diary and evaluates trigger factors and proposes individually tailored treatment plans; a web-based tool where patients communicate both with other patients and specialists. HIT-6 and EQ-5D were completed by all users at baseline and after 3, 6, 9, and 12 months. Registration ID in the German clinical trials register is DRKS00016328.To analyse the strength of the relationship between HIT-6 scores and EQ-5D domains, correlation coefficients accounting for repeated measurements were computed. We also examined the capacity of each instrument to detect changes in HRQOL over time, referred to as responsiveness, by computing standardised response mean(s) (SRM). SRM is defined as a ratio of the difference in the mean baseline and mean follow-up values divided by their mean standard deviations’ (sd) difference. We considered SMR values of less than 0.2 as small, from 0.2 to 0.5 as moderate, and values above 0.8 as large, following Cohen’s criteria . EFA wasSince there is no specific model recommended by guidelines on best practices for mapping, we applied several models . As our We also fitted adjusted limited dependent variable mixture models with one to four components, with the Stata command aldvmm, which was specifically developed to deal with health utility data . These mHIT-6 related variables, sex, age, and migraine type were pre-defined as having to be part of the model. Given that mapping algorithms are intended to be used by other researchers, we only considered age and sexWe conducted complete-case analysis based on the following variables: EQ-5D domains, HIT-6 domains, migraine type, age, and sex.R2, reporting the mean of all 10 cycles.We plotted the observed and predicted EQ-5D values to visualise the models’ performance. Given the lack of external data to conduct external validation, a tenfold cross-validation was carried out to compare the predictions of each model with the actual EQ-5D scores. This method is recommended for small samples . Models’R 3.6.3 and Stata 15 [R packages for data handling [Statistical analyses were performed using Stata 15 , 34. We handling  and plothandling , repeatehandling , and fachandling , 39, a Shandling   observations had to be removed. thus the dataset used for the analysis contains 1010 observations, based on 410 patients. 7 out of 16 were excluded from the analysis because they did not have full data on other time points.87.3% of all participants were female, with an average age of 41 years . The skewness of − 0.64 indicated that the HIT-6 scores are only slightly skewed to the left Fig. . There wIn EQ-5D, there was no floor effect , i.e. no patient had the lowest utility score possible . However, the ceiling effect  amounted to 47.3% (194/410).We consider that occupation and daily activities can be measured by the EQ-5D dimension “usual activities” and by questions 2, 3, and 4 from the HIT-6. Physical health is captured by “pain/discomfort” and “mobility” in the EQ-5D, and by question 5 from the HIT-6. Self-care is only measured by the EQ-5D.The correlation coefficient between EQ-5D score value and the HIT-6 total score amounted to − 0.30. In terms of EQ-5D value and the different HIT-6 dimensions, the coefficients ranged between − 0.153 and − 0.234. The correlation coefficients between each EQ-5D domain and the overall HIT-6 score ranged from 0.077 to 0.300 (Table A.1). Lastly, the correlation coefficients among each domain from the two instruments ranged from 0.021 to 0.227. The highest correlation (0.227) was found between EQ-5D pain/discomfort and HIT-6 q4. See Supplementary Tables A.1, A.2, and A.3 for correlation tables, additionally stratified by migraine severity level.The EQ-5D total score and the different dimensions show small SRMs, while the HIT-6 total score and its different questions show small to moderate responsiveness. For EQ-5D dimensions, SRM values range from 0.088 to 0.280 and for the HIT-6 from 0.211 to 0.669 (see Supplementary Table A.4). Although the lack of responsiveness may be in part because we are also analysing patients in the control group, this still does not explain why the responsiveness of the HIT-6 is higher than that of the EQ-5D.We considered three factors in the EFA. Factor 1 had meaningful loadings (i.e. higher than 0.3) on all EQ-5D domains, but not on HIT-6 domains. Factors 2 and 3 loaded only on HIT-6 domains, specifically questions 2–6 for Factor 2, questions 1 and 2 for Factor 3. Considering that this question had a higher loading in Factor 2, thus belonging to this factor, Factor 2 had meaningful loadings in five out of six HIT-6 domains  with the state directly after full health (0.974) may explain why these models did not perform better.No model performed best across all goodness-of-fit measures. Model E  performed the best in terms of RMSE Table . AlthougHence, if researchers wish to estimate utilities from the HIT-6 to be employed in cost-utility analyses, Model E should be the preferred model. The corresponding variance–covariance matrix is available in the Electronic Supplementary Material, in Table A.6, to allow probabilistic sensitivity analysis to be carried out and account for uncertainty. However, we would like to remark that this mapping algorithm should only be used as a last resort.We aimed to assess whether there is a conceptual overlap between the HIT-6 and the EQ-5D and to present a mapping algorithm for the estimation of the EQ-5D score (with German weights) from the HIT-6 questionnaire, a disease-specific survey widely used in clinical trials with migraine patients. Our study points to major differences in the underlying constructs of the HIT-6 and the EQ-5D. The EQ-5D showed a high ceiling effect and small SRMs across time, whereas the HIT-6 did not show a ceiling effect and had a higher responsiveness. This study also provides a mapping algorithm which can be used to map HIT-6 values to EQ-5D utility values.We expected some overlap between the two instruments since both have been validated in migraine patients. The strength of association between the instruments measured with correlation coefficients was only low to moderate—both for the total scores and for each instrument’s individual questions. Furthermore, the EFA showed that the HIT-6 and EQ-5D do not have a sufficient conceptual overlap and potentially estimate different underlying constructs. There are several reasons that might explain the lack of overlap. First, the recall period in the instruments’ questions is different. While all EQ-5D questions refer to the day the questionnaire is filled out, three questions in the HIT-6 refer to the previous 4 weeks. Second, the HIT-6 has frequency response categories , while the EQ-5D has response categories based on levels of severity. Third, the specificities of both the EQ-5D and the HIT-6 may also play a role. A criticism of the use of the EQ-5D to describe health utilities in patients with migraine is the fact that the survey is conducted at random points in time, thus not differentiating whether or not patients were having a migraine attack at the moment they filled out the survey . The 47.Given the lack of responsiveness, as well as the substantial ceiling effect of the EQ-5D for migraine patients, economic evaluations with these patients should consider other approaches to determine value, not necessarily QALYs obtained from generic utility-based instruments. In fact, the guidelines of the International Headache Society state that QALYs may fail to account for specific patient preferences due to the insensitive nature of utility instruments . Thus, tStrengths of our study include the fact that trained migraine neurologists provided the migraine diagnosis to the study participants’ and the low percentage of missing data. Furthermore, we could use multiple observations per person and evaluated this data with methods suitable for repeated measurements where possible. The conceptual overlap of EQ-5D and HIT-6 was evaluated carefully prior to investigating mapping algorithms, where the latter were carried out with a broad set of multivariable modelling approaches.A limitation of our study is that no external validation could be carried out since no dataset containing both EQ-5D answers and HIT-6 was available. Randomised controlled trials are often considered the ‘gold standard’ for evidence-based medicine , and altOur results suggest that the German versions of EQ-5D and the HIT-6 are not measuring the same underlying concepts due to conceptual differences. Therefore, mapping algorithms shall only be used as a last resort for estimating utilities to be employed in cost-utility analyses.Supplementary file1 (XLSX 16 KB)Supplementary file2 (DOCX 29 KB)Below is the link to the electronic supplementary material.


