Background: Data on the impact of sacubitril/valsartan (SV) therapy on phasic left atrial (LA) and left ventricular (LV) strain in heart failure with reduced ejection fraction (HFrEF) are limited. The aim of this study was to evaluate changes in two-dimensional speckle tracking (2D-STE) parameters with SV therapy in HFrEF patients. Methods: Prospective evaluation of HFrEF patients receiving optimized medical therapy. Two-dimensional speckle tracking (2D-STE) parameters were assessed at baseline and after 6 months of SV therapy. LA strain and strain rate (SR) in reservoir, conduit, and contraction phases were compared with LV longitudinal, radial, and circumferential strain and SR and stratified according to heart rhythm and HFrEF etiology. Results: A total of 35 patients completed the 6-month follow-up, with a mean age of 59 ± 11 years, 40% in atrial fibrillation, 43% with ischemic etiology, and LVEF of 29 ± 6%. There were significant improvements in LA reservoir, conduit, and contractile strain and SR following SV therapy, particularly among patients in sinus rhythm. There were significant improvements in longitudinal, radial, and circumferential LV function indices. Conclusion: SV therapy in HFrEF was associated with improved longitudinal, radial, and circumferential function, particularly among patients in sinus rhythm. These findings can provide insights into the mechanisms underlying the improvement of cardiac function and help assess subclinical responses to the treatment. Sacubitril/valsartan, a neprilysin inhibitor and angiotensin II receptor blocker (ARB) combination, was shown to reduce cardiovascular mortality and heart failure (HF) hospitalization by 20% in comparison to enalapril in the PARADIGM-HF trial , in diffSacubitril/valsartan is currently recommended as a Class I alternative to angiotensin-converting enzyme inhibitors (ACEI) according to the most recent Heart Failure Guidelines for ambulatory patients with HF with reduced ejection fraction (HFrEF)  who contPrevious observational and retrospective studies have demonstrated that sacubitril/valsartan induces early reverse remodeling in HFrEF patients, with a significant reduction in left ventricular (LV) dimensions, improvement in LV ejection fraction (LVEF)—both in patients with nonischemic and ischemic HFrEF—and improvement in diastolic function, systolic pulmonary artery pressure, mitral and tricuspid valve insufficiency ,8,9,10. Two-dimensional (2D) speckle tracking echocardiography (STE) is a novel tool used to assess the mechanical function of the left atrium (LA) and left ventricular (LV). The examination of LA myocardial deformation with longitudinal strain analysis can further detail LA phasic function, with greater sensitivity compared to volumetric measurements . The thrRegional LV mechanics in the longitudinal, radial, and circumferential directions can be accurately analyzed via two-dimensional STE , with suRetrospective studies have demonstrated an improved LV GLS ,20, LA rThe objective of this study was to prospectively assess LA and LV reverse remodeling with strain imaging parameters before and after sacubitril/valsartan therapy in a real-world cohort of chronic HFrEF patients receiving optimal care medication. A sub-analysis regarding cardiac rhythm and heart failure etiology was also outlined.A prospective single-center analysis was performed from October 2017 to June 2018.Ambulatory patients with chronic HF receiving an optimal standard of care therapyW, LVEF ≤40%, and New York Heart Association (NYHA) class II were asked to start sacubitril/valsartan therapy according to the current guidelines .Treatment for at least 6 months with the maximum tolerable doses of an ACEI (or ARB if appropriate), a BB, and an MRA;Implantable cardioverter-defibrillator (ICD) and/or cardiac resynchronization therapy (CRT), if indicated;Adequate care in accordance with appropriate guidelines for mitral regurgitation and coronary artery disease ;No anticipated therapy modifications for the ensuing 6 months;The analysis was conducted prospectively from October 2017 to June 2018, and at that time, recommendations did not consider SGLT2 inhibitors to be a part of optimal HF therapy for non-diabetic patients .The optimized standard of care therapy for chronic HF was defined as: Age under 18 years;Cardiac surgery; ICD/CRT implantation; atrial fibrillation ablation; or percutaneous mitral regurgitation treatment in the previous 6 months;Planned cardiac surgery; ICD/CRT implantation; atrial fibrillation ablation; or percutaneous mitral regurgitation treatment in the following 6 months;Glomerular filtration rate (GFR) < 30 mL/min;Baseline potassium values ≥ 5.5 mEq/L;Child–Pugh class B or C.Every patient signed an informed consent form. Clinical, laboratory, and transthoracic echocardiography data were gathered in the week before starting treatment with sacubitril/valsartan. Sacubitril/valsartan was switched from an ACEI after the recommended 36 h washout time.Sacubitril/valsartan therapy was started at 49/51 mg twice daily or 24/26 mg twice daily in patients receiving a dose of less than 10 mg/day of enalapril or equivalent.With the exception of patients with a systolic blood pressure of less than 100 mmHg, symptomatic hypotension, hyperkalemia greater than 5.5 mEq/L, or a decrease in glomerular filtration rate to less than 60 mL/min as determined by the Cockcroft–Gault equation, the goal was to double the dose every 2 to 4 weeks to reach the target maintenance dose of 97/103 mg twice daily.All patients were reassessed 6 months after starting sacubitril/valsartan, with reassessment including clinical evaluation, laboratory testing, and transthoracic echocardiography.Using a GE Vivid E95 ultrasound system, a full TTE investigation with a frame rate of 50–60 frames/s was carried out at baseline and 6 months after sacubitril/valsartan.Patients were lying in left lateral decubitus, and a 3.5 MHz transducer was used to conduct the investigation. All of the examinations were carried out by two cardiologists with echocardiography experience. Simpson’s biplane method was used to determine LVEF.® .For the assessment, recommendations regarding LAVI, published by The European Association of Cardiovascular Imaging (EACVI), were followed using the biplane algorithm, which incorporates both the four-chamber and two-chamber apical views . PatientOffline analysis of left atrial 2D STE data was conducted according to current recommendations . The regMeasures of LA deformation tracking were carried out using the R wave as a starting point (R-R gating). LA strain and strain rate values were registered in the reservoir, conduit, and contraction phases of the cardiac cycle . ContracSemiautomated speckle-based strain analyses in the conventional three short-axis views  and three apical views  were performed to quantify the 2D LV deformation ,25. The The Statistical Package for the Social Sciences (SPSS), version 23.0 for Windows, was used to conduct the statistical analysis. All mean estimates were shown as point estimates with a 95% confidence interval.Descriptive statistics were reported as absolute frequency (number) and relative frequency for categorical variables (percentage). Continuous variables with normal distribution were presented as mean (and standard deviation), while those with abnormal distribution were presented as median (and interquartile range [IQR]).t-test, and non-normally distributed variables were compared using the Wilcoxon signed-rank test. The Mann–Whitney U test or Student’s t-test were used accordingly to compare continuous variables. Every statistical hypothesis test was performed with a significance threshold of α = 5%. The Kolmogorov–Smirnov test and visual histogram analysis were employed to verify normality. Pearson’s chi-squared test was used to compare categorical variables. Normally distributed variables before and after sacubitril/valsartan therapy were compared using the paired samples t-test. Power and sample size calculations were performed using Stata® Software Package, Version 17.0 .A previous study investigated the impact of sacubitril-valsartan in LA reservoir strain and LV GLS in HFrEF patients . This stUsing a randomly chosen group of 20 patients, the intraobserver and interobserver variability for LA and LV 2D STE measures were evaluated. Measurements were repeated by the same observer after an interval of ≥1 week and by a second independent blinded observer. The intraclass correlation coefficient was used to measure reproducibility, with a good agreement designated as >0.80.A total of 42 patients were enrolled in the trial. Out of these, 35 (83.3%) underwent the six-month follow-up with sacubitril/valsartan. Overall, 5 (11.9%) patients discontinued treatment due to adverse events , and 2 (4.8%) patients died  .The 35 patients successfully completed the six-month follow-up and the baseline characteristics are shown in ®, Abbott Vascular, Chicago, IL, USA).In total, 31.4% were on SGLT2 inhibitors, and 85.6% of patients had an ICD, of which 20% had a CRT-D system. Three (8.6%) of the patients had previously had a transcatheter edge-to-edge mitral valve repair  patients and at 49/51 mg twice daily among 17 (48.6%) patients.At six months, 40.0% were taking 97/103 mg twice daily, 28.6% were taking 24/26 mg twice daily, and 31.4% were taking 49/51 mg twice daily.p = 0.278), the dose of MRA , or the dose of the loop diuretic reported as furosemide equivalents (43.6 ± 27.6% vs. 39.1 ± 26.5%). No variations were found in the potassium levels at the beginning and end of treatment .We discovered no significant differences in the percentage of the target BB dose  improved one NYHA class, and 2 patients (5.7%) improved two classes, with 9 patients (25.7%) remaining in the same class. During the 6 months of sacubitril/valsartan therapy, no declines in NYHA class were observed, and only 3 (8.6%) patients stayed in class III. Only 3 (8.6%) patients experienced a cardiovascular hospitalization during the six-month follow-up period.Atrial fibrillation (AF) was present in 14 (40.0%) patients at the time of the initial evaluation, with paroxysmal AF in 5 (14.3%) and permanent AF in 9 (25.7%) patients. At six months, there