Background and objectives: Evaluating left ventricular filling pressure (LVFP) plays a crucial role in diagnosing and managing heart failure (HF). While traditional assessment methods involve multi-parametric transthoracic echocardiography (TTE) or right heart catheterisation (RHC), cardiovascular magnetic resonance (CMR) has emerged as a valuable diagnostic tool in HF. This study aimed to assess a simple CMR-derived model to estimate pulmonary capillary wedge pressure (PCWP) in a cohort of patients with suspected or proven heart failure and to investigate its performance in risk-stratifying patients. Materials and methods: A total of 835 patients with breathlessness were evaluated using RHC and CMR and split into derivation (85%) and validation cohorts (15%). Uni-variate and multi-variate linear regression analyses were used to derive a model for PCWP estimation using CMR. The model’s performance was evaluated by comparing CMR-derived PCWP with PCWP obtained from RHC. Results: A CMR-derived PCWP incorporating left ventricular mass and the left atrial area (LAA) demonstrated good diagnostic accuracy. The model correctly reclassified 66% of participants whose TTE was ‘indeterminate’ or ‘incorrect’ in identifying raised filling pressures. On survival analysis, the CMR-derived PCWP model was predictive for mortality , which was not the case for PCWP obtained using RHC or TTE. Conclusions: The simplified CMR-derived PCWP model provides an accurate and practical tool for estimating PCWP in patients with suspected or proven heart failure. Its predictive value for mortality suggests the ability to play a valuable adjunctive role in echocardiography, especially in cases with unclear echocardiographic assessment. Left ventricular filling pressure (LVFP) is a critical determinant of cardiac performance and a crucial parameter in establishing the diagnosis of heart failure (HF) . LVFP isConventionally, the assessment of LVFP was predominantly conducted using multi-parametric transthoracic echocardiography (TTE) or, in borderline cases, diastolic stress testing and right heart catheterisation (RHC), particularly if there was a discrepancy between right and left ventricular filling pressures . PulmonaCardiovascular magnetic resonance imaging (CMR) is increasingly used in the diagnostic workflow of patients with suspected or proven HF, including detecting scars and ischaemia, revealing subendocardial defects through stress perfusion and quantifying infiltration or fibrosis during gadolinium analysis . SeveralWith the recognition that there is a need for practical clinical implementation, this study leverages the left atrial area (LAA), obtained from a single view , to develop a simplified model of deriving PCWP by using CMR in a cohort of patients with suspected or proven HF and to determine whether this model can risk stratify patients.We hypothesise that a CMR model that leverages the left atrial area is able to accurately predict outcomes in patients with suspected or proven heart failure. This investigation involved a well-defined cohort of 835 individuals who were referred to our research centre for the evaluation of breathlessness. The study encompassed an extensive eight-year period, commencing in 2012 and concluding in 2020. All patients underwent right heart catheterisation and CMR, with procedures performed within 24 h of each other. The inclusion criteria included the signs and symptoms of heart failure, age > 18 years, and the provision of informed consent. The exclusion criteria included pulmonary arterial hypertension (type 1) and contraindications to RHC or CMR, including claustrophobia and end-stage heart failure. Ethical approval for the research protocol was duly granted by the National Research Ethics Service, with approval reference number 16/YH/0352 . The comprehensive assessment of patients’ cardiac and pulmonary functions was carried out through the implementation of two pivotal diagnostic procedures: right heart catheterisation (RHC) and cardiac magnetic resonance imaging (CMR).Right heart catheterisation (RHC): RHC was executed using a specialised balloon-tipped 7.5 French thermodilution catheter. This meticulously conducted procedure facilitated the accurate measurement of pulmonary capillary wedge pressure (PCWP) through established methodologies. Subsequently, PCWP values were subjected to rigorous averaging over multiple cardiac cycles to ensure the precision of the obtained data.Cardiac magnetic resonance imaging (CMR): CMR investigations were conducted employing a state-of-the-art 1.5T GE HDx scanner . The CMR imaging protocol encompassed a diverse array of sequences, including two-chamber, three-chamber, four-chamber, and short-axis cine acquisitions using a retrospective cardiac-gated multi-slice steady-state free precession sequence . The short-axis cine images were used to obtain the left ventricular (LV) end-diastolic volume (LVEDV), the LV end-systolic volume (LVESV), the right ventricular (RV) end-diastolic volume (RVEDV), and the RV end-systolic volume (RVESV). From end-diastolic and end-systolic volumes, the LV stroke volume (LVSV), the LV ejection fraction (LVEF), the RV stroke volume (RVSV), and the RV ejection fraction (RVEF) were calculated. For the specific purpose of quantifying the dimensions of the left atrial area (LAA), the four-chamber view was diligently employed. Using a dedicated post-processing workstation, specifically the GE Advance 4.1, the delineation of the endocardial boundary of the left atrium occurred during the end-systolic phase, immediately preceding the opening of the mitral valve. It is noteworthy that this contouring process excluded the pulmonary veins and the left atrial appendage, which are deemed extraneous to the left atrial body. Additionally, segmentation of both the endocardial and epicardial boundaries within the short-axis stack was performed to derive ventricular volumes, with particular emphasis on left ventricular mass measurements during the end-diastolic phase.A clinical evaluation using transthoracic echocardiography (TTE) was conducted within 24 h of right heart catheterisation (RHC), following local practice guidelines. Various echocardiographic parameters were measured, adhering to the minimum dataset size recommended by the British Society of Echocardiography (BSE). Left atrial pressure was estimated using the American Society of Echocardiography (ASE) algorithm, which categorises patients into normal, elevated, or uncertain left atrial pressure based on mitral inflow parameters, tissue Doppler imaging, tricuspid regurgitation velocity, and the left atrial volume (LAV) index [Subsequent to the initial assessments, participants were diligently monitored over a mean follow-up duration of 4.0 years. Cohort stratification ensued, dividing the subjects into two distinct groups: the derivation cohort, constituting 85% of the participant pool (n = 706), and the validation cohort, encompassing 15% of the participants (n = 127). The assessment of diastolic function within the validation cohort was conducted using transthoracic echocardiography (TTE).t-test was employed as the statistical methodology of choice. Categorical data, on the other hand, underwent scrutiny through the χ2 test, a robust method for assessing associations and differences among categorical variables. For the objective of comparing cardiac outputs as determined by cardiac magnetic resonance imaging (CMR) and right heart catheterization (RHC), a paired t-test was applied, offering a suitable framework for analysing paired continuous data.In accordance with established clinical practice, all clinically acquired data were assumed to follow a normal distribution. Continuous variables were expressed as the mean ± standard deviation, serving as the primary metrics for their presentation. Meanwhile, categorical data were conveyed in terms of frequencies and corresponding percentages. To ascertain significant differences between continuous variables, a two-sample independent The dataset was stratified into two distinct cohorts: the derivation cohort, which constituted 85% of the total population (n = 706), and the validation cohort, comprising 15% of the total population (n = 127).Within the derivation cohort, statistical analysis encompassed several phases. Firstly, uni-variate linear regression was employed to derive Pearson correlation coefficients, elucidating the relationships between individual CMR metrics and pulmonary capillary wedge pressure (PCWP) as determined via RHC. Subsequently, a multi-variate regression model was crafted to establish relationships between various CMR metrics. Furthermore, the utility of supervised machine learning penalised regression models was explored for the prediction of CMR-derived PCWP.The final model derived from the derivation cohort was subsequently applied to the validation cohort. Receiver operating characteristic (ROC) analysis was conducted to rigorously assess the diagnostic performance of CMR-derived PCWP in the detection of elevated RHC-derived PCWP, thereby elucidating the model’s efficacy.For the comprehensive analysis of prognosis, Kaplan–Meier analysis was undertaken to delineate survival probabilities, while Cox’s proportional hazard model was harnessed for multi-variate prognostic evaluation.Statistical analyses were executed using SPSS version 22 , with confirmatory analyses conducted in MedCalc . Notably, supervised machine learning penalised regression was implemented in StataIC 16.p < 0.05.Throughout all analyses, unless explicitly specified otherwise, all statistical tests were two-tailed, and statistical significance was established at a threshold of The study’s primary objectives encompassed the examination of the correlation between CMR-derived PCWP and the PCWP values ascertained via RHC. Furthermore, the study sought to rigorously assess the performance of the developed model in stratifying individuals whose TTE results yielded non-diagnostic outcomes. These outcomes were classified as either ‘indeterminate’ or ‘incorrect’ in their capacity to accurately identify individuals with elevated filling pressures during invasive