Our aim was to assess the regional right ventricular (RV) shape changes in pressure and volume overload conditions and their relations with RV function and mechanics. The end-diastolic and end-systolic RV endocardial surfaces were analyzed with three-dimensional echocardiography (3DE) in 33 patients with RV volume overload (rToF), 31 patients with RV pressure overload (PH), and 60 controls. The mean curvature of the RV inflow (RVIT) and outflow (RVOT) tracts, RV apex and body  and septum) were measured. Zero curvature defined a flat surface, whereas positive or negative curvature indicated convexity or concavity, respectively. The longitudinal and radial RV wall motions were also obtained. rToF and PH patients had flatter FW (body and apex) and RVIT, more convex interventricular septum (body and apex) and RVOT than controls. rToF demonstrated a less bulging interventricular septum at end-systole than PH patients, resulting in a more convex shape of the RVFW , and worse RV longitudinal contraction . PH patients showed flatter RVFW apex at end-systole compared to rToF (p < 0.01). In both groups, a flatter RVFW apex was associated with worse radial RV contraction . In PH group, the impairment of radial contraction was also related to flatter RVIT (r = 0.407) and more convex RVOT (r = − 0.525) at end-systole (p < 0.05). In conclusion, different loading conditions are associated to specific RV curvature changes, that are related to longitudinal and radial RV dysfunction.The online version of this article (10.1007/s10554-020-02117-8) contains supplementary material, which is available to authorized users. Right ventricular (RV) remodeling in response to different loading conditions includes not only adaptations of size and function, but also changes of its shape –3, and tUsing 3DE, it has been reported that the regional curvature of the RV outflow tract and septum was more convex in patients with pulmonary hypertension (PH) compared with healthy controls, and that those changes were associated with impairment of RV pump function .Accordingly, we hypothesized that in addition to changes in RV size and function, volume and pressure overload may also affect the regional RV wall curvatures, and that those changes may be associated with differences in RV function and mechanics. Consequently, the purpose of this study was to compare the RV remodeling occurring in both pressure and volume chronic overload conditions by 3DE, and to determine the relationships between regional differences in RV shape with changes of RV function and mechanics.From May 2016 to January 2017, we enrolled 64 consecutive patients with chronic volume or pressure overload of the RV. Thirty-three rToF patients  who underwent total surgical correction in their childhood , resulting in severe pulmonary regurgitation without significantly elevated RV systolic pressure constituted the chronic volume overload group.Thirty-one patients with PH  and no more than moderate tricuspid regurgitation formed the group with RV pressure overload.Patients with either pulmonary stenosis or prosthetic pulmonary valve, greater than mild aortic or mitral valve disease, residual intracardiac shunts, atrial fibrillation, left ventricle ejection fraction (EF) < 50%, pacemaker, or poor quality of echocardiographic images were excluded from the study.The control group included 60 age- and sex- matched healthy volunteers (30 subjects for rToF and PH group each) selected from the Padua “3D Echo Normal” database (inclusion/exclusion criteria described previously) , 13.Written informed consent was obtained from all volunteers, and the study was approved by the local Ethics Committee (protocol 2380P approved on 06/10/2011).Transthoracic echocardiography was performed using a Vivid E9 scanner  equipped with M5S and 4 V probes. Digital loops were stored and analyzed offline. All measurements were performed according to the ASE/EACVI guidelines –16.The apical 4-chamber and short-axis views with color Doppler and continuous wave Doppler tracings were acquired for tricuspid and pulmonary regurgitation quantification , 16. PeaMulti-beat (4 or 6) full-volume datasets of both the RV and the left ventricle were acquired for 3DE analysis during breath-hold from the apical approach. A multislice display was used during acquisition to ensure a complete inclusion of the RV in the dataset . Image dRV volumes and EF were measured using a commercially available software package  by a single experienced investigator using a validated protocol . QuantifThe end-diastolic and end-systolic 3D RV surfaces were exported as meshes of connected points, and used as input into a custom-made software package to analyze the RV regional curvatures as previously described . To idenwww.revisionmethod.com) [The same exported 3D RV models were used as input to assess the longitudinal and radial RV wall motions and their relative contribution to global RVEF using the ReVISION method  . Brieflyhod.com) . MovemenStatistical analysis was performed using SPSS version 24.0 for Windows . The qualitative variables were expressed in absolute numbers and percentages. The continuous variables were summarized using mean value ± standard deviation.Kolmogorov–Smirnov test was used to assess distribution of variables. Normally distributed data were compared between rToF, PH and control groups with Student’s T test and in case of non-normality with Mann Whitney U test. Wilcoxon Signed Rank Test was used for the comparison of dependent variables. Pearson or Spearman correlation coefficient was used to assess correlations between RV shape and parameters of RV function.Differences were considered statistically significant if p < 0.05.In 29 (88%) rToF patients surgery was performed using transarterial approach, whereas the transventricular approach was used in the remaining 4 (12%) patients. Transannular patch was performed in 25 (76%) patients, whereas infundibulectomy was used in 4 (12%) patients. The surgical technique applied to the remaining 4 (12%) patients was unknown. Twenty-six (79%) rToF patients had right bundle branch block at the electrocardiogram, 13 (39%) rToF patients had moderate and 1 (3%) patient had severe tricuspid regurgitation. All rToF patients had severe pulmonary regurgitation.The PH cohort included 21 (68%) patients with pulmonary arterial hypertension (PAH) (12 (39%) with idiopathic PAH, 7 (23%) with scleroderma associated PAH, and 2 (6%) with PAH associated to HIV infection), 8 (26%) with chronic thromboembolic PH, and 2 (6%) with chronic obstructive pulmonary disease. Twenty (65%) patients had mild and 11 (35%) had moderate tricuspid regurgitation.Baseline demographics and clinical characteristics of the study cohort are summarized in Table As expected, rToF and PH patients showed significantly larger global and regional RV volumes both at end-diastole and end-systole, and