were no new cases of AF or catheter ablation in any patients.2, p = 0.004) significantly decreased, despite there being no changes in the E/e’ ratio. Following treatment, there was a significant increase in LVEF , which was significantly higher in patients with a better NYHA class .The outcomes of the TTE analysis are shown in n = 26, 74.3%) were assessed for contractile strain and strain rate. Notably, patients who improved their NYHA class with treatment also experienced a statistically significant improvement in their LA reservoir phase strain  and reservoir strain rate .n = 26, 74.3%). For LA and LV strain measurements, the intraclass correlation coefficient was 0.94 for intraobserver variability and 0.87 for interobserver variability.After 6 months of therapy, GLS, peak systolic longitudinal strain, systolic strain rate, and diastolic strain rates all significantly improved . AdditioThe baseline variations in the TTE parameters between patients with sinus rhythm and those with atrial fibrillation are illustrated in Sacubitril/valsartan treatment improved the GLS, peak LV longitudinal strain, longitudinal systolic, and early diastolic strain rates in patients with sinus rhythm, while only peak longitudinal strain and early diastolic strain rate were significantly improved in patients in AF.Peak LV radial strain significantly improved in both groups. However, systolic and early diastolic strain rates were improved only among patients in sinus rhythm. Only patients in sinus rhythm experienced an improvement in circumferential LV strain and strain rates . AdditioOur study’s key conclusion was that, after 6 months of sacubitril/valsartan therapy, patients with HFrEF demonstrated improvements in LA phasic strain, strain rates, and LV deformation indices, including longitudinal, radial, and circumferential strain and strain rates, particularly among patients in sinus rhythm, and independently of the cause of HFrEF. Our study also provided a summary of the individual phasic atrial function parameters as well as longitudinal, radial, and circumferential LV function STE parameters, stratifying them according to heart rhythm and HFrEF etiology, and evaluating their changes with sacubitril/valsartan treatment.We believe that this is the first prospective study to evaluate the effects of sacubitril/valsartan on LA strain assessment in the various cardiac cycle phases, LV radial and circumferential strain, and longitudinal, radial, and circumferential systolic and diastolic strain rates. Sacubitril/valsartan therapy improved LVEF, GLS, and the majority of the STE LA and LV strain parameters in a group of highly symptomatic chronic HFrEF patients, as indicated by a NYHA class of at least III in 51.4% (compared to only 23.9% in the PARADIGM-HF) and by 42.9% experiencing hospitalizations due to worsening heart failure in the previous year.The assessment of LA strain and strain rate with 2D STE has been increasingly used for an objective evaluation of LA function , as well as the assessment of LV diastolic function and the early detection of atrial dysfunction with prognostic significance in various pathological entities ,28. NotaOur results demonstrate a significant improvement in LA deformation with treatment in HFrEF patients with sinus rhythm and show a near-significant trend in patients with AF. Notably, patients in sinus rhythm showed a statistically significant improvement in LA reservoir strain compared to patients with atrial fibrillation (AF). This finding would be in keeping with the atrial structural remodeling and development of fibrosis in long-standing AF , particuAlthough it is not currently as widely accepted, the evaluation of contractile phase strain (booster pump function) has been suggested as an alternative to the reservoir function . It demoPrior research has demonstrated that sacubitril/valsartan promotes early LV reverse remodeling in chronic HFrEF patients via TTE examination ,8,34, inThis is consistent with recent research which shows that sacubitril/valsartan therapy in HFrEF could induce a chronic and progressive LV unloading state that would relieve myocardial wall tensions and lower LV end-diastolic pressure, leading to cardiac reverse remodeling and restoration of the Frank–Starling mechanism of the LV myocardium, resulting in an increased LVEF . HoweverAdditionally, our findings suggest that STE parameters can be utilized as a helpful tool to assess the subclinical response to sacubitril/valsartan therapy and possibly serve as a guide for treatment in patients with HFrEF . HoweverIt is important to recognize that our study has limitations. First of all, this was a prospective study that enrolled participants in a single center, and our findings need to be confirmed in more centers to be properly validated. Second, our study revealed encouraging outcomes on LA and LV strain after 6 months of therapy with sacubitril/valsartan, despite a small sample size. For a precise head-to-head comparison of the subgroups, specifically individuals with sinus rhythm versus individuals in AF and nonischemic HFrEF patients versus ischemic HFrEF patients, these findings would need be validated in larger trials. Thus, caution is required in the interpretation of our study’s results. Third, despite being a prospective study, the results were compared between baseline and after 6 months of sacubitril/valsartan therapy without a control group that would continue ACEI or ARB therapy. However, after the results of the PARADIGM-HF trial , it woulIn a small prospective trial, sacubitril/valsartan therapy in HFrEF patients was associated with improved cardiac performance as measured by LA phasic strain and strain rates as well as longitudinal, radial, and circumferential LV strain and strain rates, especially among patients in sinus rhythm. However, further studies are needed to investigate the impact of sacubitril/valsartan therapy among HFrEF patients. These findings may help in understanding the mechanisms underlying the improvement in cardiac function following sacubitril/valsartan therapy and gauge the treatment’s subclinical response.


Modeling the whole cardiac function involves the solution of several complex multi-physics and multi-scale models that are highly computationally demanding, which call for simpler yet accurate, high-performance computational tools. Despite the efforts made by several research groups, no software for whole-heart fully-coupled cardiac simulations in the scientific community has reached full maturity yet.in silico experiments easily reproducible and accessible to a wide community of users, including those with a background in medicine or bio-engineering.In this work we present The tool presented in this document is intended to provide the scientific community with a computational tool that incorporates general state of the art models and solvers for simulating the cardiac function within a high-performance framework that exposes a user- and developer-friendly interface. This report comes with an extensive technical and mathematical documentation to welcome new users to the core structure of  For this reason, it is still among the most arduous modeling and computational challenges in a field where ehaviors .ten Tusscher–Panfilov [Courtemanche-Ramirez-Nattel [A satisfactorily accurate model for the whole cardiac function must be able to describe a wide range of different processes, such as: the propagation of the trans-membrane potential and the flow of ionic species in the myocardium, the deformation caused by the muscle contraction, the dynamics of the blood flow through the heart chambers and cardiac valves . In partPanfilov  and the z-Nattel  ionic moThese demanding aspects make whole-heart fully-coupled simulations computationally intensive and call for simpler yet accurate, high-performance computational tools.https://wiki.u-gov.it/confluence/display/SCAIUS/UG3.3%3A+GALILEO100+UserGuide for more technical specifications).In this work we introduce nt}lifex , an openmentclass2pt{minimDespite being conceived as an academic research library in the framework of the iHEART project (see Section “Funding”), Since its initial development, erfusion , as dispmentclass2pt{minimerfusion , 10–17).As the present release focuses on modeling the cardiac fibers, in the next two paragraphs we will briefly review the physiology of myofibers and the most used mathematical methods to model them, describing in detail their implementation which is included within The heart is a four chambers muscular organ whose function is to pump the blood throughout the whole circulatory system. The upper chambers, the right and left atria, receive incoming blood. The lower chambers, the right and left ventricles, pump blood out of the heart and are more muscular than atria. The left heart (i.e. left atrium and left ventricle) pumps the oxygenated blood through the systemic circulation, meanwhile the right heart (i.e. right atrium and right ventricle) recycles the deoxygenated blood through the pulmonary circulation , 2. The endocardium, the external thin epicardium and the thick muscular cardiac tissue, the myocardium. Most of the myocardium is occupied by cardiomyocytes, striated excitable muscle cells that are joined together in linear arrays. The result of cluster cardiomyocytes, locally organized as composite laminar sheets, defines the orientation of muscular fibers . Aggregations of myofibers give rise to the fiber-reinforced heart structure defining the cardiac muscular architecture [The heart wall is made up of three layers: the internal thin itecture , 19.Fig.helical and the sheet angles, respectively [A schematic representation of the multiscale myocardial fiber-structure is shown in Fig. ectively , 22. Theocardium , 21.Atrial fibers architecture is very different from that of the ventricles, where myofibers are aligned in a regular pattern . Indeed,The cardiac muscular fiber architecture is the backbone of a proper pumping function and has a strong influence on the electric signal propagation throughout the myocardium and also on the mechanical contraction of the muscle –29. ThisDue to the difficulty of reconstructing cardiac fibers from medical imaging, different methodologies