assessment. Additionally, the prognostic potential of CMR-derived PCWP was scrutinised, particularly in comparison to RHC and TTE. Prognostic values were articulated as hazard ratios (HR) within Cox’s proportional hazard regression, supplemented by visual representation through Kaplan–Meier survival curves. For an exhaustive exposition of the study’s population, research methodologies, and the intricacies of the statistical analysis, we refer readers to the previously published documentation for comprehensive reference . A total of 835 participants were included in this study. Patient characteristics for the derivation cohort (n = 708) and the validation cohort (n = 127) are summarised in p < 0.0001). When compared to all other CMR metrics previously tested, the LAA was most strongly correlated with RHC PCWP. Within the derivation cohort, during univariable regression, the LAA demonstrated a moderate association with RHC PCWP  of the participants who had previously been marked as ‘incorrect’ or ‘indeterminate’ using TTE . p = 0.01). This was not the case for PCWP by RHC , TTE , or left ventricular mass by CMR .In Cox’s proportional hazard regression survival analysis A within 2 = 4.09, p = 0.04), whereas TTE did not demonstrate the prognostic .In Kaplan–Meier analysis B, particThis study demonstrates that, in a large heterogeneous cohort of patients with suspected or confirmed heart failure, a simplified CMR model can estimate PCWP with good diagnostic accuracy. Increases in pre-load or after-load can result in elevated filling pressures, and since the left atrial area is a marker of the pre-loading condition on the ventricle, the results of this study are physiologically conceivable . This stIncreases in intracardiac pressure due to cardiac impairment result in re-modelling of both the atrium and ventricle . The finDysfunction of the left ventricle is associated with left ventricular hypertrophy, which can be quantified using left ventricular mass . ImportaThese two main structural pathophysiological changes due to raised LVFP, namely LA dilation (predominantly pre-load-related) and LV hypertrophy (predominantly afterload-related), form the basis of the American College of Cardiology and American Heart Association grading system, commonly used to assess suspected HF patients, and are crucial components of a true physiological model . The CMRThe successful transition of research-based tools into clinical practice hinges on their practical utility for clinicians and patients, which, in the case of CMR-derived PCWP, may rest in identifying patients with abnormal PCWP and haemodynamic guidance of HF therapy . SimultaWhilst the LAV does provide a complete assessment of the left atrium, it does not appear to contribute to a more diagnostically powerful PCWP model than the LAA. So, in cases where precise estimation of atrial volume may be required, such as atrial conditions associated with atria , or in assessing chronicity of diastolic function, the LAV may be the most appropriate metric .Despite providing an enhanced characterisation of the left atrium, there are several limitations to using the LAV within a clinical setting. First, it requires meticulous image acquisition and post-processing, including accurate delineation of the endocardial borders in two views (both the two-chamber and four-chamber views), which can be time-consuming and technically demanding. Second, due to the need for endocardial contouring in multiple views, the measurement of the LAV is associated with increased observer variability. Whilst automated or semi-automated methods can reduce this variability, these tools are not universally available and may vary across clinical settings. If a comprehensive assessment of left atrial structure and function is not required, then clinicians can utilise the practicality and reliability of the left atrial area within pressure assessments, which, in its current form, is most suited to the dichotomisation of PCWP than the exact estimation of the exact value. The LAA measurement is generally simpler and more time-efficient than the LAV, requiring a single view  and less post-processing, enhancing its practicality within a busy clinical environment.In comparison to an invasive assessment of filling pressures, CMR offers a non-invasive estimate of LVFP at a lower cost with similar, if not enhanced, prognostic potential. The results of CMR-derived filling pressures can be obtained quickly with good diagnostic accuracy. Echocardiography is the first-line non-invasive method of LVFP assessment. It is versatile and cost-effective and can estimate LVFP at the bedside. The reliability of integrated echocardiographic methods for determining raised filling pressures is debatable. This current study highlights the complementary value of CMR in instances where echocardiography is non-diagnostic or indeterminate. The main utility of CMR rests in discrepant cases of echocardiographic assessment rather than accurate estimation of pressure. Further, CMR can provide a wealth of useful diagnostic and prognostic information outside of filling pressure assessment. There is a need for further work to explore the role of CMR-derived PCWP assessment in guiding therapy for patients with heart failure. In this situation, precise and accurate estimation of PCWP is less important than a change in response to therapy. This should be tested further. The described method of deriving PCWP is easily applied; there is no need for additional or specialist CMR sequences, as atrial and ventricular quantification are part of routine CMR scans. There is also an additional need to explore other CMR-derived PCWP models, which may improve accuracy, such as myocardial strain and ones that consider a patient’s sex. This large clinical study expands on previous small research studies involving ill-defined clinical groups. This real-world study utilised standard TTE, which is typically the first imaging investigation of choice in the assessment of cardiovascular structure and function. It is recognised that, since TTE is performed by a range of operators, significant variation in the parameters obtained and the accuracy of such measurements is commonplace. This can affect the estimation of filling pressures. CMR, on the other hand, is associated with much higher repeatability and, therefore, is less subject to variability. We speculate that the CMR model is less susceptible to changes in pre-load conditions than echocardiography since the left ventricular mass is not altered by acute changes in loading conditions. The left atrial area is more susceptible to changes in loading conditions, which adds value in making the model more dynamic and discriminatory. There would be value in testing this suggestion, perhaps in the same patient pre- and post-treatment. We believe that these characteristics of CMR-derived PCWP assessment make it a clinically useful non-invasive imaging test and may reduce the need for invasive assessment. The results of this study demonstrate that CMR-derived PCWP is not inferior to invasive PCWP assessment for informing prognosis and may have specific value for cases where assessment with TTE yields an indeterminate probability of ‘raised pressures’. This model, where the left atrial area is used instead of the left atrial volume, highlights how versatile the model is, accommodating several different left atrial measures as a surrogate for pressures. This study’s limitations include its single-centre nature, potentially introducing selection bias due to referrals for right-heart-catheterization (RHC) assessment, which may have contributed to an elevated mean pulmonary artery pressure in the overall population. Caution should be exercised when extrapolating these results to a more diverse and heterogeneous population. Further multi-centre studies would be beneficial to validate the model’s performance across a broader spectrum of patients and healthcare settings. Whilst the LVEF was different between the derivation and validation cohorts, this is unlikely to have influenced the validity of the observed results.Additionally, the study focused on clinically stable patients with real-world presentations of shortness of breath in outpatient departments, excluding acutely decompensated heart failure (HF) patients requiring intravenous therapy. Acutely decompensated patients often exhibit fluid shifts, hemodynamic instability, and variable filling pressures, which could introduce substantial measurement variability. However, it is worth acknowledging that these patients represent a significant and clinically relevant subgroup within the heart failure spectrum. In light of this, potential future research directions could involve developing specific protocols or methodologies for assessing acutely decompensated patients using CMR, as well as exploring the utility of the CMR-derived PCWP model in guiding their management. As a retrospective study within a specific population, the applicability of the proposed algorithm in prospectively recruited, non-selected patients remains untested. Furthermore, limited TTE analysis was conducted, and advanced echocardiographic techniques were not explored, preventing a comparison with our CMR model in these aspects. Future research should explore the use of advanced echocardiographic techniques, such as speckle tracking echocardiography or three-dimensional echocardiography, which may provide more precise measurements of the left atrial area and the left ventricular mass. A simplified CMR model can accurately estimate PCWP in patients with suspected or confirmed heart failure. The study showcases the predictive power of a simplified PCWP model, indicating its potential as a valuable adjunct to echocardiography, particularly in cases with unclear echocardiographic diastolic assessment. This study also emphasises the practicality and efficiency of utilising the left atrial area in PCWP assessment, facilitating a streamlined workflow in clinical settings. Using this revised model, CMR-derived LVFP can inform the risk of decompensation from HF requiring hospitalisation and the risk of composite MACE.