lower RVEF than controls. rToF patients demonstrated larger RV mid-cavity and long-axis diameters, larger volumes (particularly at end-diastole) and higher RVEF compared with PH group Tables  and 2.Tahttps://figshare.com/s/14c22bd00065d3de9ff3). The RV septal body curvature was more convex in rToF than in PH patients at end-diastole, but this relationship was inverted at end-systole  and RVIT, more convex interventricular septum  and RVOT than controls . RVIT convexity increased significantly from end-diastole to end-systole in rToF patients (p < 0.0001), while it did not change throughout the cardiac cycle in PH patients (p > 0.05) Table .Dynamic RV shape changes  were more pronounced in PH group Table . RespectIn both rToF and PH patients, a more convex RVOT at end-systole was associated to lower RV fractional area change  and EF , and this association was stronger in PH. Moreover, in PH patients more convex RVOT at end-systole was associated with lower TAPSE  and S’ velocity of the RVFW .In rToF patients, regional curvature values for the whole RV interventricular septum at end-systole demonstrated moderate negative correlation with RV fractional area change  and a tendency to negative correlation with RVEF (p = 0.094). In PH patients, the convexity of the interventricular septum at end-diastole showed a tendency to negatively correlate with TAPSE (p = 0.07) and RVEF (p = 0.059).In PH patients, RVIT curvature at end-systole correlated positively with RV fractional area change  and EF .The relative contribution of the longitudinal wall motion to global RVEF was significantly lower in rToF compared with their control group. Whereas, in PH patients it was the relative contribution of the radial component of RV wall motions to be more impaired in comparison to their controls Table , Fig. 2.In both groups, the RVFW apex curvature at end-diastole  and at end-systole  demonstrated a positive correlation with the radial RVEF. In addition, in rToF patients, the worse radial RV contraction was associated with less convex curvature of the whole RVFW  and the more convex septal body curvature  at end-systole. In PH patients, the impairment of radial RVEF was also related to less convex RVIT  and more convex RVOT  at end-systole.In rToF patients, the deterioration in longitudinal RVEF was associated with more convex curvature of the whole RVFW at end-systole  and RVFW apex at end-diastole . In PH patients, the longitudinal RVEF demonstrated negative correlation with the whole RV septum curvature in diastole .i. both rToF and PH patients had larger RV volumes and lower EF, flatter (less convex) RVFW and RVIT, more convex septum and RVOT than their age and sex-matched controls; ii. in rToF patients the RVFW body segment became flatter, while the FW apex changed to a more convex shape, whereas in PH patients, both RVFW components (apex and body) became flatter from end-diastole to end-systole; iii. A more convex RVOT at end-systole was associated with impaired RV systolic function in rToF and PH patients; iv. compared with PH patients, rToF showed a less convex RV septal body curvature at end-systole that was associated with a more convex shape of the RVFW, and worse longitudinal RVEF; v. both in rToF and PH patients, a flatter RVFW apex curvature was associated with worse radial RVEF, meanwhile in PH group, the impairment of radial RV contraction was also related to flatter RVIT and more convex RVOT at end-systole.As far as we know, this is the first study that used 3DE to assess regional RV shape differences in patients with distinct loading conditions of the RV and to study their relationships with RV function and mechanics. We demonstrated that: Early surgical ToF repair often leaves patients with severe residual pulmonary regurgitation, which causes progressive RV dilation and late complications , 24. TimWhen RV dilates, contractile function increases according to the Frank-Starling law, which for some time effectively compensates for altered hemodynamic conditions. However, the adaptive cardiac response to pathological loading conditions is time dependent and long-term chronic RV volume overload due to severe pulmonary regurgitation leads to stretching of myofibers with subsequent distorted meshwork, more spherical architecture, RV dilatation and decreased contractility , 30. TheMoreover, when RV preload increases, wall stress is maintained by dilation of the chamber. Previously, it was demonstrated that regional curvature differences are related to regional wall stress : decreasThe apical trabecular component of the RV yields the major adaptive response in rToF patients with volume overload . Our resThe results of our study also confirmed the observations that rToF patients with severe pulmonary regurgitation had significantly more convex RVOT compared to controls throughout the cardiac cycle . HoweverThe abnormal motion of the interventricular septum is a well known echocardiographic feature of both RV volume and pressure overload , 38, andIn pressure overload, the RV hypertrophy has been described as the initial adaptive response to increase contractility . SeveralMoreover, in patients with RV pressure overload, the RV acquire a unique shape compared to normals characterized by apical bulging  and overall rounding of the RV apex . RecentlIt was demonstrated, that in keeping with the “bellows-like” action of normal RV contraction, the FW body segment became flatter, while the apex FW changed to a more convex surface transitioning from end-diastole to end-systole . In contAccording to our results, a flatter RVIT in PH was associated with the impairment of the RV global systolic function and worse radial RVEF. Addetia et al. did not show any meaningful correlations of RVIT curvature with 2D and Doppler parameters of the right heart . HoweverFlattened septum and septal bowing towards left have been demonstrated as independent predictors of adverse events in PH and pulmonary embolism , and thaRV shape analysis using this custom software relies on accurately generated 3D endocardial surface model and therefore, it is dependent on the quality of the 3DE datasets. 