have been proposed to provide a realistic surrogate of myofibers orientation , 31–39. Alternative strategies for generating myofiber orientations are the Rule-Based Methods (RBMs) , 40–42. A particular class of RBMs, which relies on the solution of Laplace boundary-value problems, is known as Laplace-Dirichlet Rule-Based Methods (LDRBMs), addressed in –33 and rThis initial release includes a generator for myocardial fibers based on LDRBMs , with apIn this section, we briefly recall the LDRBMs that stand behind the myocardial fiber generation. In Section “Results and discussion” we will present several examples where we elaborate on how to reproduce and run the algorithms presented hereafter.getting started guide presents LDRBMs for  slabs, (based and complete) left ventricular and left atrial geometries. For further details about the LDRBMs presented here see also [This see also .1. Labeled mesh:A labeled volumetric mesh of the domain h format , see Figentclass1pt{minimaThe following common steps are the building blocks of all LDRBMs. Epicardium and endocardium:for the ventricular slab geometry Basal plane and apex:for the ventricular slab geometry see Fig. a; for thsee Fig. b; for thsee Fig. d, whereasee Fig. e; for thsee Fig. d, e; forsee Fig. c–f;Atrial pulmonary rings:the atrial geometry type also requires the definition of the boundary labels for the left 2. Transmural direction:A transmural distance 3. Normal direction:A normal  direction Rossi-Lassila (RL) et al. approach : \documeBayer-Trayanova (BT) et al. approach : \documew: w is obtained by solving: Doste et al. approach : \documeentclass1pt{minimaPiersanti et al. approach : for eacentclass1pt{minimaThe BT approach is used in the ventricular and spherical slab geometry types, see also Fig. 4. Local coordinate system:For each point of the domain an orthonormal local coordinate axial system is defined by 5. Axis rotation:The reference frame is rotated with the purpose of defining the myofibers orientation: In order to represent the fiber architecture, LDRBMs use the gradient of specific intra-chamber distances, by means of harmonic problems, combined with a precise definition of boundary sections where boundary conditions are prescribed. This strategy makes the fibers less open to subjective variability. On the other hand, the myofiber orientations could be adapted to a patient-specific setting by simply changing the parameters involved in LDRBMs  with The third-party software bundled with (in binary form), required by, copied, modified or explicitly used in packages :\documenThe libraries listed above are all free software and, as such, they place few restrictions on their use. However, different terms may hold. Please refer to the content of the folder doc/licenses/ for more information on license and copyright statements for these packages.Finally, an MPI installation  any The following steps are required in order to run the https://doi.org/10.5281/zenodo.5810268. After extracting the archive, the AppImage file should be made executable by typing the following command in a terminal:The Finally, lifex_fiber_generation-1.4.0-x86_64.AppImage can be executed with:not required. Please note that, in order for the above procedure to succeed, AppImage relies upon the userspace filesystem framework FUSERoot permissions are We also refer the reader to the AppImage troubleshooting guide.47Each o be run . They inIn case an application has sub-dependencies (such as a linear solver), also the related parameters are included .Every application comes with a set of command line options, which can be printed using the -h (or –help) flag:The first step before running an executable is to generate the parameter file(s) containing all the default parameter values. This is done via the -g (or –generate-params) flag:that by default generates a parameter file named after the executable, in .prm format.standard are printed. The parameter file verbosity can be decreased or increased by passing an optional flag minimal or full to the -g flag, respectively:By default, only parameters considered The parameter basename to generate can be customized with the -f (or –params-filename) option:Absolute or relative paths can be specified.At user’s option, in order to guarantee a flexible interface to external file processing tools, the parameter file extension ext can be chosen among three different interchangeable file formats prm, json or xml, from the most human-readable to the most machine-readable.As an example, the three parameter files displayed in Listings 1, 2 and 3 are semantically equivalent.pattern description);a given pattern, specifying the parameter type  and, whenever relevant, a range of admissible values , e.g.:The executable can be run by simply omitting the -g, whereas the -f option is used to specify the parameter file to be If no -f flag is provided, a file named executable_name.prm is assumed to be available in the directory where the executable is run from.The path to the directory where all the app output files will be saved to can be selected via the -o (or –output-directory) flag:If the specified directory does not already exist, it will be created. By default, the current working directory is used.Absolute or relative paths can be specified for both the input parameter file and the output directory.Parallel run In order to run an app in parallel, the mpirun or mpiexec wrapper commands (which may vary depending on the MPI implementation available on your machine) should be prepended, e.g.:where <N_PROCS> is the desired number of parallel processes to run on.As a rule of thumb, 10,000 to 100,000 degrees of freedom per process should lead to the best performance.Dry run and parameter file conversion Upon running, a parameter log file is automatically generated in the output directory, that can be used later to retrieve which parameters had been used for a specific run.By default, log_params.ext will be used as its filename. This can be changed via the -l (or –log-file) flag, e.g.:The file extension is not mandatory: if unspecified, the same extension as the input parameter file will be used.dry run option is enabled via the -d (or –dry-run) flag, the execution terminates right after the parameter log file generation. This has a two-fold purpose: before running the actual simulation (if any of the parameters does not match the specified pattern or has a wrong name or has not been declared in a given subsection then a runtime exception is thrown);checking the correctness of the parameters being declared and parsed converting a parameter file between two different formats/extensions. For example, the following command converts input.xml tooutput.json:If the The LDRBMs described in Section “Laplace-Dirichlet rule-based methods” have been applied to a set of idealized or realistic test cases, namely ventricular and spherical slabs, based and complete left ventricular and left atrial geometries.setting up input data ;setting up the parameter files associated with a given simulation scenario and running the corresponding simulation;post-processing the solution and visualizing the output.A mesh sensitivity analysis has been performed and reported in Section “Mesh sensitivity and validation”.This section presents the results obtained, as well as a possible pipeline for reproducing such test cases, consisting of the following steps: https://doi.org/10.5281/zenodo.5810268.Additional input data  associated with the guided examples described below can be downloaded from the release archive getting started guide, we provide different ready-to-use meshes, namelya set of four idealized geometries consisting of a ventricular slab, a spherical slab, an idealized based left ventricle and an idealized left atrium, see Fig. two realistic geometries composed by a left ventricle and a left atrium, see Fig. The idealized meshes have been generated using the built-in CAD engine of gmsh, an open-source 3D FE mesh generator, starting from the corresponding gmsh geometrical models  defined using their boundary representation, where a volume is bounded by a set of surfaces. For details about the geometrical definition of a model geometry we refer to the online documentation of gmsh.49In this In order to perform the mesh generation, starting from the geometrical files provided in this tutorial, the following command can be run in a terminal:where geometry.geo is the geometrical file model, mesh.msh is the output mesh file, which will be provided as an input to the The realistic left ventricle and left atrium have been produced starting from the open-source meshes adopted in  for the and in  for the and usinAll the characteristic informations of the ready-to-use meshes, above described, are reported in Table Parameter files for fiber generation are characterized by a common section named Mesh and space discretization. Select Element type = Tet for tetrahedral meshes or Element type = Hex for hexahedral meshes. Finally, specify in FE space degree the degree of the (piecewise continuous) polynomial FE space used to solve the LD problems described above. Finally, we remark that The Geometry type parameters enables to specify the kind of geometry provided in input, in order to apply the proper LDRBM algorithm among the ones described above. Once specified, parameters related to the specific algorithm and geometry will be parsed from a subsection named after the value of Geometry type.All parameters missing from the parameter file will take their default value, which is hard-coded.The parameter Geometry type = Slab must be set to prescribe fibers in slab geometries and the path of the input mesh file in Filename.Ventricular slab For a ventricular slab geometry the user should set Sphere slab = false. Labels for the top (Tags base up) and bottom (Tags base down) surfaces of the slab, as well as for the epicardium (Tags epi) and endocardium (Tags endo) must be prescribed. Finally, the helical and sheetlet rotation angles at the epicardium and endocardium must be provided in the corresponding alpha epi, alpha endo, beta epi, beta endo parameters.Spherical slab For a spherical slab geometry the user should set Sphere slab = true. The epicardial coordinates  of the north (North pole) and south (South pole) poles of the sphere of the slab, and the labels of the endocardium (Tags endo) and epicardium (Tags epi) must be prescribed. Finally, the helical and sheetlet rotation angles at the epicardium and endocardium must be provided in the alpha epi, alpha endo, beta epi, beta endo parameters. A fiber architecture for the sphere slab with radial fiber The parameter Geometry type = Left ventricle (Left ventricle complete) prescribes fibers in a based (complete) left ventricular geometry. Other mesh-related parameters have the same meaning as described above.Based left ventricle The parameters needed are the labels for the basal plane (Tags base), the epicardium (Tags epi) and endocardium (Tags endo) of the ventricle. The RL or BT approach can be toggled via Algorithm type. The helical and sheetlet rotation angles at the epicardium and endocardium must be prescribed in alpha epi, alpha endo, beta epi, beta endo. Finally, for the RL approach the outward normal vector to the basal plane must be specified in Normal to base, whereas for the BT approach the apex epicardial coordinates  (Apex) of the ventricle is needed.Selecting the RL approach as Algorithm type, this setup can be also exploited in bi-ventricular geometries (not included in the example meshes). In this case, the mesh must have two additional surface labels in the right ventricular endocardium: one delimiting the part facing to the septum (e.g. 15) and the other for the remaining part (e.g. 25). In this way, it is sufficient to set Tags endo as the two endocardial labels (excluding the right septum) and Tags epi as the epicardial label and the right endocardial septum label. Further detail on this approach can be found in .Complete left ventricle The labels for the mitral (Tags MV) and aortic (Tags AV) valve rings, the epicardium (Tags epi) and endocardium (Tags endo) of the ventricle are required. The apex epicardial coordinates  must be set in Apex. Finally, the helical and sheetlet rotation angles at the epicardium and endocardium must be prescribed in alpha epi, alpha endo, beta epi, beta endo. A specific helical and sheetlet rotation angles around the outflow tract of the left ventricle  can be specified by setting alpha epi OT, alpha endo OT, beta epi OT, beta endo OT.Fibers in a left atrial geometry can be generated by setting Geometry type = Left atrium. Other mesh-related parameters have the same meaning as described above.Idealized left atrium The parameter Appendage = false prescribes fibers in the hollow sphere geometry. The labels for the mitral valve ring (Tags MV), the right (Tags RPV) and left (Tags LPV) pulmonary veins rings, the epicardium (Tags epi) and endocardium (Tags endo) of the idealized atrium must be provided. Finally, the dimension of each atrial bundle is needed: Tau bundle MV for the mitral valve bundle; Tau bundle LPV and Tau bundle RPV for the left and right pulmonary valves ring bundles.Realistic left atrium The parameter Appendage = true prescribes fibers in a realistic left atrial geometry. The user should provide labels for the mitral valve ring (Tags MV), the right (Tags RPV) and left (Tags LPV) pulmonary veins rings, the epicardium (Tags epi) and endocardium (Tags endo) of the idealized atrium. The epicardial coordinates  for the apex of the atrial appendage must be provided in Apex. Finally, the dimension of each atrial bundle is needed: for the mitral valve bundle Tau bundle MV; for the left and right pulmonary valves rings bundle Tau bundle LPV and Tau bundle RPV, respectively.To enable the output the user should set Enable output = true and specify the corresponding output filename in Filename. This will produce a XDMF schema file named output_filename.xdmf (wrapped around a same-named HDF5 output file output_filename.h5) that can be visualized in ParaView,Moreover, the HDF5 file format guarantees that the output can easily be further post-processed, not only for visualization purposes but rather to be fed as an input to more sophisticated computational pipelines.The robustness of the algorithms presented above is confirmed by performing a mesh sensitivity analysis. Specifically, we consider the ventricular slab geometry shown in Fig. As the fibers field is orthonormalized, the difference between two numerical solutions is only due to the orientation angle. This allows us to define an error estimate as:We show the error distribution in the whole domain in Fig. on angle .The interest of accurately reconstructing a fiber orientation field consists of providing it as an input to more sophisticated computational models, such as for cardiac electrophysiology and electromechanics. As the dynamics of such physical models demands for a high resolution in both time and space , 17, 53,The proposed LDRBMs have been validated in , where tFurthermore, the anisotropic nature of the fiber orientation strongly influences the electrophysiological, mechanical, and electromechanical cardiac function. Therefore, an indirect way to validate the fiber field provided by LDRBMs is to compute quantitative indices or biomarkers in such kind of simulations.Matching quantitative indices in a physiological range is only possible when the fiber reconstruction algorithm is accurate enough: this is shown in  for the heart modules for the simulation of cardiac electrophysiology, mechanics, electromechanics, and blood fluid dynamics models.As anticipated in Section ”Background”, more modules will be successively published in binary form, starting from an advanced solver for cardiac electrophysiology, blood fluid dynamics and other solvers for the cardiac function;in the meantime, the source code associated with previous binary releases will be gradually made publicly available under an open-source license.In the long run, also modules unrelated to the cardiac function are expected to be included within In the near future, the deployment of in silico experiments for the whole-heart cardiac function, boosting both the user and developer experience without sacrificing its computational efficiency and universality.in silico scenario analyses of myofibers orientation; such a tool supports either idealized and realistic, (left) ventricular and atrial geometries. It also offers a seamless integration of LDRBMs into more sophisticated computational pipelines involving other core models – such as electrophysiology, mechanics and electromechanics – for the cardiac function, in a wide range of settings covering from single-chamber to whole-heart simulations.We believe that the release of https://lifex.gitlab.io/heart.html: we encourage users to interact with the The content of this initial release is published on the official website https://lifex.gitlab.io/.News and announcements about Project name: Project home page: https://lifex.gitlab.io/heart.htmlOperating system(s): Linux (x86-64)Programming language: C++Other requirements: glibc version 2.28 or higherLicense: CC BY-NC-ND 4.0Any restrictions to use by non-academics: no additional restriction.


Mitral valve prolapse (MVP) is a prevalent cardiac disorder that impacts approximately 2% to 3% of the overall population. While most patients experience a benign clinical course, there is evidence suggesting that a subgroup of MVP patients face an increased risk of sudden cardiac death (SCD). Although a conclusive causal link between MVP and SCD remains to be firmly established, various factors have been associated with arrhythmic mitral valve prolapse (AMVP). This study aims to provide a comprehensive review encompassing the historical background, epidemiology, pathology, clinical manifestations, electrocardiogram (ECG) findings, and treatment of AMVP patients. A key focus is on utilizing multimodal imaging techniques to accurately diagnose AMVP and to highlight the role of mitral annular disjunction (MAD) in AMVP. Mitral valve prolapse (MVP) is a prevalent cardiac disorder that impacts approximately 2% to 3% of the overall population, with a similar prevalence in males and females ,2,3. It MVP can lead to serious complications such as significant mitral regurgitation (MR), atrial fibrillation, bacterial endocarditis, congestive heart failure, stroke, ventricular arrhythmia (VA), and even sudden cardiac death (SCD) ,11,12,13As a result, the term “arrhythmic mitral valve prolapse (AMVP)” has been introduced, sparking a debate about its definition and clinical significance in terms of diagnosis, risk stratification, and treatment ,15. At tThis review provides a comprehensive overview of the historical background, epidemiology, pathology, clinical manifestations, characteristics of electrocardiogram (ECG), and mechanism of VA occurrence concerning AMVP. Moreover, we delve into the imaging diagnosis of AMVP, highlighting the distinctive echocardiography, computed tomography (CT), and cardiac magnetic resonance (CMR) characteristics while also summarizing the associated risks of each imaging technique. By carefully assessing these risks, we aim to present diagnostic tools that could be used in risk stratification for the better management and prevention of MVP-related SCD.EHRA expert consensus statement on arrhythmic mitral valve prolapse and mitral annular disjunction complex states that the diagnostic requirements for AMVP are the presence of MVP ), combined with frequent  burden) and/or complex VA (ventricular tachycardia (VT), non-sustained ventricular tachycardia (NSVT) and ventricular fibrillation (VF)), in the absence of any other definitive arrhythmic substrate  × 100. It quantifies the degree of myocardial shortening that occurs after the peak systolic strain during the cardiac cycle. It has been reported that post-systolic shortening in two or more myocardial segments could be associated with increased mortality and morbidity . In a reTTE and TEE are routine tools in practice ,72. NoneCMR is a non-invasive imaging technique with unlimited imaging planes, which can provide reproducible quantitative data on cardiac structure and function ,88.CMR allows for precise measurements of the left ventricular mass and end-diastolic thickness. This encompasses gauging the ratio of the basal-to-mid left ventricular wall thickness, identifying MAD and systolic