TAPSE did not show correlations with any TA size or “sphincter-like” functional parameters as determined using 3DE. Conclusions. Three-dimensional echocardiography is capable of measuring TA dimensions and functional “sphincter-like” properties, which are associated with MME-derived TAPSE, suggesting a sensitive and harmonic TA function in healthy adults without functional tricuspid regurgitation.Introduction. The tricuspid valve is an atrioventricular valve located on the right side of the heart, which consists of the fibrous tricuspid annulus (TA), three valvular leaflets and a supporting apparatus, the papillary muscles and the tendinous chords. The TA is an oval-shaped three-dimensional (3D) fibrous structure with a complex spatial movement during the cardiac cycle. Three-dimensional echocardiography (3DE) could help during “en-face” assessment of TA dimensions and related functional properties featuring its “sphincter-like” function. TA plane systolic excursion (TAPSE) is a displacement of the lateral edge of the TA toward the apex in systole measured in apical long-axis using M-mode echocardiography (MME). The aim of this study was to determine potential relationships between TA size and its “sphincter-like” and “longitudinal” functions in healthy adults with no functional tricuspid regurgitation. Methods. The present study consisted of 119 healthy patients  who underwent routine echocardiography with M-mode-derived TAPSE measurement and 3DE. Two subgroups of healthy subjects were compared with each other. A total of 29 subjects with TAPSE between 17 and 21 mm were compared with 90 cases with TAPSE ≥ 22 mm. Results. Subjects with TAPSE of 17–21 mm had tendentiously dilated TA dimensions compared with subjects with TAPSE ≥ 22 mm. Significant differences could be detected in the end-systolic TA area (5.85 ± 1.90 cm Evaluation of the right side of the heart has come to the forefront of scientific thinking in recent years. The reason for this is twofold: on the one hand, new therapeutic procedures have become clinically usable that can be used for many disorders affecting the right side of the heart . On the other hand, non-invasive examination options that are easy to learn and use and enable a detailed and extensive analysis have become widespread in routine clinics, e.g., three-dimensional echocardiography 3DE) /end-diastolic TAD) × 100;−TA fractional area change (TAFAC), defined as ([end-diastolic TAA − end-systolic TAA]/end-diastolic TAA) × 100.n (%). Statistical significance was considered to be present when p < 0.05. Levene’s test was accomplished for assessing homogeneity of variances, while the Shapiro–Wilks test was used to test whether variables were normally distributed. Student’s t-test was used for normally distributed datasets, while the Mann–Whitney–Wilcoxon test was performed for non-normally distributed datasets. Pearson’s coefficients were measured to characterize correlations between variables. SPSS software  was used for the statistical analyses.Continuous data were presented as average ± standard deviation (SD), while categorical data were demonstrated as Demographic data. Two subgroups of healthy subjects were compared with each other: 29 subjects with TAPSE between 17 and 21 mm  were compared to 90 subjects with TAPSE ≥ 22 mm .M-mode and two-dimensional Doppler echocardiography. In Three-dimensional echocardiography. Three-dimensional echocardiography-derived LV volumes, mass and EF together with TA dimensions and functional properties are presented in Correlations. TAPSE did not show correlations with any TA sizes or ”sphincter-like” functional properties as assessed using 3DE.Feasibility of TA measurements using 3DE and M-mode echocardiography. This study comprised 154 healthy adults, but due to insufficient image quality, 35 cases had to be excluded. Therefore, the overall feasibility was 77.3%.2 and −0.04 ± 0.69 cm2 for end-diastolic and end-systolic TAA and −0.10 ± 0.61 cm and 0.05 ± 0.60 cm for end-diastolic and end-systolic TAP with a correlation coefficient of 0.96, 0.96, 0.97, 0.96, 0.96 and 0.96 , respectively (interobserver agreement). Similarly, the mean ± SD of the differences in values measured two times by the same observer was 0.02 ± 0.21 cm and −0.03 ± 0.17 cm for end-diastolic and end-systolic TAD, −0.02 ± 1.18 cm2 and −0.03 ± 0.38 cm2 for end-diastolic and end-systolic TAA and −0.04 ± 0.73 cm and 0.07 ± 0.58 cm for end-diastolic and end-systolic TAP with a correlation coefficient of 0.95, 0.96, 0.95, 0.96, 0.96 and 0.97 , respectively (intraobserver agreement).Reproducibility data of 3DE-derived TA assessments. The mean ± SD of the differences in values measured by two examiners proved to be 0.03 ± 0.20 cm and 0.02 ± 0.39 cm for end-diastolic and end-systolic TAD, 0.03 ± 0.70 cmIn recent decades, there has been a huge development in cardiovascular imaging due to the technological advances characterizing this period. In addition to magnetic resonance imaging and computer tomography becoming accessible and important imaging methods in cardiology, new echocardiographic methods have emerged and become part of the daily routine. Two-dimensional speckle-tracking echocardiography (2D-STE) is a widely used method for the quantitative characterization of wall movements using strain parameters. Its advantage lies in its simplicity, and it is an option available in most modern devices. The prognostic value of LV global longitudinal strain calculated with 2D-STE has been confirmed . DespiteOwing to the advantages of 3DE detailed above, this method is suitable for performing physiological studies by calculating several parameters at the same time using a digitally acquired 3DE database. In our present study, the LV volumes and the LV-EF were determined during 3DE along with the annular data of TV and the TAFAC and TAFS parameters characterizing the sphincter-like function of TA. Moreover, TAPSE was measured at the same time as the 3DE ,10,11,20In a healthy person, the TA is a saddle-shaped dynamic structure, the expansion of which is accompanied by a change in its shape; as a result, it becomes more circular and planar . In the Evaluation of TAPSE is a well-known, old-fashioned, simple M-mode echocardiographic method with a significant prognostic value. It is easy to reproduce as a one-plane measurement of TA function in a longitudinal direction featuring its longitudinal displacement . TAPSE iNormal reference values for TA derived from 2D echocardiography and cardiac magnetic resonance imaging are available ,24. HoweNon-invasive cardiovascular imaging technologies, including echocardiography, are developing rapidly in the XXIst century, allowing more detailed non-invasive morphologic and functional analysis of not only of the atria and the ventricles, but the valves as well. Moreover, these imaging techniques have become part of the daily routine of cardiologists. Three-dimensional echocardiography is a good example of this enormous technological advancement, allowing detailed analysis of cardiac mechanics ,5,6,7. HIn the present study, 3DE-derived TA dimensions and TAFAC were demonstrated to be associated with TAPSE assessed via M-mode echocardiography in healthy subjects without FTR. Lower TAPSE was associated with lower TAFAC, which was related to more dilated end-systolic TAA. However, direct correlations between TA functional features could not be demonstrated. This result suggests a relationship between echocardiographic TA dimensions and TA features for “sphincter-like” (TAFAC) and “longitudinal” (TAPSE) functions. These results could suggest sensitive and harmonic cooperative ”sphincter-like” and “longitudinal” TA functions in healthy adults before FTR develops. However, other studies are required to confirm the presented results and to demonstrate abnormalities in the ”sphincter-like” (TAFAC) and “longitudinal” (TAPSE) properties of TA function in different disorders with FTR.Although the TA has a characteristic spatial saddle shape, only its 2D-projected image was analyzed ,2.The image quality of echocardiographic analysis is an important issue, still being worse in the case of 3DE than in the case of 2D echocardiography, which should be taken into account when interpreting the findings. 3DE has several technical difficulties, including lower frame rate and larger transducer size, which can significantly affect image quality. Nevertheless, considering both the advantages and disadvantages, the clinical role of 3DE is unquestionable ,6,7.Three-dimensional echocardiography-derived image quality is also highly dependent on stitching and motion artifacts ,6,7.This study did not compare 2D echocardiography versus 3DE in the measurement of TA.Three-dimensional echocardiography-derived chamber quantifications of atria and ventricles were also not performed in this study.Validation of our 3DE results using other imaging methods could have further strengthened the significance of our scientific findings. Similar studies may be the subject of clinical trials in the future.STE-derived featuring of the TA function was not purposed either.As FTR was assessed visually, using a more advanced quantification technique would have strengthened our findings ,2,3.Healthy subjects were involved in this study. However, neither special laboratory tests nor imaging testing were performed to completely exclude disorders in the early stages.The following limitations arose during assessments:Three-dimensional echocardiography is capable of measuring the TA’s dimensions and functional ”sphincter-like” properties, which are associated with TAPSE, suggesting a sensitive and harmonic TA function in healthy adults without FTR.