3D analysis of regional endocardial curvature is fully automated once the endocardial surface is defined, and therefore it is 100% reproducible. In turns, the results could be affected by the variability of 3D RV endocardial reconstruction that was performed using a commercially available software. This issue has been already addressed in another publication where the methodology proved fair to excellent reproducibility in terms of intraclass coefficient of variation . MoreoveThe diagnosis of PH was confirmed by right heart catheterization. However, for many patients the right heart catheterization was done at the beginning of the follow-up and not all results were available, so we decided to use echocardiography to measure systolic pulmonary artery pressure.Finally, the absence of a true reference method to test the accuracy of our measurements, could be considered as a limitation of this study and only prospective outcome studies can assess the clinical value of our approach.This is the first study to quantitatively define the differences of regional RV shape changes in rToF and PH patients and their relations with RV global function and mechanics using 3DE.According to our findings, the RV in volume and pressure overload can be differentiated from normal RV using regional curvature–based analysis. Thus, since RV dilation results in regional inhomogeneity of shape, it is obvious that traditional parameters of RV geometry and function are not sufficient to assess the RV remodeling process occurring in rToF and PH. Moreover, our results suggest that RV remodeling in distinct loading conditions is significantly related to RV function and mechanics. This is the first study to show that changes in the shape of different RV parts affect RV mechanics. It is well known that some RV segments, such as RVOT, are very difficult to assess using standard 2DE. Thus, these findings highlight the importance of 3DE in more precise assessment of RV pump function in rToF and PH patients.Consequently, quantitative analysis of regional curvature, as described in this study, could potentially be used to characterize the dynamic behaviour of the RV in distinct conditions and diseases, providing additive information which is not available using conventional parameters or even 3D volumes and EF. Moreover, ability to assess RV regional remodeling in different conditions and diseases could provide insights into pathological mechanisms, resulting in a useful support tool for disease evaluation and therapy planning.video 1 and 2), pulmonary hypertension (PH) (video 4 and 5) and repaired tetralogy of Fallot (rToF) (video 5 and 6) patients. Blue denotes more concave surface and red denotes more convex. In rToF and PH patients, the right ventricular free wall is flatter, and the interventricular septum is more convex compared to normal subject throughout the cardiac cycle. In PH patients the septal body curvature significantly increases from end-diastole to end-systole, whereas in rToF patients its convexity decreases in systole.Electronic supplementary material 1 (MOV 432 kb)Electronic supplementary material 2 (MOV 438 kb)Electronic supplementary material 3 (MOV 412 kb)Electronic supplementary material 4 (MOV 436 kb)Electronic supplementary material 5 (MOV 375 kb)Electronic supplementary material 6 (MOV 398 kb)Below is the link to the electronic supplementary material. Right ventricular 3D curvature changes during cardiac cycle in a normal subject (


Neonatal hypertension has been increasingly recognized in premature infants with bronchopulmonary dysplasia (BPD); of note, a sub-population of these infants may have impaired left ventricular (LV) diastolic function, warranting timely treatment to minimize long term repercussions. In this case series, enalapril, an angiotensin-converting enzyme (ACE) inhibitor, was started in neonates with systemic hypertension and echocardiography signs of LV diastolic dysfunction. A total of 11 patients were included with birth weight of 785 ± 239 grams and gestational age of 25.3  weeks. Blood pressure improvement was noticed within 2 weeks of treatment. Improvement in LV diastolic function indices were observed with a reduction in Isovolumic Relaxation Time (IVRT) from 63.1 ± 7.2 to 50.9 ± 7.4 msec and improvement in the left atrium size indexed to aorta (LA:Ao) from1.73  to 1.23 . Neonatal systemic hypertension is often underappreciated in ex-preterm infants and may be associated with important maladaptive cardiac changes with long term implications. It is biologically plausible that identifying and treating LV diastolic dysfunction in neonates with systemic hypertension may have a positive modulator effect on cardiovascular health in childhood and beyond. Recent evidence suggests that adults born prematurely are at increased risk of heart failure, hypertension, and decreased exercise capacity, which present earlier and more frequently than their term born counterparts ,2. IncreNeonatal systemic hypertension is increasingly recognized in the subpopulation of infants with bronchopulmonary dysplasia (BPD); early treatment is warranted to minimize the development of end-organ complications ,8. AlthoA retrospective cohort study of neonates with systemic hypertension and echocardiography features of LV diastolic dysfunction who received enalapril was conducted. Patients were identified between July 2020 and July 2021 from the Hemodynamics Program echocardiography database at a large quaternary referral center . Routine TnECHO screening of preterm infants born at gestational age ≤30 weeks and/or weight ≤1500 g for chronic pulmonary hypertension (cPH) is performed at the earlier of either 8 postnatal weeks or 36 weeks postmenstrual age to facilitate timely detection.Enalapril Treatment Protocol: Treatment with enalapril is indicated for patients with concurrent systemic hypertension and TnECHO evidence of LV diastolic dysfunction according to a standardized systemic hypertension guideline  develope2)] were collected for each infant at the time of each TnECHO evaluation; immediately prior to initiation of enalapril, and then weekly for up to four weeks. Since most patients were on noninvasive respiratory support, a modified respiratory severity score (mRSS) . TDI of the tricuspid annulus was obtained just below the lateral tricuspid annulus in the apical four-chamber . 2D-STE 26, its use in neonates is limited. Left ventricular end-systolic wall stress (ESWS) (g/cm2) was calculated using mean blood pressure (MBP) from the right arm oscillometric measurement at the time of TnECHO and M-mode derived indices as per the following formula: (1.35 × MBP × LVIDs)/(4 × LVPWs × (1 + LVPWs/LVIDs)) [Afterload evaluation: Surrogate indices of pulmonary and systemic vascular resistance and afterload were evaluated . Pulmona/LVIDs)) ,29. Outcomes: The primary outcome was change in either IVRT, E/A ratio or E/e′. Secondary outcomes included indices of cardiorespiratory stability and echocardiography indices of pulmonary hemodynamics, LV or RV systolic performance. 