curling (presence or absence) and quantifying it, measuring the mitral valve leaflet length, leaflet diastolic thickness, annulus diameter , and prolapse distance ,90 Figu.More importantly, CMR can help determine the myocardial composition and identify VAs’ specific risk factors, assess myocardial fibrosis/scar, describe its location, and quantify it . Late gaHan et al.  first exFollowing their identification of fibrotic changes through post-mortem examinations, Basso et al. hypothesized that these alterations could be discerned in vivo through CMR. They performed CMR and histopathological examinations on a group of 43 instances of SCD involving young patients with MVP. The results indicated the presence of PM fibrosis (88%) or inferobasal fibrosis (93%). LGE distribution on CMR exhibited heightened gadolinium in pathological tissue relative to healthy tissue, which is associated with histopathological fibrosis .This insight was validated in another 3680 autopsy patients, 62 of whom were MVP (1.7%), 74% of whom had myocardial fibrosis involving one or both PMs  and the adjacent left ventricular wall  .Another study found that compared with non-MVP-related MR, CMR in MVP patients showed significant left ventricular fibrosis, and the left ventricular fibrosis increased with the severity of MR, which tended to localize in specific regions of the LV and was associated with sustained VT or VF. Among them, the incidence of left ventricular fibrosis was 36.7% in MVP patients and only 6.7% in non-MVP patients. In addition, fibrotic myocardium was most commonly found in the inferior basal wall in MVP patients (31.1%). This suggests that there is a unique pathophysiology in MVP patients beyond volume overload. Left ventricular fibrosis, in the case of primary MR, could potentially serve as an indicator of heightened risks for arrhythmic events .The EHRA expert consensus has concluded that CMR should be performed in all individuals who have experienced sustained VAs or survived SCD before the implantation of an ICD . This isTo date, only a limited number of studies have evaluated the diagnostic accuracy of CT for MVP ,97. CT iAlthough cardiac CT demonstrates outstanding diagnostic accuracy in identifying the presence of MVP in patients, the limitations of cardiac CT for mitral MVP assessment include concerns about radiation exposure, a suboptimal temporal resolution, and a constrained capability to thoroughly examine each leaflet .MAD occurrence is associated with the presence of advanced myxomatous disease, which is characterized by significant leaflet redundancy and BiMVP. MAD causes annulus and left ventricular de-anchoring , leadingAccording to Maurice Enriquez-Sarano , MAD canAt present, the definition of MAD has not yet determined the threshold, and the threshold is set arbitrarily in most studies ,38,41. FRisk stratification in MVP is a complex task due to the absence of a single risk factor that reliably predicts malignant VAs and SCD. Furthermore, the combination of risk factors that elevate the risk in MVP patients remains unclear. This presents the challenge of identifying high-risk individuals within a larger population of low-risk patients . MultiplThe EHRA expert consensus classifies MVP-related VAs into low, intermediate, and high-risk groups, which are aligned with a broader classification of VAs . As VAs According to the EHRA expert consensus , there aAMVP patients are typically prescribed the same medications for VAs as other patients, such as calcium channel blockers, β blockers, and other antiarrhythmic drugs . HoweverCatheter ablation is an effective method for treating scar-related malignant arrhythmias ,111. PVCThe current evidence is insufficient to support prophylactic ICD implantation in individuals at high risk of MVP-related SCD. Some experts have suggested using electrophysiology studies for risk stratification in AMVP patients, and if sustained VT is present, ICD implantation is recommended for primary prevention .Before the use of antiarrhythmic drugs, catheter ablation, and ICD, several small data studies have suggested that AMVP could be treated surgically with a lower rate of postoperative arrhythmias and antiarrhythmic drug discontinuation or reduction, even in the absence of significant MR ,113.Making treatment choices for AMVP must prioritize an individualized approach, considering the patient’s specific clinical characteristics and consultation with a healthcare professional experienced in managing MVP and arrhythmias. Further research is needed to establish more robust guidelines for the management of AMVP.This review suggests that AMVP constitutes a noteworthy factor contributing to SCD. The risk factors associated with SCD in the context of AMVP encompass anomalies and detected abnormalities in electrocardiography , morphological patterns on TTE , as well as LGE on CMR, which offer potential avenues for the initial risk stratification among individuals diagnosed with MVP. Subsequent prospective investigations could be undertaken to validate and incorporate established parameters that assist in identifying MVP patients with an elevated susceptibility to encounter VAs and SCD, potentially proving advantageous for the implementation of primary prevention therapies.


CVs were highest in the left atrium (LA), followed by the left ventricle (LV), right ventricle (RV), and right atrium (RA). As for VA, LV was highest, followed by RV, LA, and RA. The left chambers had a higher overall CV and VA than the right. Within the chambers, CV varied more in the right than in the left chambers, and VA varied in the ventricles but not in the atria. There was a slightly positive correlation between CVs and VAs at velocity values of <1.5 m/s. Conclusions: In healthy porcine hearts, the left chambers showed higher VAs and CVs than the right. CV differs mainly within the right chambers and VA differs only within the ventricles. A slightly positive linear correlation was found between slow CVs and low VAs.Background: Ultra-high-density mapping systems allow more precise measurement of the heart chambers at corresponding conduction velocities (CVs) and voltage amplitudes (VAs). Our aim for this study was to define and compare a basic value set for unipolar CV and VA in all four heart chambers and their separate walls in healthy, juvenile porcine hearts using ultra-high-density mapping. Methods: We used the Rhythmia Mapping System to create electroanatomical maps of four pig hearts in sinus rhythm. CVs and VAs were calculated for chambers and wall segments with overlapping circular areas (radius of 5 mm). Results: We analysed 21 maps with a resolution of 1.4 points/mm Cardiac arrhythmias are a disruption of the normal cardiac rhythm and can range from simple changes in heart rate to complex fibrillation events. They may result in various clinical symptoms, from reduced physical resilience to sudden cardiac arrests . Atrial Re-entry mechanisms cause many cardiac arrhythmias. The zones of slow conduction play a key role in developing and maintaining reentrant tachycardias ,3,4,5. TUntil recently, there have been few, mostly incomplete data on conduction velocities in healthy hearts.Hansson et al. collected data from the right atrial wall with an epicardial electrode array . Martin None of these studies provided an overall approach with reference values or comparisons between physiological conduction velocity and voltage amplitude in all four heart chambers. Characterizing normal heart electrical physiology is crucial to distinguish between physiological and diseased patterns.In this study, we aimed to define and compare a basic value set for unipolar conduction velocities and voltage amplitudes in all four heart chambers and their separate walls in healthy, in vivo porcine hearts using ultra-high-density mapping. In addition, we analysed whether conduction velocity and voltage amplitude are correlated in healthy hearts. Our velocity calculations for the three-dimensional myocardial surface were based on overlapping circular areas.Experimental data were collected from four juvenile healthy swine , 3–4 months old), two of which were female (pigs 3 and 4). The study was approved by the government of Bavaria (ROB-55.2-2532.Vet_02-1 7-174).Electrophysiological studies were performed in vivo under general anaesthesia and mechanical ventilation during intrinsic sinus rhythm. Sedation was administered intramuscularly with ketamine 10–15 mg/kg), azaperone (2 mg/kg), and atropine (1 mg). Anaesthesia was introduced with 1% and maintenance with 2% propofol i.v. We administered acetylsalicylic acid (250 mg i.v.) and heparin (150 IE/kg i.v. as a bolus and 200 IU/mL i.v. as continuous drip infusion depending on activated clotting time) for intraoperative anticoagulation after the sheath was placed. Intraoperative analgesia was provided by fentanyl boluses (0.015 mg/kg i.v.) every 20–30 min, and metamizole (40–50 mg/kg i.v.) was administered before the first incision. Transvenous catheters were inserted under fluoroscopic guidance. Access to the left heart was gained via a transseptal approach. Electroanatomical mapping was performed during sinus rhythm using Rhythmia, an ultra-high-density mapping system , and its proprietary, 64-lead, multi-electrode basket mapping catheter Intellamap Orion . The sedation dosage was constant throughout the whole period of mapping to ensure comparable conditions between the different maps. The catheter is bidirectionally steerable and consists of eight splines, each containing eight electrodes spaced 2.5 mm apart [–15 mg/kgAfter completing the electrophysiological studies, the annotated beats were manually checked for plausibility and, if necessary, reannotated in Rhythmia to specifically ensure that no His–Purkinje-system signals were falsely annotated. Transitions to other cardiac chambers, arteries, and veins were identified based on the morphology and amplitude of electrograms and marked as cutouts blue in . The meaTo compute local conduction velocities and voltage amplitudes from the measured activation times while considering the variability of wavefront directions, we defined circular areas with an approximately 5 mm radius on the map surfaces and left