Transcatheter mitral valve replacement (TMVR) is a rapidly evolving treatment for mitral regurgitation. As with transcatheter aortic valve replacement, multidetector computed tomography analysis plays a central role in defining the candidacy, device selection and safety for TMVR procedures. This contemporary review will describe in detail the multidetector computed tomography data collection, analysis, and planning for TMVR procedures in patients with native mitral regurgitation as well as in those with failed surgical prosthetic mitral valve replacement or surgical mitral valve repair. Mitral regurgitation (MR) occurs from different mechanisms involving the mitral valve (MV) complex. MR is broadly classified as degenerative MR when caused by primary leaflet disorders  and as functional MR (FMR), which can be caused by left atrial and/or left ventricular remodeling. Although both MR categories are potentially suitable for transcatheter edge-to-edge MV repair (TEER), patient-specific anatomical features may preclude the use of this therapy.Transcatheter mitral valve replacement (TMVR), on the other hand, can be broadly divided as for the treatment of native MR or for the treatment of patients with failure of prior surgical MV replacement or MV repair. TMVR for native MR is indicated for high-risk surgical candidates and is currently under investigational research studies in the United States of America. TMVR devices for native MV replacement include Tendyne , Intrepid , SAPIEN M3, EVOQUE , and Cephea . TMVR has also been approved by the U.S. Food & Drug Administration (FDA) for the treatment of failed bioprosthetic valves  and of prior MV annuloplasty repair  with the use of a balloon-expandable transcatheter aortic valve device . In patients not suitable for TEER, given the presence of mitral annular calcification (MAC) and small MV area, the option for TMVR valve-in-MAC (ViMAC) has also been performed under research registries either with specific native TMVR devices or with SAPIEN 3.Multimodality imaging is key for successfully selecting patients suitable for TMVR. Both echocardiography and multidetector computed tomography (MDCT) are necessary imaging tools for the MR diagnosis, evaluation of severity and mechanism, TMVR procedure planning, and follow-up of patients after TMVR. This review presents comprehensive updated information on MDCT analysis for TMVR screening, procedure planning, and patient follow-up of patients.The anterior MV leaflet (AML) and posterior MV leaflet are structurally and functionally different.In the context of TMVR, the MV leaflets may serve as a fixation for TMVR devices (in which the device grabs the leaflets) but may also contribute to LVOT obstruction (LVOTO) after device implant . Therefore, measurement of the AML length and the location of papillary muscle insertion into the leaflets should be assessed, identifying any potential interference with device fixation.The mitral annulus anatomically is a nonplanar 3-dimensional saddle-shaped structure that shares close proximity to the aortic valve via the mitral-aortic intervalvular fibrosa. Mitral annulus sizing is an important step in TMVR planning. Mitral annulus dimensions are dynamic and therefore should be measured in both systolic and diastolic phases. MDCT scan data acquisition, therefore, needs to be not only electrocardiogram (ECG) gated but also must encompass the entire cardiac cycle, preferably without dose modulation. Changes in the mitral annulus size in degenerative MR are more dynamic than in functional MR.For TMVR screening and planning, the mitral annulus segmentation is typically performed using dedicated software with the semi-automated creation of multiplanar reformat images and a user-defined interpolated cubic spline connecting 16 seed points deposited at the base of the MV leaflets. The 2 mitral annular trigones are defined by the MV commissures at the transition between the AML and posterior MV leaflet. Two geometrical shapes for the native MV annulus can be considered: (1) a saddle-shaped, which incorporates the mitral-aortic intervalvular fibrosa; or (2) a D-shaped mitral annulus, which truncates the anterior horn into a straight line connecting the 2 trigones.MAC often occurs in elderly patients with concomitant aortic stenosis and/or with chronic renal failure. This higher risk population represents a challenging cohort that was initially excluded from TMVR trials. However, increased experience with both balloon-expandable SAPIEN 3 transcatheter aortic valve replacement device and dedicated Tendyne  TMVR device have been reported with favorable results, provided no LVOTO is identified on screening analysis.Both transthoracic and transesophageal echocardiography (TEE) are established imaging methods for the diagnosis of MR severity and etiology. Improvements in MDCT technology  have allowed high-quality functional evaluation, which is very complementary to echocardiography. Functional 3D MDCT can be especially useful when MR etiology is unclear, by combining comprehensive assessment of subvalvular components and detailed quantification of the mitral annulus, left atrial, and left ventricular remodeling .Figure 3The MDCT acquisition protocol for TMVR planning will vary depending on scanner type, iodine contrast concentration, patient’s renal function, and body habitus. Accordingly, each institution should customize its acquisition protocol for TMVR. For a comprehensive review of this topic, which is beyond our scope, see a study by Pulerwitz et al.At our center, we largely use the third generation MDCT dual-source Somatom Force  scanner, which has the best temporal resolution in class (66 msec), allowing for consistent diagnostic imaging in patients with higher heart rates and atrial fibrillation. As such, premedication for heart rate control is typically not used. Volumetric MDCT scanners are recommended, as they provide whole heart coverage  at a single heartbeat, albeit with slower temporal resolution than dual-source scanners.The acquisition protocol starts with a single contrast bolus  injection with a flow rate of 4-7 mL/s, followed by 60 mL of a 100% saline chaser. Then, the cardiac scan acquisition is triggered using a bolus tracking method with the ROI at the descending aorta at the carina level after an attenuation threshold that varies according to the kV selected , typically at 120 HU. A retrospective ECG gated scan (full cardiac cycle coverage) is performed without dose modulation. After the cardiac scan, a high-pitch spiral scan immediately follows to allow for the assessment of appropriate transapical access planning with full chest imaging. Functional images are reconstructed in isotropic voxels of 1.0 mm at every 5% of R-R interval (0-95%). In cases with significant heart rate variability, manual ECG editing and absolute reconstruction at every 50 milliseconds based on the duration of the shortest R-R interval are performed to reduce motion artifacts, as exemplified in High-quality functional images are necessary for pre-TMVR MDCT assessment. Although the minimum requirement for TMVR would be a 64-detector-row single-source MDCT scanner, this platform can be challenging and often problematic, given the longer acquisition time and breath-hold need, increasing the likelihood for misregistration and motion artifacts, particularly in symptomatic patients who often have arrhythmias and/or faster heart rates. Suboptimal temporal resolution can further amplify such imaging artifacts and make TMVR planning difficult, particularly in the presence of mitral annular calcifications, high-density prosthetic materials, and cardiac arrhythmias.Screening and planning for TMVR includes assessment of risk of LVOTO, a potentially fatal complication of TMVR. After TMVR device implantation, the device struts displace the native AML toward the interventricular septum, thereby creating a neo-LVOT area confined by the deflected AML, the strut of the TMVR device, and the basal interventricular septum.2,2, all systolic phases should be evaluated and the mean neo-LVOT area value used to reference LVOTO prediction. This has to do with the fact that most left ventricular (LV) stroke volume is ejected during early to mid-systole, thus using only the end-systolic phase would be overconservative, excluding a significant proportion of patients that could still benefit from TMVR therapies.Neo-LVOT area thresholds predictive of LVOTO after TMVR are typically ≤1.7-2.0 cm,Modifications of neo-LVOT area might be necessary to reduce the risk of LVOTO post-TMVR. Techniques such as pre-emptive alcohol septal ablation 12,13 or Transseptal and transapical are the 2 main access routes used for TMVR. The location of the transseptal puncture or transapical access is key to achieving optimal coaxial TMVR device deployment. Cardiac MDCT can help identify the optimal access location to achieve the perpendicular coaxial trajectory to the mitral annulus by aligning fluoroscopic projections with key anatomical landmarks.18For transapical access planning, once the MDCT chest data set including the heart and ribcage is loaded, a virtual handle following a straight trajectory, coaxial to the mitral annulus centroid, is simulated, and the ideal intercostal space for the transapical access is evaluated . Commonl,Cardiac MDCT can also assist in the planning of the transseptal approach. Commonly, this site is inferoposterior to achieve the best height and coaxial approach to the MV and annulus. Fluoroscopic views should be provided to help intraprocedural guidance by TEE and fluoroscopy . The disDefining the fluoroscopic angles for optimal device deployment and anchoring is also an important role of preprocedural MDCT. The septal-lateral (SL) and the trigone-to-trigone (TT) angles are orthogonal to the mitral annulus axis. The TT is in a direction parallel to the TT distance, whereas the SL is perpendicular to the TT distance, as demonstrated in Transcatheter mitral ViV replacement is an FDA–approved TMVR treatment option for high-risk patients with degenerated surgical bioprosthetic valves. The safety and outcomes of this procedure have progressively improved, driven in large part by preprocedural MDCT planning. Recent registry data of 1529 mitral ViV TMVR procedures using the balloon-expandable THV SAPIEN 3 device had a 5.4% mortality at 30 days and 16.7% at 1 year, both rates substantially lower than predicted by Society of Thoracic Surgeons risk of operative mortality score.One of the first steps is to confirm, or at times to correct, the operative surgical report by identifying the size and type of the surgical heart valve (SHV).Proper sizing of the THV for TMVR ViV procedures is critical. Oversizing is often more aggressive in mitral ViV than aortic ViV to prevent device migration and embolization, which are more prone to occur in mitral ViV due because of higher systolic closing pressure. Currently, THV sizing is mainly based on the true inner diameter (true ID) of the SHV proposed by Bapat et al., whose ViV app is a critical planning tool for SHV reference and TMVR planning.,Particularly in the mitral ViV field, SHV leaflets must be considered for the neo-LVOT assessment. Porcine SHV leaflets have a shorter length  than bovine leaflets; therefore, after THV deployment, this shorter leaflet length does not cover all the THV cells interposing the LVOT, and usually, a larger neo-LVOT can be expected.The next step in the TMVR ViV planning requires simulation of the balloon-expandable transcatheter THV using specific postprocessing software. A virtual cylinder simulating the THV with adjustable diameter, height, sealing skirt height, and tilting angle is embedded in functional MDCT images and aligned with the SHV frame. The neo-LVOT area is traditionally measured in mid to late-systole with the cylinder in place, as demonstrated in Factors such as THV canting, tilting, and flaring toward the LVOT may reduce the neo-LVOT area. These factors are mainly procedure-related and more difficult to simulate, but careful MDCT analysis can provide some predictors. For example, if the aortomitral angle (angle between the SHV and the aortic annulus) is obtuse (≤115°), the risk of LVOTO may increase as the THV would be oriented by the SHV struts toward the LVOT.At least 25 different types of surgical mitral annuloplasty rings are currently available, with variable shapes, sizes, rigidity, and radiopacity. TMVR for ViR procedures was recently FDA-approved for high-surgical-risk patients using balloon-expandable Edwards SAPIEN 3 transcatheter aortic valve device. Given the circular shape of SAPIEN 3 THV device, the surgical annuloplasty ring must be or become circular to appropriately encircle the rounded THV during deployment. Circular rings up to size 34 mm, which can fit a SAPIEN 