2 or Fisher’s exact test. Results were considered significant if p < 0.01, based on Bonferroni correction for three variables which constituted the primary outcome. Data was analyzed using SPSS version 27 statistical software . No sample size calculation was performed as there are insufficient data regarding the impact of enalapril on LV diastolic function; therefore, for this hypothesis generating study, we used a sample size of convenience.Statistical analysis: Descriptive statistics were used for demographics and clinical data. The Shapiro–Wilk test was used to test continuous variables for normality. Mean with standard deviation and median with interquartile range were calculated for data with normal and non-normal distribution, respectively. Comparative evaluation of pre- and post-enalapril clinical and TnECHO variables was performed using paired t-test for normally distributed variables and Wilcoxon Signed Rank test for non-normally distributed variables. Categorical variables were presented as frequencies (%) and compared using the χn = 1), dexamethasone (n = 1), prednisolone (n = 1)) as scheduled tapers for management of bronchopulmonary dysplasia. Additionally, two infants were on nasal canula at time of initiation of enalapril therapy.Between July 2020 and July 2021 a total of eleven patients were identified who received enalapril therapy for late onset systemic hypertension and LV diastolic dysfunction. All eleven eligible infants were included in this study, of whom three were born less than 24 weeks gestation. Baseline neonatal demographics and indices of illness severity are outlined in As part of the workup for systemic hypertension, renal ultrasound with Doppler was obtained in all patients. All studies were reported as normal, although one patient had diffuse echogenicity that was not attributed to renal intraparenchymal disease. Baseline plasma troponin and creatinine levels were also normal in all cases. Four patients developed systemic hypertension prior to 36 weeks postmenstrual age; therefore, amlodipine treatment was initiated . Despiten = 2). In our unit, chlorothiazide is used frequently in the management of BPD. After enalapril initiation, chlorothiazide use decreased from 72.7% (n = 8) to 45.5% (n = 5). In addition, lower dosing required prior to home going (30 to 20 mg/kg/d) with plans to outgrow discharge dose.Impact of Enalapril on Cardiorespiratory Health: Infants were monitored closely for normalization of their BP . Each inImpact of Enalapril on TnECHO indices: In this observational study of infants with systemic hypertension and impaired LV diastolic performance, improvements in BP and echocardiography indices after treatment with enalapril were noted; specifically, a reduction in IVRT which coincided with normalization of left heart volume loading (LA:Ao ratio) and trends towards improvement in LV afterload  were noted. Although this is a small cohort study, these data suggest a potentially important relationship between systemic BP and LV diastolic function which is potentially modifiable with ACE inhibitor treatment. In the context of the increasing scientific evidence that adults born prematurely are at increased risk of hypertension, cardiac maldevelopment, and heart failure, our data highlights the importance of prospective characterization of the determinants of cardiac performance.The immature myocardium contains underdeveloped contractile machinery with disorganized myofibrils, an immature calcium handling system, and inadequately compliant collagen, which predisposes the neonatal heart to diastolic dysfunction and poor tolerance to increased afterload . As pretPrematurity may disrupt the normal deposition of elastin in the large conduit arteries that typically occurs around term. This interruption in normal development may be further compounded by perinatal interventions such as oxygen and steroids. Survivors of prematurity in an era when generous oxygen use was the standard practice, had increased aortic stiffness . The usePersistent exposure to a high-volume PDA shunt can have serious hemodynamic consequences including both pulmonary over circulation and systemic hypoperfusion, which may have an additional negative modulator effect on LV diastolic function through coronary hypoperfusion . AdditioTargeted therapies which act on the RAAS system may offer a novel approach to infants with cardiac-lung disease. Inhibition of ACE rather than angiotensin receptor blockers  has beenLimitations: There are several important limitations in this study particularly related to its retrospective nature and small sample size. First, some infants with systemic hypertension and LV diastolic dysfunction were treated initially with amlodipine as enalapril is not started before 36 weeks PMA due to the concern for potential nephrotoxicity during nephrogenesis. Once infants are greater than 36 weeks PMA, with signs of LV diastolic dysfunction, they are transitioned to enalapril as nephrogenesis is nearing completion . It is iIn summary, enalapril treatment in infants with systemic hypertension and LV diastolic dysfunction led to interval improvements in blood pressure, left heart volume loading, LV diastolic function, and afterload. These findings are important as systemic hypertension is often underappreciated in ex-preterm infants and may be associated with maladaptive cardiac changes including LV diastolic dysfunction. Reports that adult survivors of prematurity are at increased risk for cardiovascular disease, heart failure, ischemic heart disease, cardiometabolic impairment, and systemic hypertension in early adulthood lends additional credence to the findings ,60,61,62


Background: Little is known about the efficacy of permanent left bundle branch area pacing (LBBAP) in delivering cardiac resynchronization therapy (CRT). This study aimed to evaluate the effect of LBBAP on mechanical synchronization and myocardial work (MW) in heart failure (HF) patients and to compare LBBAP with biventricular pacing (BVP).Methods: This is a multicenter, prospective cohort study. From February 2018 to January 2021, 62 consecutive HF patients with reduced ejection fraction (LVEF ≤ 35%) and complete left bundle branch block (CLBBB) who underwent LBBAP or BVP were enrolled in this study. Echocardiograms and electrocardiograms and were conducted before and 3–6 months after implantation. Intra- and interventricular synchronization were assessed using two-dimensional speckle tracking imaging (2D-STI). The left ventricular pressure-strain loop was obtained by combining left ventricular strain with non-invasive blood pressure to evaluate mechanical efficiency.Results: The echocardiographic response rates were 68.6 and 88.9% in the BVP and LBBAP groups, respectively. Left bundle branch area pacing resulted in significant QRS narrowing  and improvement in LVEF . The global wasted work (GWW)  and global work efficiency (GWE)  were significantly improved along with shorter peak strain dispersion (PSD)  and interventricular mechanical delay (IVMD) , indicating its efficiency in improving mechanical synchronization. In comparison with BVP, LBBAP delivered greater improvement of QRS narrowing  and better mechanical synchronization and efficiency.Conclusions: Left bundle branch area pacing was effective in improving cardiac function, mechanical synchronization, and mechanical efficiency and may be a promising alternative cardiac