out the cutouts. We used spherical filters from ParaView  to create circular areas on the curved heart surface ,12, as sThe mean voltage amplitude and conduction velocity of the covered map surface were calculated for each sphere. We divided the theoretical circle diameter, determined from the actual circular surface area, by the time difference between the first and last activations in each area to calculate conduction velocity, as seen in (1).All values and metadata were calculated and exported from ParaView using a custom-written Python script.Statistical analysis was performed using the statistical programming language R, v4.1.2 .The relationship between conduction velocity and voltage amplitude, respectively, with the two factors mapping location and heart rate, was investigated by means of linear mixed effects analysis using lme4 ,15 sinceWe used the lmerTest ,17 and ep-value). Correlations were tested via Pearson’s correlation coefficient, reported in the format (r (degrees of freedom) = r-statistic, p = p-value). Velocity values of >6 m/s were defined as outliers and ignored in the calculations. The p-values of <0.05 were considered significant. Measured amplitude values are reported as unipolar signals.Post hoc test results are reported on the original scale. All estimated values are provided for a heart rate of 90 bpm. Estimates are reported in the format  or voltage amplitude (p = 0.30).Since the study was performed on two male and two female pigs, we performed a linear mixed-effects analysis to test whether sex affected conduction velocity and voltage amplitude. In our study, sex had no influence on conduction velocity  (0.79 ± 0.05 m/s), followed by the left ventricle (LV) (0.59 ± 0.04 m/s), the right ventricle (RV) (0.54 ± 0.03 m/s), and the right atrium (RA) (0.50 ± 0.03 m/s).The overall unipolar voltage amplitude at a heart rate of 90 bpm is highest in the LV (10.98 ± 0.34 mV), followed by the RV (7.83 ± 0.32 mV), LA (4.81 ± 0.35 mV), and RA (3.35 ± 0.31 mV) .p < 0.001) and has a lower voltage amplitude  than the LA. By contrast, the voltage amplitude is higher in the LV than in the RV , and no significant difference in conduction velocity was observed between the ventricles . We found no significant difference in conduction velocity between RA and RV. Voltage amplitudes were generally lower in the atria than in the ventricles (p < 0.001)  .Each heart chamber was divided into subregions representing different walls. The following conduction velocity and voltage amplitude estimates are normalized to a heart rate of 90 bpm.p < 0.044), lateral , and septal walls . In the RV, the anterior wall (0.44 ± 0.04 m/s) showed the lowest conduction velocity and was significantly different from the posterior , lateral , and septal walls . All other walls within these right heart chambers did not differ significantly.In the RA, the conduction velocity was highest in the posterior wall (0.61 ± 0.04 m/s), compared to the superior . We did not find any significant difference in conduction velocity between any other regions of the LA and LV  and was significantly faster than the anterior wall, which had the slowest conduction velocity .The RV had high voltage amplitudes at the posterior (9.59 ± 0.52 mV) and septal walls (10.64 ± 0.52 mV), which were significantly higher than at the anterior (5.95 ± 0.52 mV) and lateral (6.73 ± 0.54 mV) walls (p < 0.001). The lateral wall (13.48 ± 0.61 mV) had the highest voltage amplitude   had the lowest voltage amplitude and was significantly different from any other (< 0.001) .p = 0.008) was observed (|r| < 0.2).No general linear correlation between voltage amplitude and conduction velocity (r(2736) = 0.05, p < 0.001) for the LA. In the other heart chambers, no linear correlation was observed (RA r(1252) = 0.11, p < 0.001; LV r(496) = 0.09, p = 0.053; RV r(574) = −0.07, p = 0.114)  = 0.30, = 0.114) .p < 0.001), LV (r(424) = 0.23, p < 0.001), and RA (r(1105) = 0.25, p < 0.001). No correlation was found in the RV (r(496) = −0.09, p = 0.05).At velocities of <1.5 m/s, a low positive linear correlation between voltage amplitude and conduction velocity was observed in the LA (r(310) = 0.47, To our knowledge, the current study is the first to use an ultra-high-density mapping system to systematically analyse intrinsic conduction velocities and voltage amplitudes in healthy pig hearts.Our first key finding was that the highest conduction velocity of the heart chambers was found in the LA, whereas the highest amplitudes were measured in the LV. The left heart chambers showed higher voltage amplitudes and conduction velocities than their right counterparts. One explanation might be that a high conduction velocity in the left heart chambers is crucial to ensuring a synchronized electrical excitation of the chambers because of their larger size and greater myocardial mass . As gap Our second key finding was that within one heart chamber, conduction velocity varied more in the right heart chamber than in the left. In the RA, the posterior wall showed higher conduction velocities than the septal, lateral, and superior wall segments. In the RV, the anterior wall showed lower conduction velocities than the lateral, posterior, and septal wall segments. Within the LA, only the superior and anterior walls differed significantly, with the superior wall conducting the fastest. We interpret this finding as a measurement of the fast-conducting Bachmann bundle, which confirms the validity of our data ,21. The Our third key finding was that there was no significant difference in voltage amplitude within the atria, except for one within the ventricles. In the RV, the posterior and septal walls showed higher voltage amplitudes than the anterior and lateral walls. In the LV, the lateral wall showed the highest voltage amplitude, whereas the posterior wall showed the lowest. The amplitudes in all segments of the ventricles were in the high range of >5 mV. In other words, no relevant low-voltage areas could be identified in absolute numbers. Further investigations should reveal whether differences in this high-amplitude range correspond to physiological structures.Our fourth key finding was that in healthy, juvenile pig hearts, there was a slightly positive correlation between conduction velocity and voltage amplitude at velocities <1.5 m/s in all chambers except the RV. This finding might be due to the correlation between slow conduction zones and low-voltage areas in partially scarred myocardium ,23.2 compared to the resolutions of 0.2 points/mm2 in another work characterizing left atrial slow conduction zones among patients with atrial fibrillation [The mapping resolution was very high compared to the published data. On average, the maps in our analysis showed a mapping resolution of 1.4 points/mmillation . The numillation .Our data are comparable to published human data on conduction velocities derived from electrodes with small surfaces and small inter-electrode distances. Martin et al. measured the conduction velocities among patients with ischemic cardiomyopathy . Kléber In our analysis, we used unipolar signals, not bipolar signals, to calculate ultra-high-density 3D voltage maps. Moreover, unipolar mapping has been useful for identifying alterations in voltage amplitude, reflecting histologically proven viable myocardium in the scar areas of ischemic origin , as wellOur data are derived from healthy porcine hearts, and their validity might be limited when transferred to human hearts. Healthy human heart measurements and outside interventions for all four heart chambers remain scarce for ethical reasons. Studies describing models to estimate local atrial conduction velocities  may deveThe porcine hearts were healthy and juvenile. Correlations between conduction velocities and voltage amplitudes that are presumed and observed in diseased hearts may be absent in healthy hearts. Therefore, conclusions regarding diseased and aged hearts can be misleading.The sample size was limited to four pigs due to animal welfare. Despite using the random effect ‘heart’, we cannot rule out the possibility that strong inter-individual differences interfered with our statistical model.The signals were recorded with one ultra-high-density mapping system and one distinct mapping catheter. There are several mapping systems on the market with different mapping catheter designs. As there are no head-to-head comparisons between different ultra-high-density mapping systems, limitations or advantages are unknown with regard to signal quality.Since the velocity was calculated using time differences between the first and last excitations in the circle, colliding wavefronts might be misinterpreted. The probability of colliding wavefronts in healthy hearts should be low. The small radius of the circles prevents disturbances in analysing velocities due to colliding wavefronts.The heart chambers and different segments of each heart chamber were mapped consecutively. Therefore, an overtime effect on velocities or voltages cannot be fully excluded. We tried to keep the influence of time low by adhering to strict timelines for mapping. Furthermore, we did not administer any anti-arrhythmic drugs that could influence cardiac electrophysiology.Heart rate was estimated over a recording period of approximately 5 min, which may cause inaccuracies in the heart rate analysis. To allow a better interpretation of results, we assumed a linear relation in our mixed-effects model, which provided a good approximation of higher-dimensional interactions.Anaesthesia has been shown to influence cardiac electrophysiology ,35,36,37In healthy porcine hearts, conduction velocities and voltage amplitudes differ between the left and right heart chambers. Within each heart chamber, voltage amplitude differs only in the ventricles and conduction velocity differs more in the right than in the left chambers.There is a slightly positive correlation between conduction velocity and voltage amplitude at velocities of <1.5 m/s in the atria and LV of healthy porcine hearts.A comprehensive characterization of the conduction velocities and voltage amplitudes of all heart chambers could facilitate future computations for human heart models.