29 mm, are usually suitable for ViR. Oval rings, if deformable (semirigid) and complete, are also suitable ; however, as the ring circularizes and expands, the manufacturer’s ring dimensions are not reliable, and MDCT helps measure and estimate THV size. Incomplete rings or bands do not provide proper anchoring and are, usually, not suitable for ViR. Rigid rings provide proper anchoring, but oval- or D-shaped rings can deform the THV, leading to malfunction, intravalvular regurgitation, or (more commonly) PVL.,2. After ViR TMVR, the AML is displaced anteriorly (toward the septum) by the THV stent frame. When the AML is elongated, it may extend beyond the ventricular edge of the THV. This overhanging and often mobile part of the AML may move anteriorly toward the interventricular septum during ventricular systole leading to dynamic LVOTO,,The neo-LVOT assessment for ViR procedures is similar to ViV and ViMAC and is described in ,ViMAC using balloon-expandable THV or specific TMVR devices are treatment options for high-surgical-risk patients. Cardiac MDCT has been an integral component for preprocedural ViMAC planning by providing (1) anchoring parameters (MAC distribution and characteristics), (2) landing zone and oversizing dimensions, (3) neo-LVOT area and other predictors of LVOTO.MAC is a subannular process where the THV device fixation will occur. The MAC circumferential extent (in degrees) and its characteristics  are important predictors of THV migration or embolization, especially for devices in which the anchoring mechanism is through radial force . Circumferential and contiguous calcification that involves the fibrous trigones, preferentially not brittle or spiked, is required for proper THV anchoring. A recent MDCT-derived score was developed to predict THV migration or embolization for balloon-expandable THV using a combination of 4 MAC featuresThe MAC contour is irregular and has a 3-dimensional distribution, making accurate annulus or landing zone sizing more variable. Although the mitral annulus measurement methodology is not standardized for these patients, a reasonable approach is using a multiplanar reconstruction with a thick slab and maximum intensity projections.2. A higher cutoff may be used for ViMAC procedures to account for this factor. Similar to ViR, the presence of the AML may cause a dynamic LVOTO because of systolic anterior motion, and its length should be measured as already described  is under investigation for use in symptomatic patients with MR (with or without MAC) through the SUMMIT trial (NCT03433274). Its unique design and anchoring mechanisms offer potential advantages compared with balloon-expandable THVs. Initial multicentric data demonstrated Tendyne’s safety and effectiveness.The echocardiographic assessment post-TMVR evaluates LV function, device stability, LVOT velocity, residual MR or PVL, and postprocedural MV gradients. Assessment of new TMVR device leaflet mobility, presence/absence of hypoattenuated leaflet thickening, and device malposition can be challenging to assess by transthoracic echocardiography. Although routine post-TMVR MDCT imaging surveillance is not recommended outside of research protocols, post-TMVR MDCT should be considered whenever echocardiographic imaging is suboptimal, findings are ambiguous, and especially when transmitral gradients are elevated (>5-6 mmHg).The post-TMVR MDCT imaging acquisition protocol is similar to pre-TMVR implant with full cardiac cycle coverage and optional dose modulation. Post-TMVR hypoattenuated leaflet thickening with or without restricted leaflet mobility can be detected by MDCT even the mean transvalvular pressure gradient is minimally elevated . Post-TMCardiac MDCT is a fundamental diagnostic imaging tool for TMVR planning, enabling comprehensive evaluation of patient cardiac anatomy and function, which informs patient suitability, device selection, and risk of potential complications. The knowledge continues to evolve in this dynamic field, and constant developments require training and immersion from imagers involved to gain expertise in the planning of these procedures.The authors have no funding to report.10.13039/100006520Edwards Lifesciences, 10.13039/100008497Boston Scientific, 10.13039/100011949Abbott Vascular; and 10.13039/100016262Abbott Northwestern Foundation; research support from Circle Cardiovascular Imaging, 3Mensio, and 10.13039/501100011699Siemens Healthineers. P.S. has received consulting fees from Abbott Structural, Medtronic, Boston Scientific, Edwards Lifesciences Admedus, Gore and Teleflex; has received research grant support from Abbott Structural, 10.13039/100004374Medtronic, and 10.13039/100008497Boston Scientific; and has been a speaker for Abbott Structural. S.G. is a consultant for Medtronic, Edwards Lifesciences, and Abbott Vascular; received institutional research grants from 10.13039/100006520Edwards Lifesciences, 10.13039/100011949Abbott Vascular, Gore, and 10.13039/100008497Boston Scientific; and is a proctor for Edwards Lifesciences. M.G. has received consulting fees from Abbott Vascular and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.J.L.C. has received consulting fees from Abbott Vascular, Aria CV, Boston Scientific, Edwards Lifesciences, Medtronic, Gore WL, TriFlo, Xylocorand; has received institutional research grants from


Native T1 mapping values are elevated in acutely injured myocardium. We sought to study whether native T1 values, in the non-infarct related myocardial territories, might differ when supplied by obstructive or nonobstructive coronary arteries.N = 60, mean age 59 years) with the first STEMI following primary percutaneous coronary intervention, underwent cardiac magnetic resonance within 5 ± 2 days. A retrospective review of coronary angiography reports classified coronary arteries as infarct-related coronary artery (IRA) and non-IRA. Obstructive coronary artery disease (CAD) was defined as stenosis ≥50%. Native T1 values were presented using a 16-segment AHA model according to the three main coronary territories: left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA).Consecutive patients (p = 0.04). The cutoff native T1 value for predicting obstructive non-IRA RCA was 1,302 msec with a sensitivity and specificity of 83% and 55%, respectively . Logistic regression model adjusted for age and infarct size demonstrated that native T1 was an independent predictor for the obstructive non-IRA LAD  and RCA .The cutoff native T1 value for predicting obstructive non-IRA LAD was 1,309 msec with a sensitivity and specificity of 67% and 82%, respectively (AUC 0.76, 95% CI: 0.57–0.95, Elevated native T1 values are independent predictors of obstructive non-IRA in STEMI patients. These results suggest the presence of concomitant remote myocardial impairment in the non-infarct territories with obstructive CAD. Cardiac magnetic resonance (CMR) native T1 mapping allows accurate noninvasive quantitation of the myocardial damage by measuring the longitudinal myocardial relaxation , 3, 4. TN = 60) with the first STEMI between January 2017 and October 2018 were enrolled in a single-center study . STEMI was defined as per current guidelines, and clinical management was undertaken according to contemporary practice [Consecutive patients , and stenting of the IRA within 6 h of symptom onset. The decision to perform simultaneous non-IRA revascularization was at the discretion of the performing invasive cardiologist. Exclusion criteria included prior history of myocardial infarction, coronary artery bypass graft surgery, significant valvular disease, known cardiomyopathy, hemodynamic instability, implanted pacemakers or defibrillators, and claustrophobia. The control group consisted of 21 otherwise healthy volunteers  who underwent a dedicated CMR study in order to provide normal reference values of myocardial native T1, as part of 3 Tesla MRI scanner calibration. Written informed consent to perform CMR was signed by all subjects, according to the local institutional review board requirements. A binary definition of obstructive and nonobstructive coronary artery disease (CAD) was used: obstructive CAD was defined as ≥50% of stenosis and nonobstructive CAD was defined as <50% stenosis, or normal coronary arteries, according to the prior studies . A retro3 saline at 5 mL/sec, and 15 s later, the remaining contrast dose followed by 20 cm3 saline were infused at a slower rate of 1 mL/sec. Ten minutes after contrast injection, short-axis and 2-, 3-, and 4-chamber inversion recovery LGE images were acquired with an inversion-recovery gradient-echo imaging sequence to evaluate focal myocardial fibrosis. The infarct size was determined by the percentage of myocardial LGE that was calculated using the standard 5SD method . LV ejection fraction and T1 maps were analyzed using a dedicated platform  by two experienced readers  who were blinded to the clinical data of patients.CMR was performed using a 3 Tesla MRI scanner  5 ± 2 days post-primary PCI. The CMR protocol included the following sequences: Balanced Turbo Filed Echo (BTFE), native modified look-locker inversion (MOLLI) recovery T1 mapping, and late gadolinium enhancement (LGE). To assess left ventricle (LV) systolic function, consecutive 8-mm short-axis images and 2-, 3-, and 4-chamber long axis images of the LV were acquired using a cine BTFE. Short-axis cine images were acquired covering the entire LV using retrospective gating. Two to three-fold accelerated parallel imaging (SENSE) was used to shorten the breath-hold. Three-ventricular short axis MOLLI images were acquired at the base, midpoint, and apex of the LV for native T1 evaluation. Native T1 was acquired using MOLLI 5s(3s)5s. Typical imaging parameters − field of view: 300 × 300 mm, slice thickness 10 mm, slice gap 5 mm, flip angle 20°, repetition time 2.14 msec, echo time 0.96 msec, matrix 142 × 142 pixels, actual experimental pixel size = 2.1 × 2.1 mm, interpolated reconstructed pixel size = 1.17 × 1.17 mm, SENSE factor 2, trigger delay end-diastole, inversion times ranging from 129 to 5,466 msec, 206 msec acquisition time for single image, MOLLI native T1 maps were generated from 3 BTFE images with variable inversion preparation time as previously described [T1 maps were evaluated for technical image quality, excluding segments with breathing, motion, or adjacent extra-cardiac tissues-related artifacts. After visual assessment of confident maps, motion correction was performed if needed. Segmental T1 values were derived from short-axis T1 maps using a 16 segment AHA model in relation to three major coronary artery territories , 10. Segp value”), linear regression , and a t test to compare the obstructive and nonobstructive groups . The specificity and sensitivity of the mean native T1 value for predicting obstructive non-IRA stenosis (for each vessel separately) were assessed using the C-statistic, equivalent to the area under the receiver-operating characteristic curve [All variables with a normal distribution are expressed as mean and standard deviation (SD). Native T1 values were presented as mean ± SD value per coronary territory  and compared between the IRA, non-IRA obstructive (stented and not stented), and non-IRA