resynchronization therapy. Biventricular pacing (BVP) is a traditional method of cardiac resynchronization therapy (CRT), and long-term studies have shown a significant reduction in mortality in heart failure (HF) patients with complete left bundle branch block (CLBBB) , 2. HoweAs first published in 2017 , Huang ePrevious studies have proven the role of two-dimensional speckle tracking imaging (2D-STI) in evaluating intra- and interventricular dyssynchrony , 10. TheThis study is a multicenter, prospective cohort study. Sixty-two consecutive patients referred for CRT according to the 2016 European Society of Cardiology (ESC) guidelines  were recThe inclusion criteria were as follows: (a) symptomatic patients with LVEF ≤ 35% despite optimal medical treatment for at least 3 months; (b) CLBBB morphology and QRSd ≥130 ms; and (c) age ≥18 years old. The exclusion criteria were as follows: (a) narrow QRS or non-LBBB morphology; (b) absence of clinical follow-up or poor condition of the acoustic window; and (c) life expectancy < 1 year. An echocardiographic response was defined as a ≥10% absolute increase in LVEF compared with the baseline, and a super-response was defined as an absolute increase ≥20% in LVEF compared with the baseline or LVEF ≥50% at follow-up.Left bundle branch area pacing was performed with an LBBAP pacing lead  supported by a delivery catheter  under a 30° right anterior oblique (RAO) fluoroscopic view. The left bundle branch was located between the tricuspid valve, non-coronal sinus, and right coronary sinus. When the pacing lead was first applied on the right side of the interventricular septum, the paced QRS morphology demonstrated a “w” shape with a notch at the nadir of the QRS in lead V1. The sheath with the LBBAP pacing lead was then screwed counterclockwise into the interventricular septum, usually 10–20 mm away from the His bundle region. Twelve-lead ECG and intracardiac electrograms were simultaneously recorded and applied to identify the ideal pacing site. During the advancement process, the notch at the nadir of the QRS gradually moves up to the end of the QRS wave. Once the R wave appears at the terminal of QRS in surface lead V1, indicating the right bundle branch block (RBBB) pacing morphology, the lead advancement process should cease. The position was reconfirmed by intra-sheath radiography or trans-thoracic echocardiography. The ideal pacing site should meet the following criteria: (1) the QRSd narrows significantly, and the LBBB can be partly or completely normalized; and (2) the fast peak left ventricular activation time (LVAT) measured in leads V4–V6 is constant regardless of high or low output. The coronary sinus-left ventricular (CS-LV) lead was implanted as a backup for resynchronization therapy. If LBBAP could effectively normalize LBBB or narrow QRS ≤ 140 ms, devices were set in LBBAP only. Otherwise, sequential pacing of the LBBAP and CS-LV lead was programmed, and optimal narrow QRS was obtained by adjusting the LV–RV (V–V) interval. The right atrial leads (Boston 4480) were implanted into the right atrial appendage. The AV interval was optimized according to surface ECG in full consideration of the conduction delay between the left bundle branch pacing pulse and the QRS wave (20–30 ms).The left ventricular lead (Boston 4675) was inserted into the lateral, posterolateral, or posterior veins, preferably after retrograde coronary venography. The right ventricular (Boston 0693) and atrial leads (Boston 7736) were fixed on the right ventricular septum or apex and right atrium, respectively. The A–V and V–V intervals were routinely adjusted during the follow-up to achieve optimized narrowing of the QRSd.Medical history, physical examinations, New York Heart Association (NYHA) functional classification, 12-lead electrocardiogram, and echocardiograph were evaluated at baseline and at 3–6 months during follow-up. QRS duration was measured by a standard 12-lead electrocardiogram (ECG) from the starting point of the Q wave to the end point of the S wave, while paced QRSd was measured from the pacing stimulus to the end point of the S wave.Echocardiography was performed using GE Vivid E9 or E95 ultrasound equipment  by experienced senior echocardiography physicians. Standard echocardiogram indices, including left atrial diameter (LAD), left ventricular end systolic/diastolic diameter (LVESD/LVEDD), and left ventricular end-systolic/diastolic volume (LVEDV/LVESV), were acquired. Left ventricular ejection fraction (LVEF) was evaluated by two-dimensional biplane Simpson's method. Echocardiographic images of the apical two-, three-, and four-chamber views were collected continuously for at least five cardiac cycles, and the mean frame rate of images was 60 ± 5 frames/s. Non-invasive blood pressure recordings representing left ventricular pressure were taken by a brachial artery sphygmomanometer at the same time.The qualification of MW was conducted by software  using the AFI package and analyzed according to the following steps. First, the duration of isovolumic and ejection phases was defined by valvular timing  according to pulse wave Doppler imaging. Then, global myocardial longitudinal peak strain (GLS) was calculated by speckle tracking analysis using standard apical views  . FinallySegment systolic time to peak longitudinal systolic strain was assessed for every participant. The difference in systolic times to peak 2-D strain between segments was calculated to reflect intraventricular mechanical synchronization. Peak strain dispersion (PSD) is defined as the standard deviation of time to peak longitudinal systolic strain of LV segments. Interventricular mechanical delay (IVMD) was measured to reflect the mechanical synchronization between the left and right ventricles evaluated by pulse wave Doppler imaging.t-tests or non-parametric tests for continuous data at baseline. Paired samples t-tests or non-parametric tests were used to compare the echocardiographic parameters at baseline and follow-up. A linear mixed-effects model was used to investigate the independent association between different pacing strategies and changes in echocardiographic outcomes. A P-value < 0.05 was indicative of statistical significance.Statistical analysis was performed with SPSS 13.0 software . Continuous variables are presented as the mean ± standard deviation. Categorical variables are expressed as percentages. Differences between groups were assessed with chi-square analysis for categorical variables and 4).A total of 62 advanced HF patients  with CLBBB were enrolled between February 2018 and January 2021 at the three centers. The clinical characteristics of all patients are summarized in Left bundle branch area pacing implantation was successful in 27 of the 34 patients (79.4%), with full correction of LBBB or narrow QRS ≤ 140 ms. Sequential pacing of the LBBAP and