Advances in cancer therapies have led to a global improvement in patient survival rates. Nevertheless, the price to pay is a concomitant increase in cardiovascular (CV) morbidity and mortality in this population. Increased inflammation and disturbances of the immune system are shared by both cancer and CV diseases. Immunological effects of anti-cancer treatments occur with both conventional chemotherapy and, to a greater extent, with novel biological therapies such as immunotherapy. For these reasons, there is growing interest in the immune system and its potential role at the molecular level in determining cardiotoxicity. Early recognition of these detrimental effects could help in identifying patients at risk and improve their oncological management. Non-invasive imaging already plays a key role in evaluating baseline CV risk and in detecting even subclinical cardiac dysfunction during surveillance. The aim of this review is to highlight the role of advanced cardiovascular imaging techniques in the detection and management of cardiovascular complications related to cancer treatment.  Several definitions of cardiotoxicity or cancer therapy-related cardiac dysfunction (CTRCD) have been provided over the years. Nevertheless, the unifying element for diagnosis is the detection of a new cardiac dysfunction defined as either reduction in the left ventricular ejection fraction (LVEF) or, more recently, in the global longitudinal strain (GLS) . Both AmRadionuclide techniques, particularly with positron emission tomography (PET) imaging, have also become key in pre-clinical and clinical studies of CTRCD. For example, myocardial perfusion imaging (MPI) with myocardial blood flow (MBF) quantification is crucial for the investigation of derangements of the coronary circulation that may result from cancer therapies, including radiation therapy. Moreover, cardiovascular molecular imaging has evolved significantly over the past few decades due to the advent of PET and radio-labeled imaging probes that can elucidate the biomolecular events that underlie clinical phenotypes; thus, providing new insights into the pathophysiology, diagnosis, management, and risk stratification of individuals with CTRCD.2 up to 48% at 700 mg/m2 [Anthracycline chemotherapy (AC) is currently prescribed for a wide range of malignancies and exhibits a well-known cumulative-dose cardiotoxicity ,11. The 00 mg/m2 ,11. The 00 mg/m2 . All the00 mg/m2 . Instead00 mg/m2 . Advancep < 0.01) [p < 0.0001) [A baseline assessment of LVEF and CV risk factors is mandatory to assess overall suitability to AC therapy, stratify patients according to their CV risk, and plan a tailored follow-up schedule . As alre < 0.01) . Althoug < 0.01) . Both T1 < 0.01) . A signi < 0.01) . After t < 0.01) . LGE can < 0.01) ,24. More < 0.01) . The rig < 0.01) . A signi < 0.01) . However < 0.01) . Circumf 0.0001) . Compare 0.0001) . Anti-human epidermal growth factor receptor 2 (HER2) is a monoclonal antibody used in HER2-positive breast cancer, causing cardiotoxicity in nearly 30% of patients, with an even greater risk when used in combination with AC ,30. AntiMultigated acquisition (MUGA), or equilibrium radionuclide angiography (ERNA), was the initial radionuclide technique used to monitor LV function in patients receiving AC. However, this is now used less frequently than echocardiography or CMR, which do not require radiation exposure and can provide additional information regarding cardiac structure and function . Current18F-fluorodeoxygluocose (FDG) is a glucose analogue that enters the cells through various types of glucose transporters (GLUT), and intracellular retention is dependent upon the enzymatic activity of hexose-6-phosphate-dehydrogenase within the endoplasmic reticulum [eticulum ,39,40. Feticulum , inflammeticulum , and hypeticulum  are poteeticulum . The sameticulum . While teticulum , but alseticulum . These feticulum . However99m-Technetium (Tc)-annexin binds to phosphatidylserine, which is exposed in early apoptosis, and studies in doxorubicin-treated rats have shown increased myocardial uptake of this marker prior to the onset of ventricular dysfunction [18F-CP18 (a caspase 3 substrate) in rats treated with doxorubicin, suggesting that imaging of the apoptotic cascade may result in earlier detection of chemotherapy-related myocardial injury [There are several other molecular imaging targets that have been evaluated in pre-clinical studies, which may help identify subclinical myocardial injury. function ,50. Incrl injury .123I-metaiodobenzylguanidine (MIBG), a marker of myocardial sympathetic innervation, has been evaluated in patients treated with anthracyclines since damage to the sympathetic nervous system is hypothesized to contribute to the pathophysiology of patients with heart failure. Prior research has suggested that a reduction in 123I-MIBG myocardial uptake may precede impairment in left ventricular function, and pre-clinical data indicate that there may be an injury to sympathetic neurons in anthracycline-mediated cardiotoxicity [123I-MIBG myocardial uptake and changes in LVEF [18F-flubrobenguane [18F-dihydroxyphenylalanine [toxicity ,53. Studtoxicity . While stoxicity ,56, a mo in LVEF , suggestbenguane  and 18F-lalanine .111In-antimyosin), with prior studies demonstrating increased myocardial uptake with increasing doses of doxorubicin, preceding myocardial dysfunction and correlating with a reduction in LVEF [18F-dihydroethidium (DHMT), and increased ROS production was noted to be an early marker of LV dysfunction. Similar findings were subsequently reported in a large animal model [Direct cardiomyocyte injury and sarcolemmal damage can be imaged using antimyosin antibodies -3--methylpentadecanoic acid (123I-BMIPP), a fatty acid analogue, has been studied in patients with lung cancer treated with taxanes, and reduced uptake was associated with a reduction in LV function, raising the possibility that this marker can be used to predict and detect cardiotoxicity [68Ga-fibroblast activation protein alpha inhibitor (68Ga-FAPI) to detect myocardial fibroblast activation in patients undergoing surveillance PET scans for cancer staging [Administration of taxane-based chemotherapy results in derangements in fatty acid metabolism due to impairment of microtubules . 123I-15toxicity . Finally staging . Additiop < 0.001) and no dose considered actually safe [Radiation therapy (RT) is the cornerstone of several haematological and solid malignancies. Despite several attempts over the last few years to reduce its potentially harmful effect, RT is still associated with an increased relative risk of cardiac mortality ranging from 2.2 to 12.7% and an almost five-fold increased risk of heart failure ,71. A cllly safe . The CV lly safe ,74. Radilly safe . The reslly safe . There illy safe . Ionizinlly safe . Early rp < 0.01) [n = 28) of RT-treated patients found no association between cardiac doses and native T1 values or LGE presence at a longer follow-up (mean 46.4 months). Therefore, the authors suggest that the early changes observed by Takagi’s group could have been influenced by concomitant chemotherapy [All patients should undergo a thorough baseline assessment of CV risk factors and LVEF before RT, using echocardiography as a first-line imaging modality ,15,78,79 < 0.01) . Howeverotherapy . Neverthotherapy . These dotherapy . Interesotherapy . The resotherapy . The perotherapy . In addiotherapy . Valvulaotherapy . Despiteotherapy . Stress otherapy ,91. Thisotherapy ,93. Moreotherapy ,95  following thoracic irradiation . The autImmune checkpoint inhibitors (ICI) are monoclonal antibodies targeting the host immune negative regulation receptors, including cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death receptor 1 (PD-1), and programmed cell death ligand 1 (PD-L1). These drugs can therefore modulate the immune system response and drive an immune-mediated attack against cancer cells with a demonstrated benefit in terms of overall prognosis and survival in a wide range of tumors . HoweverCMR is extremely helpful in the diagnosis of myocarditis . The revp = 0.025) [An international registry of 103 patients with ICI-associated myocarditis described LGE in approximately half of the patients, with predominant mid-wall (49%) and subepicardial (26.5%) distribution  and, mor= 0.025) . Increas= 0.025) .Molecular MRI imaging of myocarditis is being investigated in animal models and has not yet been translated into clinical practice. Maier et al. recently tested a new contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (=LIBS − MPIO). Histology confirmed CD41-positive cases, indicating platelet involvement in myocarditis in mice; quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection . This stDetection of ICI-related myocarditis with radionuclide molecular imaging techniques is also possible and remains an area of ongoing investigation ,116,117.Preliminary reports suggest that FDG-PET can be utilized to diagnose active ICI-related myocarditis, with one case report indicating that it can be helpful even in the absence of abnormalities on CMR ,114. WheHowever, the need for a dietary preparation to suppress physiologic myocardial glucose uptake is an inherent limitation, which affects or reduces the specificity of the test to differentiate between nonspecific and pathologic uptake. 68Ga-DOTATOC has also been studied in patients with suspected ICI myocarditis [68Ga-DOTATOC uptake may precede LGE and T2 elevation on CMR. Furthermore, one study found that myocardial 68Ga-FAPI uptake was higher in patients with suspected ICI myocarditis compared to patients receiving ICI without evidence of cardiac involvement, suggesting that 68Ga-FAPI should be studied more extensively in this patient population [Imaging of the somatostatin receptor using 68Ga-DOTATATE and carditis ,124. Thepulation ,125.However, the future of molecular imaging is geared towards the development of more disease-specific or targeted probes. In this sense, there is a significant interest in developing and testing novel immunotherapeutic drugs, including PD-1 and PD-L1 PET probes (thus imaging the targets of ICI) ,53, radiAs anti-cancer treatments continue to evolve and survival from cancer improves, the role of a multidisciplinary cardio-oncology team becomes of utmost importance in the management of these complex patients through a more personalized approach, from surveillance and early identification of cardiotoxicity to prevention and therapeutic management of complications. Cardiovascular imaging has evolved as a key tool to this purpose, allowing a non-invasive evaluation complementary to biomarkers and clinical assessment. In this regard, advanced imaging techniques offer the advantage of tissue characterization that, beyond LV function assessment, can provide early identification of cardiac injury with possible impact on therapeutic management and prognosis. Although reliable, accurate, and reproducible, a routinary use of these advanced techniques may be limited in clinical practice by high costs, long acquisition time, and availability of the modality. The application of rapid CMR protocols that are proven to provide high diagnostic accuracy in an average scan time of approximately 15 min (12 ± 4 for a non-contrast study) may increase the overall availability of the modality . The mos