nonobstructive coronary arteries. The mean native T1 value (per coronary territory) was tested with a one-way ANOVA test . Thus, 853 myocardial segments comprised the study group. The control group included a total of 336 myocardial segments, out of which 22 segments (6%) were excluded due to artifacts . Baseline characteristics of the study cohort are presented in Table . Average LV ejection fraction was 53 ± 11%. The average infarct size by LGE % of LV mass was 26 ± 12. LGE was present only in infarcted segments.The study cohort included 60 STEMI patients with a total of 960 myocardial segments, out of which 107 segments (11%) were excluded due to artifacts  was performed in 9/20. Triple-vessel obstructive CAD was documented in 9/60 of the patients; of them, complete revascularization (IRA and non-IRA) was performed in 1/9 patient. Thus, a total of 40/60 patients underwent complete revascularization. The decision to re-vascularize a non-IRA during the primary PCI was under the discretion of the performing invasive cardiologist. Staged PCI was scheduled and performed  in the rest of the patients 19/60. No patients with ≥50% left main stenosis were present in the cohort; thus, the revascularization of the left main stem was not performed.p < 0.001). Native T1 values in all IRA territories were significantly higher in comparison to the non-IRA territory and the control group in a per-vessel analysis (Table p = 0.016) and RCA (p = 0.007) territories but not for LCX (Table p = 0.04), shown in Figure 1. The cutoff native T1 value for predicting obstructive non-IRA RCA was 1,302 msec with a sensitivity and specificity of 83% and 55%, respectively , shown in Figure p = 0.31). Logistic regression model to predict the obstructive non-IRA after adjustment for age and infarct sizes demonstrated that native T1 value was an independent predictor of obstructive non-IRA LAD  and obstructive non-IRA RCA   on CMR performed early following STEMI. Native T1 values were found to be independent predictors of obstructive non-IRA LAD and RCA, after adjustment for the patient's age and infarct size. Using receiver-operating characteristic analysis, native T1 thresholds for distinguishing obstructive from nonobstructive vessel were found to be 1,309 msec for the LAD and 1,302 msec for the RCA. Thus, the early post-STEMI CMR with native T1 mapping may offer noninvasive, quantitative evaluation of the entire myocardium including the either infarct or the remote non-infarct territories. Despite the finding of significantly elevated T1 values in IRA-LCX, T1 values were not found to be significantly different between obstructive and nonobstructive non-IRA LCX. This was partly because of the cases of dominant LCX artery, LCX segments were classified as RCA, thus decreasing the number of the actually analyzed LCX segments, thus influencing the statistical results. Interestingly, no significant difference was found between native T1 values in the stented versus non-stented obstructive non-IRA in STEMI patients. A plausible explanation could be that early post-PCI myocardial relaxation time does not immediately normalize due to residual stunning or micro-embolization during PCI.Native T1 values reflect the physical magnetic properties of myocardium, measuring the longitudinal relaxation time, and are increased in segments with myocardial impairment. Native T1 mapping allows the detection of focal or diffuse myocardial fibrosis in various conditions, e.g., cardiomyopathies, myocardial inflammation (as myocarditis) or infiltration , as well as ischemic myocardial damage. The cutoff stenosis of >50% for obstructive CAD has been used in prior nuclear study . Liu et Multivessel coronary disease is common among STEMI patients undergoing primary PCI and is associated with increased 30-day mortality . PreviouThe study is retrospective with a relatively small cohort. There were a relatively small number of patients with LCX-IRA. Also, LCX segments were documented with non-negligible artifacts, leading to exclusion from analysis. Thus, the analysis of LCX-related myocardial segments was not representative. Native T1 values were not evaluated before and after revascularization, and thus, the discussion regarding the peri-procedural native T1 dynamics is beyond the scope of this study. Extracellular volume was not analyzed in infarct or non-infarct remote areas. It also must be mentioned as a clinical heterogeneity in the study by leaving complete revascularization at the discretion of the interventional cardiologist.The current study documented significantly higher mean native T1 values in the non-infarct territories supplied by obstructive coronary arteries. Elevated native T1 values are independent predictors of obstructive non-IRA in STEMI patients.The study was reviewed and approved by the Sheba IRB-Helsinki Committee  5897-19-SMC. Written informed consent for patient participation was not required for this study in accordance with the national legislation and the institutional requirements.No funding sources to declare.Yafim Brodov: substantial contributions to the conception or design of the work; acquisition, analysis, gathering or interpretation of data for the work; drafting the work and revising it critically for important intellectual content; and final approval of the version to be published. Shlomi Matetzky and Eli Konen: drafting the work or revising it critically for important intellectual content and final approval of the version to be published. Mattia Di Segni: contributions to the design of the work (data gathering). Anan Younis: contributions to the design of the work (data gathering and management). Ayas Massalha, Anat Berkovitch, and Fernando Chernomordik: contributions to the design of the work (data management). Arkadi Beytelman: contributions to the design of the work . Orly Goitein: substantial contributions to the conception or design of the work; acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; and final approval of the version to be published.No conflict of interest to disclose.All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.


Coronary microcirculation has multiple layers of autoregulatory function to maintain resting flow and augment hyperemic flow in response to myocardial demands. Functional or structural alterations in the coronary microvascular function are frequently observed in patients with heart failure with preserved or reduced ejection fraction, which may lead to myocardial ischemic injury and resultant worsening of clinical outcomes. In this review, we describe our current understanding of coronary microvascular dysfunction in the pathogenesis of heart failure with preserved and reduced ejection fraction. Percutaneous revascularization for epicardial coronary artery disease (CAD) as an initial treatment strategy did not improve survival even in chronic coronary syndrome patients with evidence of moderate-severe ischemia  . Revascu−6, 10−5, and 10−4 mol/L]: %change in CBF), 33% had isolated endothelium-independent CMD , and 10% had combined CMD, leaving a total of 72% with abnormal coronary microvascular function. Importantly, no single clinical characteristics could identify the presence of either endothelium-dependent or endothelium-independent CMD. Both endothelium-dependent and endothelium-independent CMD were associated with higher all-cause mortality; however, patients with endothelium-dependent CMD displayed a greater left ventricular end-diastolic dimension, while those with endothelium-independent CMD displayed impaired left ventricular diastolic function with a higher E/e’ ratio, indicating that both pathways have different effects on the pathophysiology of HFpEF  can frequently manifests in patients with heart failure with preserved ejection fraction (HFpEF). PROMIS-HFpEF  trial is a prospective multinational multi-center observational study enrolling 202 patients with HFpEF (left ventricular ejection fraction [LVEF] ≥40%), revealing that 75% of patients with HFpEF had CMD defined as adenosine stress transthoracic Doppler echocardiography-derived coronary flow reserve (CFR) <2.5 in the absence of unrevascularized epicardial CAD . One-yeaof HFpEF .The effects of the endothelium-dependent and endothelium-independent CMD on hemodynamics during exercise were rigorously analyzed in 51 patients who underwent exercise right heart catheterization and concurrent invasive coronary reactivity testing for assessment of unexplained exertional symptoms in the absence of obstructive CAD (<50% stenosis) and impaired systolic left ventricular function (LVEF >50%). Pulmonary artery wedge pressure (PAWP) at peak exercise was significantly higher in patients with endothelium-dependent CMD or endothelium-independent CMD than those without, with a significant negative correlation between mean PAWP at peak exercise and %change in CBF in response to acetylcholine (an indicator of endothelium-dependent coronary microvascular function) or CFR (an indicator of endothelium-independent coronary microvascular function). Furthermore, this study uniquely demonstrated that higher CFR was significantly correlated with a greater exercise capacity, while there was no significant correlation between %change in CBF and exercise capacity, underlining the mechanistic importance of endothelium-independent pathway in HFpEF pathology . In factAtrial fibrillation (AF) is frequently observed in patients with HFpEF, and its presence has been associated with poorer long-term clinical outcomes , 17. ComTET2 and DNMT3A, and an increased risk of cardiovascular disease, possibly via the interleukin-6 (IL-6) signaling pathway (TET2 and DNMT3A is an independent risk factor for CMD, with CHIP mediating 32% of the increased risk of major adverse cardiovascular events in CMD patients (Endothelium-independent CMD, characterized by a decline in coronary flow reserve - defined as the ratio of hyperemic flow to resting flow - can be attributed to either increased resting flow or decreased hyperemic flow. The former subtype has been linked to dysfunctional autoregulation of the coronary microvasculature, while the latter has been associated with structural microvascular alterations in CMD. In diabetic patients, a decline in CFR has been observed in conjunction with increasing resting coronary flow , 26. In  pathway , 53. Anopatients . Higher patients . These dpatients . Althougpatients . A recenpatients . FurtherThere is scarce evidence for an association between CMD and HFrEF in comparison to HFpEF. Given the systemic nature of microvascular disease –64, the Coronary microvascular dysfunction can often coexist in heart failure patients with preserved and reduced ejection fractions. Although the underlying pathophysiology of functional or structural CMD may differ, both may equally contribute to worse clinical outcomes. There is a paucity of available data on whether comorbid CMD is a potential target for heart failure therapy. Furthermore, it needs to be clarified whether different CMD subtypes respond differently to a treatment. However, further phenotypic assessment of heart failure patients may pave the way to a clearer understanding of the pathogenesis of heart failure and the unmet clinical needs of heart failure patients.