CS-LV was programmed to achieve further narrowing QRSd in 5 of 34 patients (14.7%). Left bundle branch area pacing implantation failed in 5.9% (2/34) because of an inability to achieve conduction system capture. During the implantation process, 4 of 32 (12.5%) patients had transient III° atrioventricular conduction blocks, but all recovered after their operations. No ventricular septal ruptures were observed during the procedures.P < 0.001), with significantly improved cardiac function . An echocardiographic response, defined as ≥10% absolute improvement in LVEF compared with the baseline was observed in 24 of 27 patients (88.9%). Super-response (absolute increase ≥20% of LVEF or LVEF ≥50%) was identified in 12 of 27 patients (44.4%). The echocardiographic response rate in non-ischemic cardiomyopathy patients and ischemic patients was 90.0% (18/ 20), 85.7% (6/7), respectively. There was a significant reduction in left ventricular end-systolic diameter and volume  , the NYHA functional class was improved from 3.0 ± 0.5 at baseline to 1.6 ± 0.6 (< 0.001) .P < 0.001). Left bundle branch area pacing significantly shortened the duration of IVMD  and PSD  during the follow-up. Postoperatively, the 17-segment maximum time difference to peak 2-D strain  was significantly shortened in the LBBAP group. There was significant improvement in the time difference to peak 2-D strain between basal anteroseptal vs. posterior segments  and basal anterior vs. inferior segments  (As shown in = 0.016) .P < 0.001), with a significant reduction in GWW . Global constructive work and GWI were also significantly ameliorated  (P = 0.001), inferior , posterior , anterior , and anteroseptal  segments. There was a trend toward a reduction in mean segmental WW in every segment and it was significantly reduced in the septal , inferior  segments compared with the baseline. The MW differences between the lateral and septal segments were significantly reduced at the time of follow-up   . As with= 0.001) .P = 0.001). Although the degree of LVEF improvement did not achieve any significant difference, GLS was better ameliorated in the LBBAP  group than in the BVP group (p < 0.001) than in the BVP group. The IVMD and PSD, which reflect interventricular and intraventricular mechanical synchrony, were better improved in the LBBAP group than in the BVP group .A linear mixed-effects model was used to compare the parameters between LBBAP and BVP with consideration of baseline variables and follow-up duration. The echocardiographic response rate, defined as a ≥10% absolute increase in LVEF compared with the baseline, was 68.6 and 88.9% in the BVP and LBBAP groups, respectively. A relatively low no-response rate was observed in the LBBAP (11.1 vs. 31.4%) group compared with the BVP group. During the short-term follow-up, improvement of overall NYHA functional class in LBBAP was greater than that in BVP group , GWI , and GCW . As with segmental myocardial work, segmental MWE was significantly improved in all LV segments except for the lateral segment in the LBBAP group. Biventricular pacing was poor at improving MWE in the posterior , lateral , and anterior segments . Wasted work was significantly ameliorated in the septal , and inferior  segments in both groups. Myocardial Work differences between the lateral and septal segments was significantly reduced in both groups  (P = 0.006). Although it did not reach statistical significance, the MWE improvement in posterior segment was greater than that in the BVP group   . Compare= 0.068) .This multicenter study evaluated the efficacy of LBBAP in advanced HF patients, focused mainly on mechanical synchronization and MW, and compared LBBAP with traditional BVP from an echocardiographic view. The major findings in our study cohort are as follows: (1) during the short-term observation, LBBAP was efficient in improving cardiac function, mechanical efficiency, and mechanical synchronization. (2) Our preliminary comparison between LBBAP and BVP showed that LBBAP resulted in greater improvement of mechanical synchronization and MW. To our knowledge, this is the first report which demonstrated the effects on mechanical synchronization and MW in patients with LBBAP.Biventricular pacing is a well-established therapy for HF patients, but the non-response rate remains high. Although great efforts have been made to improve the response rate, the effect is far from satisfactory. This is partly due to limited mechanical dyssynchrony and MW . PermaneThe duration of QRS has been accepted as a surrogate for predicting electrical synchronization . Salden Mechanical efficiency was also evaluated in our study. The pressure-strain loop, which has emerged as a novel non-invasive method developed from STI, is efficient in quantitatively assessing mechanical synchrony and mechanical efficiency associated with LV pressure . As showP = 0.001) and WW reductions  in the septum, indicating major improvement in LV function. Reducing septal-lateral work differences in the LV is an important determinant of reverse remodeling after CRT implantation (In HF patients with CLBBB, abnormal electrical conduction leads to dyssynchronous ventricular contraction. Early contraction of the septum and systolic lengthening of the LV lateral wall may cause energy waste, which leads to inefficient mechanical wall motion . In prevantation , 30, 31.A preliminary comparison between LBBAP and BVP revealed that LBBAP induced better improvement in specific echocardiographic parameters reflecting mechanical synchronization and MW and resulted in a relatively high echocardiographic response rate. Although the baseline MW in the groups was comparable and we used a linear mixed-effects model to reduce bias, this non-randomized study did not provide sufficient data to draw the conclusion that LBBAP is superior to BVP. However, analysis of segmental MW led to a better view of left ventricular motion patterns and mechanical synchronization. Biventricular pacing achieves ventricular mechanical synchronization by sequential RV and CS-LV lead pacing. This is not physiological, and the CS-LV lead is hard to implant in the region with the most delayed activation due to anatomical variability in coronary veins in clinical practice. In our study, BVP showed less efficacy in improving MWE and reducing WW in posterior and anterior segments, indicating its limited efficacy in achieving optimal synchronization of wall motion. This might be the reason why the non-response rate of BVP in our study was high. In the LBBAP group, the MWE tended to improve in every LV segment except for the lateral segment. Compared with BVP, LBBAP lead to better improvement of MWE in specific segments. Overall improvement of segmental MWE result in better GWE and better mechanical coordination. Moreover, LBBAP could activate the left bundle branch area. Thus, electrical stimulation passes down through the intrinsic conduction system instead of the intercellular electrical conduction, which may better maintain left ventricular systolic synchronization in HF patients.Left bundle branch area pacing was effective in improving cardiac function, mechanical synchrony and efficiency and may be a promising alternative CRT.This is an observational study involving a limited number of participants. The follow-up period was short, and the long-term effects of LBBAP on cardiac function and mechanical synchronization need to be validated by more patients with longer follow-up periods. Although the clinical characteristics were comparable at baseline and we used a linear mixed-effects model with consideration of clinically relevant parameters to reduce the bias, this non-randomized study did not provide sufficient data to draw the conclusion that LBBAP is superior to BVP.