The RV functional parameters were comparable among BH, FB, and RMB with a difference of less than 5%. The scan times for BH  and FB  were significantly reduced compared to for RMB (261 ± 68 s). (4) Conclusions: CS-FB and CS-BH real-time cine cMRI in children with CHD provides diagnostic image quality with excellent accuracy for measuring RV function with a significantly reduced scan time compared to RMB. (1) Purpose: to compare right ventricular (RV) functional parameters in children with surgically repaired congenital heart disease (CHD) using single/double breath hold (BH) and free-breathing (FB) real-time compressed sensing (CS) cine cardiac magnetic resonance (cMRI) with standard retrospective segmented multi breath hold (RMB) cine cMRI. (2) Methods: Twenty patients with CHD underwent BH and FB, as well as RMB cine cMRI, at 3T to obtain a stack of continuous axial images of the RV. Two radiologists independently performed qualitative analysis of the image quality  and quantitative analysis of the RV volume measurements. (3) Results: The best image quality was provided by RMB  compared to BH (3.9; range 3–5;  Accurate and reproducible volumetric and functional assessment of the right ventricle (RV) plays an essential role in the management of children with surgically repaired congenital heart disease (CHD) ,2. DecisMoreover, the image quality in cMRI greatly depends on heart rate and heart rate variability, thus limiting cMRI, especially in patients with arrhythmias . TherefoRetrospectively electrocardiogram (ECG)-gated BH cine cMRI is well established and generally considered the reference standard for assessing the RV volume and function with high reproducibility ,14. At the expense of lower image quality, real-time sequences in the past provided higher temporal resolution compared to that of standard sequences. With recent technical advances and the introduction of techniques such as compressed sensing (CS) reconstruction, it is now possible to acquire the entire heart in a single-shot manner within a single breath hold (SB) or—depending on the number of slices and the patient’s constitution—a double BH command. It is even possible with a free-breathing (FB) technique, with increased spatial resolution and acceptable reconstruction times . The left ventricle is routinely assessed using a short-axis orientation. The best orientation for functional assessment of the RV is still debated, but volumes of the RV in a dedicated axial orientation seem to agree more closely with the flow measured in the pulmonary trunk than do volumes acquired with the short-axis orientation ,16,17.The aim of this study was to compare standard retrospective segmented multi-breath hold (RMB) cine cMRI of the RV in the dedicated axial orientation with BH and FB compressed sensing real-time cine cMRI regarding image quality and RV function in children with surgically repaired CHD. n = 5), coarctatio aortae (n = 2), atrioventricular septal defects (n = 2), pulmonary artery ectasia or stenosis (n = 3), Ebstein’s anomaly (n = 3),  vitia (n = 2), transposition of the great arteries (n = 1), partial anomalous pulmonary venous return (n = 1), and Bland–White–Garland syndrome (n = 1). There were no specific study inclusion or exclusion criteria in addition to the usual contraindications for cMRI, such as unsafe implants.Twenty patients were prospectively included in this intraindividual, comparative study. The patients presented with the following surgically repaired cardiac disorders: tetralogy of Fallot , and the HIPAA  criteria were applied. Patients and/or parents were required to give their informed consent for the routine cMRI, as well as for the additional CS sequences obtained. CMRI imaging was performed using a 3T MRI system  with dedicated phased-array cardiac receiver coils . The patients were placed in a supine position. Stacks of axial slices covering the entire RV were acquired. A retrospective ECG-gated segmented k-space balanced steady-state free precession pulse sequence  was used as the reference sequence. The aforementioned RMB sequence was performed using the multi-BH technique with one BH per slice at the end of expiration. In all patients, prospective, adaptive triggering to the ECG was used for the acquisition of equally planned CS real-time cine cMRI scans using the BH and FB techniques. Detailed imaging parameters are reported in Additionally, T2w half-Fourier acquisition single-shot turbo spin echo imaging (HASTE) and standard retrospective ECG-gated bSSFP sequences were performed on the right and left ventricles, including 4-chamber, 3-chamber, and 2-chamber views; sections across the outflow tracts of the right and left ventricles; and short-axis stack images of the left ventricle. To determine the reference positions for flow measurements, contrast-enhanced MR angiography sequences of the pulmonary arteries and aorta were acquired. In all study examinations, phase-contrast flow measurement was performed in the pulmonary artery, positioned midway between the level of the pulmonary valve and the bifurcation of the branch pulmonary arteries, to compare it with the RV stroke volumes (RVSVs), calculated from the standard (RVSVRMB) and CS cine data (RVSVBH and RVSVFB). The presence of larger shunts or valve insufficiencies was excluded by comparing them with phase-contrast flow measurements in the ascending aorta and with the left ventricular stroke volume.Analysis was performed by two readers with 18 and 7 years of experience in cardiovascular imaging. Each observer scored and processed all 20 cases in random order while blinded to the diagnoses, patients, sequences, and other imaging data. The end systolic and end diastolic phases were detected automatically based on the smallest and largest RV volumes over the entire cardiac cycle , and theThe values obtained were indexed for body surface area, calculated according to the Mosteller formula . The acqThe subjective image quality was evaluated on a 5-point Likert scale  (7). The diagnostic confidence was rated on a 3-point scale . Descriptive statistical data analysis provided the mean values, range, and standard deviation.p-values < 0.05. Statistical analyses were performed using SPSS Statistics software , and GraphPad Prism software .Assumptions of normality were checked by the D’Agostino–Pearson test and by visual inspection of log-transformed quantile–quantile plots. Correlation analyses of functional parameters were performed using Pearson’s correlation test since a normal distribution could be assumed. Functional RV parameters, scan time, and image quality were compared by Wilcoxon’s non-parametric rank-sum test. Bland–Altman plots and linear regression analyses were applied for the comparison of functional values during RMB, SB, and FB by both readers. Inter- and intra-reader agreement was determined by calculating intraclass correlation coefficients (ICCs) for functional results and weighted kappa statistics for subjective quality assessment. A value of 0.01–0.2 indicated slight agreement, 0.21–0.40 indicated fair agreement, 0.41–0.60 indicated moderate agreement, 0.61–0.80 indicated good agreement, and >0.8 indicated excellent agreement ). cMRI in patients with congenital heart disease (CHD) remains challenging in routine clinical practice. However, accelerated techniques such as compressed sensing (CS) offer the potential for high-quality imaging with reduced acquisition times, thereby alleviating the burden of cMRI for chronically ill children in the future. In our study, we employed real-time CS with breath hold (BH) and free-breathing (FB) protocols to perform cMRI in children with surgically repaired CHD. The results revealed diagnostic image quality that was comparable to that achieved with conventional right ventricular retrospective segmented multi-breath hold balanced steady-state free precession (RMB) acquisition techniques. Although the image quality of the CS techniques was slightly inferior to that of standard RMB acquisition, the BH and FB protocols yielded image quality that was nearly equivalent. Notably, BH and FB consistently produced diagnostic images, whereas RMB failed in a case with arrhythmia. Furthermore, the use of BH or FB significantly reduced the scan time. When assessing right ventricular (RV) parameters, both inter-reader and intra-reader variability were low for BH, CS, and RMB.In patients without congenital anomalies of the cardiac anatomy, the CS imaging technique has been shown to be accurate and sufficiently reproducible in the evaluation of both LV and RV functional parameters, whereas the subjective image quality has been rated lower compared to RMB ,16,22,23Steeden et al. reported significant differences in RVSV and RVEF parameters when comparing RMB and BH imaging protocols. In their study, the RV functional parameters of pediatric patients were obtained with a short-axis ventricular view . The besThe spatial resolution is slightly lower with CS protocols compared to RMB since, to prevent artifacts, the field of view must cover the entire anatomy when using CS . MoreoveIn our examination protocols, the RMB images were always acquired at the end of expiration, whereas with FB protocols, the data acquisition was conducted in multiple breathing phases. Since inspiration causes negative intrathoracic pressure, the ventricular functional parameters might be affected as well . HoweverRMB relies on the regular periodicity of the heart rate to acquire data across multiple cardiac cycles, which are then merged to reconstruct a complete cine slice representing successive heartbeats. However, in the presence of arrhythmia, artifacts can occur due to the reconstruction using data from different phases of the cardiac cycle ,28. To mEspecially in the context of pediatric patients, time is a crucial factor in determining the success of magnetic resonance imaging (cMRI) due to their limited compliance and the frequent need for sedation or general anesthesia during examinations. The ability to obtain high-quality images in a shorter period is highly desirable, as it reduces the potential physical side effects associated with prolonged anesthesia exposure. Moreover, younger patients with CHD often present with unstable clinical conditions, further emphasizing the importance of minimizing scan time to reduce potential risks and complications. A study conducted by Jaimes et al. demonstrated a direct correlation between the duration of the magnetic resonance imaging (MRI) protocol and the success of non-sedated MRI examinations in children aged 1 to 7 years. Specifically, the success rate of studies utilizing protocols with an acquisition time of less than 20 min exceeded 80% .CS examination protocols offer significant advantages in terms of time efficiency compared to conventional methods. In our study, we found that CS sequences utilizing the FB technique allowed for the acquisition of a complete ventricular stack in just 14 s, without any significant loss of image quality. On the other hand, the standard RMB imaging using traditional techniques required a minimum of 3.5 min. This substantial reduction in scan time with CS protocols has the potential to revolutionize the imaging process for children with CHD.Another noteworthy advantage of CS imaging, specifically with FB protocols, is the ability to overcome the need for artificial ventilation during breath hold examinations. By eliminating these requirements, CS imaging offers improved patient safety and reduces the complexity of the clinical workflow.Overall, the utilization of CS real-time imaging in children with CHD holds great promise for functional cardiac analysis. The significant time savings, reduced need for sedation or anesthesia, avoidance of artificial ventilation/intubation, and relative insensitivity towards arrhythmia-induced artifacts make CS an attractive option in this patient population. Some limitations of the study must be stated. First, the study population was rather small. Second, our cohort did not include many patients with arrhythmia.Real-time BH and FB reduce the time to obtain cine cMRI to evaluate RV parameters with sufficient accuracy. CS delivered diagnostic image quality in a significantly shorter examination time compared to RMB imaging protocols. Thus, CS has the potential to replace standard RMB examinations in children with CHD.