Background: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are commonly used anticoagulants for the management of arterial and venous thromboses. However, it is crucial to be aware that LMWH can, in rare cases, lead to a dangerous complication known as heparin-induced thrombocytopenia (HIT). The objective of this study was to evaluate the pharmacovigilance and clinical features of HIT associated with LMWH, as well as identify treatment strategies and risk factors to facilitate prompt management.Methods: We extracted adverse event report data from the FDA Adverse Event Reporting System (FAERS) database for pharmacovigilance assessment. Case reports on LMWH-induced thrombocytopenia dated up to 20 March 2023 were collected for retrospective analysis.Results: Significantly elevated reporting rates of HIT were shown in adverse event (AE) data of LMWHs in the FAERS database, while tinzaparin had a higher proportional reporting ratio (PRR) and reporting odds ratio (ROR) than other LMWHs, indicating a greater likelihood of HIT. Case report analysis indicated that a total of 43 patients showed evidence of LMWH-induced thrombocytopenia with a median onset time of 8 days. Almost half of the events were caused by enoxaparin. LMWHs were mainly prescribed for the treatment of embolism and thromboprophylaxis of joint operation. Patients with a history of diabetes or surgery appeared to be more susceptible to HIT. Clinical symptoms were mostly presented as thrombus, skin lesion, and dyspnea. Almost 90% of the patients experienced a platelet reduction of more than 50% and had a Warkentin 4T score of more than 6, indicating a high likelihood of HIT. In all patients, LMWHs that were determined to be the cause were promptly withdrawn. Following the discontinuation of LMWHs, almost all patients were given alternative anticoagulants and eventually achieved recovery.Conclusion: LMWH-induced thrombocytopenia is rare but serious, with increased risk in patients with diabetes or a surgical history. Prompt recognition and management are crucial for the safe use of LMWHs. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have been extensively studied and have demonstrated efficacy in the treatment of arterial and venous thromboses. They are commonly prescribed for conditions such as deep vein thrombosis, pulmonary embolism, acute coronary syndrome, and prophylaxis in high-risk surgical procedures . HeparinIn recent years, increasing efforts have been made to improve the diagnosis and management of HIT. Advances in laboratory testing, including enzyme-linked immunosorbent assays (ELISAs) and functional assays, have improved the specificity and sensitivity to HIT antibodies. In addition, novel non-heparin anticoagulants, such as direct oral anticoagulants (DOACs), have been developed as alternative therapies for HIT. However, despite these advances, HIT remains a challenging diagnosis that requires a high index of suspicion and prompt initiation of appropriate therapy to reduce the risk of thromboembolic complications. The importance of early recognition and appropriate management of HIT cannot be overstated, as delays in diagnosis and treatment can result in terrible consequences, including limb loss, organ damage, and even death .To date, there is a paucity of data regarding HIT associated with LMWHs. In our study, we extracted adverse event report data from the FAERS database for pharmacovigilance assessment and subsequently collected case reports on LMWH-induced thrombocytopenia for a real-world retrospective analysis. We summarized clinical features, risk factors, management, and outcomes of patients with HIT after anticoagulation with LMWHs, which will provide valuable information for the prompt recognition and management of HIT.The FAERS database, which is the drug adverse event reporting system of the US FDA, collects adverse event report data for various drugs, providing strong evidence for drug safety and pharmacovigilance. In order to assess the safety of LMWHs and evaluate the risk of their adverse events (AEs) in clinical use, we retrieved and extracted AE data reported between Quarter 1(Q1) in 2004 and Q3 in 2022 for seven types of LMWHs  from the data publicly released by the FAERS database .After extraction, the data were initially utilized for baseline analysis, which included variables like gender, age, outcomes, and reporter country. The AEs extracted were then classified according to the Medical Dictionary for Regulatory Activities , which included categories such as vascular and lymphatic disorders, gastrointestinal disorders, infections and infestations, respiratory disorders, and metabolic and nutritional disorders, among others. We selected HIT among AEs related to vascular and lymphatic disorders and analyzed the association of these LMWHs with HIT by calculating the proportional reporting ratio (PRR) and reporting odds ratio (ROR). In this process, the keywords of PT were set as “heparin-induced thrombocytopenia,” “heparin-induced thrombocytopenia test,” and “heparin-induced thrombocytopenia test positive.”2 > 4, and N >2. For ROR, the screening criteria for a significant signal were the lower limit of two-sided 95% confidence interval (CI) > 1 and N >2.In pharmacovigilance assessment, disproportionality emerges when a specific AE is induced by a given drug. We used PRR and ROR to identify the statistical associations between LMWHs and HIT. PRR and ROR are calculated using the following formulas: PRR = [a/(a+b)]/[c/(c + d)]; ROR = (a/c)/(b/d). In the formula, “a” represents the number of reports of a specific AE caused by the given drug; “b” represents the total number of all other AEs related to the given drug; “c” represents the number of reports of a specific AE caused by all other drugs; and “d” represents the total number of all other AEs related to all other drugs . For PRRUsing PubMed/MEDLINE, Web of Knowledge, Embase, Ovid, Springer Link, Elsevier, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Chinese VIP databases, our searches for relevant literature were performed using the following keywords: “enoxaparin,” “bemiparin,” “edoxaban,” “nadroparin,” “tinzaparin,” “reviparin,” “parnaparin,” “low-molecular-weight heparin,” “heparin-induced thrombocytopenia,” “heparin related thrombocytopenia,” “anticoagulant-related HIT,” “anticoagulant-related HIT,” “anticoagulant associated HIT,” and “HIT.” Case reports and case series of HIT associated with LMWHs were included as preliminary studies. Duplicate literature, reviews, mechanism research, observational studies, animal studies, and articles without full text were excluded. We conducted thorough searches of various electronic databases without any specified start date up to 20 March 2023 and with no language restrictions.We used self-designed tables to extract various clinical features of the patients from cases. These features included gender, age, anticoagulant administration, medical history, combined medication, baseline platelets or PLT, clinical manifestations of HIT, coagulation function, liver and kidney function, the time from taking LMWHs to HIT diagnosed, peak PLT at HIT diagnosis, anti-PF4 antibody, Warkentin 4T score, platelet recovery time, treatments, and prognosis. Specifically, the Warkentin 4T score in HIT incorporates four criteria: extent of platelet reduction, timing of platelet reduction, presence of thrombosis, and other causes of platelet reduction. Each criterion is assigned a score ranging from 0 to 2 points, with a higher cumulative score indicating a greater likelihood of HIT.We retrieved information about three out of seven LMWHs available in the FAERS database: enoxaparin, dalteparin, and tinzaparin. As the FAERS database only recorded adverse events of HIT related to these three LMWHs, our analysis focused on these drugs. The AE data of three types of LMWHs in the FAERS database help comprehensively understand the safety profiles of these drugs. The overall number of the reported AEs of enoxaparin, dalteparin, and tinzaparin was 242, 34, and 30, respectively. Most AEs of the three LMWHs occurred in people aged over 60, ranging between 50% and 70%. The proportion of AEs in male and female patients is similar. Among the AEs of enoxaparin and tinzaparin, male patients accounted for more than 50%, and in the AEs of dalteparin, female patients accounted for more than 50%. The LMWH with the highest proportion of deaths among the outcomes of AEs was tinzaparin, accounting for 36.67%, while the lowest was enoxaparin, accounting for 21.90%. Enoxaparin had the highest proportion of reported cases in the United States, accounting for 38.43% .Since HIT related to nadroparin, bemiparin, reviparin, and parnaparin was not reported in the FAERS database, we only obtained PRR and ROR values of HIT for the other three drugs. PRR and ROR are used to measure the likelihood of a specific AE occurring with a drug, with higher values indicating a stronger association between the drug and the given AE. The PRR values of HIT for enoxaparin, dalteparin, and tinzaparin were 98.22, 100.48, and 195.81, and the ROR values for these three LMWHs were 100.51, 103.10, and 206.06, respectively. Tinzaparin had higher PRR and ROR values, indicating a greater likelihood of HIT occurring with this drug compared to the other two LMWHs .A total of 43 patients from 40 studies were included in this analysis after full-text screening, involving 39 case reports  and one The clinical characteristics of HIT presented by the 43 included patients are summarized in ^9/L. In a subset of cases, the decrease in PLT count was even more severe, with four patients having a PLT count below 20 × 10^9/L. Additionally, nearly 90% of patients had a PLT reduction ratio greater than 50%. The lowest PLT count and the proportion of PLT decrease varied among different drugs  count compared to their baseline, with 77.5% of patients having a PLT count of less than 100 × 10nt drugs . Among tr levels . ElevateThe treatments of HIT were recommended to immediately stop heparin therapy and initiate non-heparin-based anticoagulants. In our included cases, LMWHs, judged as the culprits, were immediately withdrawn in all patients . Almost Concerns have been raised regarding the risk of HIT in patients exposed to UFH, while there are limited data on HIT associated with LMWHs in recent years. HIT induced by LMWHs is often overlooked. This study investigated the characteristics of the AEs caused by three types of LMWHs in the FAERS database, as well as the reporting rate for HIT events. Additionally, we conducted a literature review on the cases of HIT caused by LMWHs to further understand the features, treatments, and prognoses of these patients. The results from the literature review and the FAERS database analysis showed some similarities to a certain extent. Specifically, in terms of age, the proportion of AE reports involving LMWHs in the database was similar to that reported in the literature, with a higher proportion observed in older individuals (over 60 years of age). Regarding outcomes, the reporting rates of death events associated with the three types of LMWHs in the database ranged from 20% to 37%. Similarly, out of the 43 reported cases of HIT, one resulted in death, one worsened, and 41 patients recovered. These findings suggest that with appropriate clinical intervention, most cases of HIT can be successfully treated and resolved. Furthermore, the analysis of the database revealed that tinzaparin had the highest PRR and ROR values for HIT, indicating a potentially higher likelihood of causing HIT compared to other LMWHs. On the other hand, based on the case literature reports, enoxaparin was found to be associated with the highest number of HIT cases.HIT is a rare and serious AE caused by heparin, which can be divided into type I and type II. Type I is an early-onset, mild thrombocytopenia that does not lead to thromboembolism, whereas type II is immune-mediated and clinically severe, causing both thrombocytopenia and thromboembolism with approximately 50% of patients developing arterial or venous thrombosis usually occurring 5–10 days after starting heparin therapy . LMWH haThe immunopathological mechanism underlying the development of HIT is still unclear. PLT factor 4 (PF4) is a positively charged protein released from the α-granules of activated platelets and combines with the negatively charged heparin through the electrostatic interaction of the vascular epidermis to form a complex . ImmunogIn this study, the primary causes of the use of LMWH were mainly the treatment of thrombosis and the thromboprophylaxis of joint operation, fractures, surgical procedures, and dialysis. In addition patients are often accompanied by a history of diabetes, surgery, obesity, hypertension, or tumors. These factors deserve special attention from clinical physicians. Although the prognosis of HIT is relatively good, the mortality rate can be as high as 20%–30%, if timely diagnosis and intervention are not employed. It is extremely important to closely monitor the PLT count to prevent the occurrence of HIT . It is sThis study is the first drug safety study that combines the FAERS database and case reports to study HIT induced by LMWHs. The advantage of this study is that it makes full use of the database and literature resources and comprehensively collects and analyzes a large amount of relevant data, so as to deepen the understanding of the occurrence and characteristics of HIT. This study can provide some guidance for improving clinical prognosis; however, there are certain limitations. First, although the sample size is relatively large, the data are not complete because the FAERS database and literature cases can only provide an analysis of the existing data and cases, ignoring unreported or unprocessed information, so the results may have selection bias. Second, this method cannot directly explain the mechanism underlying the development of HIT caused by LMWHs and requires specific mechanisms to be studied through cell and animal experiments. Third, the lack of multivariable analyses here to implicate the specific role of LMWH in the development of HIT while controlling for other clinical factors is a major limitation to the study. Lastly, prospective or randomized controlled trials are needed to elucidate the relevant characteristics of HIT induced by LMWH administration.HIT is a rare but potentially fatal complication of LMWHs. Due to its low incidence and difficult diagnosis, it is often overlooked by clinicians, thus leading to serious outcomes without timely and effective intervention. However, adverse outcomes can be completely avoided by strengthening the understanding of the disease. Our research found that patients who are obese, diabetic, infected, or having a history of surgery, hypertension, or tumor are more likely to develop HIT during LMWH anticoagulation. The pathological mechanism underlying the development of HIT is complex, and the most obvious pathological features are thrombocytopenia and thrombosis. The current guidelines recommend close monitoring of PLT changes and timely HIT antibody testing, if HIT is suspected after LMWH administration. These are critical for treatment and prognosis. In the future, further prospective studies are needed to clarify the risk factors, pathological mechanisms, and related treatments of HIT.


Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure–volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems-level cardiovascular dynamics can quantitatively reproduce in-vivo data and qualitatively match prior findings from animal studies on LV ischemia.Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure–volume loop data (The online version contains supplementary material available at 10.1007/s10439-023-03293-z. Coronary artery disease, which can lead to myocardial infarction, accounts for roughly 41% of all cardiovascular-related deaths . AcutelyThe right ventricle (RV) is mechanically linked to the LV through the interventricular septum (S). Previous canine studies  in the aIn-vivo experiments provide insightful but isolated measurements of cardiovascular function. In-silico computational models can integrate multimodal data  from in-vivo experiments to characterize a subject’s hemodynamic state. These models can also test mechanistic hypotheses surrounding disease progression. For example, early work using isolated ventricular elastance models in a closed loop compartment model investigated the link between LV systolic dysfunction and pulmonary venous pressure . While rThese prior computational studies did not explicitly account for biventricular interaction or include multiscale mechanisms. The cutting-edge reduced order model of ventricular interaction is the three-segment (“TriSeg”) model by Lumens et al., which represents the LV, RV, and S as thick walled, spherical chambers driven by myocyte dynamics . SeveralHere, we combine our previously reported multiscale model  with dat3 and used in the computational model described later. We assume the septum occupies 1/3 of the LV volume [All animal procedures were approved by the University of Wisconsin-Madison Institutional Animal Care and Use Committee. Three adult C57/B16 male mice (20–22 weeks old) were anaesthetized with 5% isoflurane and maintained with 1–2% isoflurane and room air throughout all procedures. Mice were put on a heated platform to maintain a body temperature of 37 °C and measure ECG activity. Transthoracic echocardiography  was used to identify systolic and diastolic inner diameter and fractional shortening for both the LV and RV. A cutdown was performed on the right carotid artery and a 1.2 Fr pressure catheter (Transonic) was placed and advanced to the ascending aorta to measure systemic pressures. Finally, the thoracic cavity was entered, and the heart was exposed. A 1.2 Fr pressure–volume catheter with 4.0 mm spacing (Transonic) was inserted into the LV via direct stick through the myocardial wall. Baseline systemic and LV data were recorded. The catheter was removed and a second 1.2 Fr pressure–volume catheter with 3.5 mm spacing (Transonic) was place in the RV free wall aligned with the pulmonary valve. Baseline systemic and RV data were collected. A 7-0 suture was placed around the left anterior coronary artery mid-ventricle and tied while still recording RV data. Typical ECG changes and blanching were noted. Pressure and volume measurements were recorded at 500 Hz and analyzed on commercially available software . Then, the mice were sacrificed and the four heart chambers were dissected and weighed . Heart cV volume . A schemWe use the MATLAB  Gaussian smoothing filter to smooth pressure–volume signals. We use a smoothing factor of 0.05, corresponding to 11-45 data point smoothing depending on signal length. We visually inspected signals to ensure systolic, diastolic, and general waveform shape were maintained. In-house algorithms were used to separate signals into beat-by-beat datasets for analyses. To account for discrepancies in pressure–volume phase due to catheter placement, volume traces were slightly shifted to ensure maximal chamber volume occurred at the upstroke of ventricular pressure. We use a heartbeat averaged waveform from each animal and cardiovascular component when performing model calibration and uncertainty quantification.We use a previously developed multiscale cardiovascular model , 18. TheThe sarcomere length ero load . SarcomeThe decay in activation saturates at the diastolic value quations  and 5)  \documenThe active stress, arameter . PassiveThe passive stresses are separated into those attributed to the extracellular matrix (ECM) and Titiniffening .3), mid-wall curvature 2) and parameterized by a reference mid-wall area, 2), and a wall volume, 3). Tension balance across the LV, RV, and S walls are enforced by two algebraic constraints. Details regarding the chamber equations can be found in the Supplementary Material. All four heart chambers are enclosed in a pericardium. We assume that the pericardial sack has a reference volume, The sarcomere model is embedded within each cardiac chamber and the interventricular septum. Ventricular interaction across the septal wall is prescribed using the TriSeg model . Cardiache heart . PericarArteries and veins are modeled as compliant compartments. Changes in blood volume mentclass2pt{minim3. [The mathematical model includes 18 differential equations  . This erThe inferred log-scaled parameters, entclass1pt{minimaculating 16\documeThe matrix equation , and \doentclass1pt{minimainterval . We expoThe corresponding response confidence and prediction intervals around the optimal model output, https://github.com/mjcolebank/Colebank_2023_AcuteIschemia).We simulate myocardial infarction by reducing LV active force at the sarcomereEchocardiography and pressure–volume loops for each mouse are shown in Fig. A total of 100 Morris screening initializations were run per mouse. Parameter ranking for the five different model outputs are provided in Fig. The remaining 20-parameter subset is examined using local sensitivity analysis for each mouse. The matrix .We infer entclass1pt{minimaWe simulate ischemia by decreasing the LV active force generation using entclass1pt{minimaWe also investigate the systems-level effects of LV ischemia. Figure Longitudinal strains for the LV, RV, and S at baseline and during ischemia are provided in Fig. To better understand the effects of decreased LV contractility, we show LV pressure versus sarcomere length for various values of This study combines multiscale computational modeling and parameter inference with in-vivo rodent data to investigate the acute biventricular consequences of LV myocardial ischemia. We identified a subset of cardiovascular parameters that can be made mouse-specific and calibrated them to hemodynamic data. We demonstrate that simulated acute LV ischemia raises septal wall strain, elevates left atrial pressure, and alters LV pressure–length relationships while RV function is relatively unchanged.Multiscale models suffer from an imbalance in the number of model parameters versus available data. This inhibits inferring all system parameters and requires model analysis for robust parameter subsets. Morris screening is an efficient global sensitivity method to determine which parameters are non-influential, reduce simulation uncertainty, and enforce unique parameter values for each dataset . Our scra et al.  performeWe employed local sensitivity methods to further reduce our parameter space. Colunga et al.  used locIdentifying animal-specific parameters from in-vivo data can provide insight into unmeasurable properties of the cardiovascular system. Invasive measurements usually require multiple animals for sufficient evidence to test hypotheses; however, a combination of these data with mechanistic modeling can help investigate mechanisms of disease at a reduced animal burden. These models can also link data from multiple scales and multiple organs to highlight their underlying interactions, which is difficult to do with experiments alone.Several previous studies have calibrated models to pressure–volume data in rodents. The study by Tewari et al.  calibrat rodents , yet thientclass1pt{minima rodents  showed tCalibrated model simulations shown in Fig. Uncertainty quantification is a necessary, but often overlooked, step in the model analysis pipeline. Parameter confidence intervals, as determined in this work, provide substantially more information than point estimates alone. These analyses are warranted, especially as in-silico models gain traction as a potential bench side tool in the clinic. Here, we use asymptotic analyses based on frequentist statistical theory and incorporate heteroskedasticity by constructing error variance estimates for each measurement location , 20. ModMyocardial infarction is a precursor to long-term cardiac dysfunction and a risk factor for heart failure. There are multiple systems-level changes that occur during the onset of LV ischemia, which are critical in understanding survival rates and long-term cardiac remodeling . A combiData from all three mice show a reduction in fractional shortening and LV contractile function during ischemia. We simulate impaired LV function by reducing the active force generation by sarcomere shortening in the LV. Other authors have considered more sophisticated simulation strategies for ischemia. Witzenburg et al.  separateOur simulated LV pressure–volume loops in Fig. Experimentally, Damiano et al.  examinedData from both ventricles enhance estimates of ventricular indices, including stroke work Fig. b. PhilipThe effects of myocardial infarction on LV systolic function are well studied, yet less work has focused on global changes during acute LV ischemia. Left atrial pressure–volume loops shift upward Fig.  with theStrain results Fig.  confirm As LV active force is reduced Below is the link to the electronic supplementary material.