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Zhongshan Hospital, Fudan University. The patients/participants provided their written informed consent to participate in this study.WL and CH collected data, analyzed and interpreted the results, and drafted the manuscript. YW, YC, YZ, YL, and SZ collected and analyzed the data. XS and HC contributed to the design, planning, conduct of the study, and critically revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on reports of the incidence, diagnosis and current treatment options. We summarise opinions on whether PPCM is triggered by vascular and/or hormonal causes and examine the influence of comorbidities such as preeclampsia. Two articles published in 2021 strongly support the hypothesis that PPCM may be a familial disease. Using large cohorts of PPCM patients, they summarised the available genomic DNA sequence data that are expressed in human cardiomyocytes. While PPCM is considered a disease predominately affecting the left ventricle, there are data to suggest that some cases also involve right ventricular failure. Finally, we conclude that there is sufficient evidence to warrant an RNAseq investigation and that this would be most informative if performed at the cardiomyocytes level rather than analysing genomic DNA from the peripheral circulation. Given the rarity of PPCM, the combined resources of international human heart tissue biobanks have assembled 30 ventricular tissue samples from PPCM patients, and we are actively seeking to enlarge this patient base by collaborating with human heart tissue banks and research laboratories who would like to join this endeavour. Therefore, it is a disease that affects the heart muscle that occurs either late in pregnancy, or within 6 months following delivery. However, it is not uncommon for the onset of heart failure to present up to 6 months post-partum. PPCM is life-threatening and despite being the largest contributor to pregnancy-related heart failure, the cause remains unknown, i.e. idiopathic  of < 45% in the absence of other identifiable causes. It is diagnosed in the third trimester or most commonly within the first 6 months post-partum.PPCM is not a precisely defined entity  as a “bridge” to heart transplantation   is derived from the placenta and is elevated in preeclampsia, a pregnancy associated complication characterised by hypertension and proteinuria occurring after 20 weeks of gestation in previously normotensive women. sFlt is toxic to the heart and is therefore a potential cause of PPCM , desmoplakin (DSP) and BAG cochaperone 3 (BAG3) which had not previously been associated with PPCM.Goli et al.  performeTTN mutations, truncations that occur in titin where it binds to the myosin thick filaments in the A band of the sarcomere are most common  encodes a sarcomeric protein, the largest known protein to man , PPCM is a diagnosis of exclusion. Even when the LVEF is < 45%, the left ventricle may not be dilated  failure, the involvement of RV dysfunction has largely been ignored. A search of PubMed revealed at least one report on RV failure by Haghikia et al.  who usedAlthough PPCM was first discovered in the 1800s, our understanding of the underlying aetiology of PPCM remains elusive. We propose that a combined proteomic-transcriptomic approach to examine a large as possible cohort of PPCM patients is required. However, acquiring a large cohort of PPCM tissue samples has been a challenge, due in part to the rarity of the disease. The pooling of existing PPCM samples from international heart tissue banks will yield about 30–40 PPCM patient LV samples, sufficient to establish sample variance and to estimate the number of patients required. Further international collaboration will be needed to substantially increase these numbers. Identifying new sources of PPCM samples will only be useful if the quality of the sample collection and preservation is comparable.Here is what we do. We prepare for collecting a transplanted heart well in advance, so when we are called by the transplant coordinator,In a report of the long-term outcomes for 1,938 PPCM transplant patients and 28 age-match controls, Bouabdallaoui et al.  concludeWe therefore need to look for existing (and future) sources of PPCM transplanted hearts. The registry of the International Society for Heart and Lung Transplantation  tissue. While this is not the ideal source for RNA sequencing because formalin fixation degrades RNA and crosslinks it to its ligands, the 10 × Genomics FFPE Visium slides employ clever chemistry to retrieve and immobilise mRNA and visually connect it to the cells of origin. The current technology has a spatial resolution of 55 µm but in 2022 Visium slides will be released that have a resolution of about 5 µm, sufficient to examine the individual nuclei of human cardiomyocytes see .As a collective, we have agreed to contribute LV and RV tissue samples to undertake RNAseq analysis from PPCM patients and compared them to tissue-type matched healthy female donor hearts provided by the Sydney Heart Bank  provides information about the specific nature and modification status of the proteins , it was the understanding that depletion of myosin cross-bridges in the “super relaxed state”  or a CRISPR-Cas9-generated M-band TTNtv. The amount of truncated TTNtv protein increased in proportional to the inhibition of proteasomal activity. However, in the engineered hiPSC-CMs the depressed contractility due to the TTNtv could be reversed by correcting the mutation using CRISPR-Cas9 which eliminated the truncated TTN and raised the level of wild-type protein, thus restoring function. This exciting paper is more promising than anything reported so far.Then more recently, Fomin et al.  from a lThe authors of this review issue an open invitation to clinical research groups to collaborate with us so we can collaborate by assembling a large cohort of tissue from PPCM to better understanding of why the hearts decline and fail.