Cardiovascular research is in an ongoing quest for a superior imaging method to integrate gross-anatomical information with microanatomy, combined with quantifiable parameters of cardiac structure. In recent years, synchrotron radiation-based X-ray Phase Contrast Imaging (X-PCI) has been extensively used to characterize soft tissue in detail. The objective was to use X-PCI to comprehensively quantify ischemic remodeling of different myocardial structures, from cell to organ level, in a rat model of myocardial infarction. Myocardial infarction-induced remodeling was recreated in a well-established rodent model. Ex vivo rodent hearts were imaged by propagation based X-PCI using two configurations resulting in 5.8 µm and 0.65 µm effective pixel size images. The acquired datasets were used for a comprehensive assessment of macrostructural changes including the whole heart and vascular tree morphology, and quantification of left ventricular myocardial thickness, mass, volume, and organization. On the meso-scale, tissue characteristics were explored and compared with histopathological methods, while microstructural changes were quantified by segmentation of cardiomyocytes and calculation of cross-sectional areas. Propagation based X-PCI provides detailed visualization and quantification of morphological changes on whole organ, tissue, vascular as well as individual cellular level of the ex vivo heart, with a single, non-destructive 3D imaging modality. While ischemic heart disease is one of the most studied cardiac pathologies, many questions remain regarding the understanding of myocardial remodeling with improved treatment and more tissue salvage as the ultimate goal. To develop protective or tissue repair strategies, the in-depth understanding of the underlying pathophysiological processes and the involved structural changes of the heart are of paramount importance. Ideally this is amalgamated in an imaging modality enabling the integration of structural information from cell to organ level.1. These processes may result in changes in cardiac size, myocardial mass,  geometry, cardiomyocytes appearance and orientation, and ultimately function of the whole organ, thus having a profound impact on patient outcome. One of the typical examples of negative cardiac remodeling is induced by ischemic heart disease, with a myocardial infarction (MI) being the trigger of an adverse cascade. Major insights in the remodeling processes have been gained from animal models of cardiovascular disease  where using ex vivo gross anatomical morphology or histology have improved our knowledge of the induced changes5.Cardiac remodeling is a combined response of cardiomyocytes and other cells, myocardial tissue, and the heart as an organ, to different adverse pathophysiological processes In clinical practice, ischemic heart disease is assessed by means of diagnostic imaging modalities, encompassing those that visualize the coronary arteries, but also that quantify the resulting adverse remodeling: coronary angiography, echocardiography, magnetic resonance imaging, computed tomography, and nuclear cardiology imaging are often combined as complementary techniques. Histopathological analysis is seldom utilized in routine clinical assessment of myocardial remodeling, but remains a standard research tool for detailing tissue and cell structure, while additional methods of histochemical staining help differentiate the expression of specific cellular or extracellular signals in tissues. Cardiovascular research, as well as clinical cardiology, are in an ongoing quest for a superior (imaging) method that could integrate gross-anatomical information with microanatomy, combined with quantifiable parameters of cardiac structure.16.In recent years, synchrotron radiation-based X-ray Phase Contrast Imaging (X-PCI) has been extensively used to characterize soft tissue in detail. Synchrotrons are large scale facilities that generate highly collimated and brilliant X-ray beams. By exploiting the refractive properties of these beams in dedicated setups, X-PCI is able to image soft tissues or organs non-destructively in 3D and at high-resolution (down to < 1 µm), with increased contrast in comparison to conventional absorption imaging. Particularly in the cardiovascular field, X-PCI has so far been utilized for ex vivo imaging of animal models, human fetus hearts and transmural samples of adult human hearts, both normal and diseasedThe aim of our study was to use X-PCI to comprehensively quantify remodeling of different myocardial structures, from cell to organ level, as a consequence of MI in a rat model.The obtained 3D datasets can be easily used to assess the gross anatomical features of imaged hearts. In Fig. Supplementary Figure When quantifying LV cavity volumes, myocardial mass and wall thickness; thinner walls, larger cavity volumes and increased myocardial mass were observed in the infarcted hearts as compared to the control rat heart  values of an infarcted and control rat heart is shown in Fig. As expected, the HAs in control heart show predominance of positive angles in the endocardium with a smooth progression to negative angles when approaching the epicardium. A similar pattern of cardiomyocyte organization can be seen in the non-affected segments of the post-MI heart. In the infarct zone, the HA still show the ‘normal’ positive values at the endocardium  shows clear differences in the local cardiomyocytes organization between different regions of the post-MI heart, as well as between the control rat heart and post-MI hearts in general Table . MI segm19.The segmentation and subsequent visualization of the vascular tree allowed to identify the precise location of left coronary artery occlusion. It also showed a lack of collateral circulation in the MI area, confirming the development of the transmural MI. On the other hand, it also showed increased vascular spaces in the infarct area that may represent various stages of angiogenesis and a basis for future (retrograde) collateral circulation formation Fig. . Similarvirtual histology PB X-PCI, and conventional histology. Besides close resemblance of the images produced by these two different techniques, the information content is similar. We may clearly observe the preserved longitudinally arranged cardiomyocytes on the endocardial side, and circumferentially arranged towards the mesocardium. Virtual histology obtained by PB X-PCI, due to its three-dimensionality, allows for easy tracking of entire cardiomyocytes bundles, providing information on its interrelation with the overall myocardial structure.Several specific myocardial segments were used for high resolution (HR) imaging, serving as a form of virtual histology, and compared to classical assessment. At the effective pixel size of 0.65 µm, and in the whole heart, with no further specimen preparation or staining, the cardiomyocytes, forming the local 3D myocardial micro-organization, could clearly be visualized Fig. . The intTo illustrate the potential for tissue characterization, Fig. Figure In the early phases of an MI, reticular fibers  are usually present, representing the ongoing healing process. In our samples, reticular fibers could not be visualized, confirming that the scarring process of the infarcted areas has been finalized, and that true transmural scars are formed Figs. , 6.2  and 459 (410–530) μm2 (septum) vs. 296 (285–322) μm2 and 311 (275–318) μm2), indicating a significant difference between peri-MI and contralateral areas of post-MI hearts, as well as compared to the control rat heart  in the post-MI hearts in contrast to control rat heart 764 640–810) μm0 μm2  slicing methods help, but only up to a certain point23. The major drawbacks of histological procedures therefore include time-consuming sample preparation, usually demanding destruction of tissue, as well as different staining methods. Additionally, the need for thin slices makes 3D assessment of the analyzed structure very difficult since the off-line reconstructions of 3D structures are often performed from 2D images, with problems with slice loss or distortion21.The entirety of information gained by PB X-PCI in an animal model of ischemic heart disease would conventionally require using several different imaging modalities in conjunction with (destructive) histopathological analysis. Whole-heart morphology and quantification of cardiac remodeling is usually obtained by means of echocardiography, (micro-) computed tomography, or magnetic resonance imaging in in vivo research animal models or in clinical medicine16. For example, Gonzalez-Tendero et al. illustrated that PB X-PCI can quantify cardiac structures and tissue with enough details to reveal microfiber and vascular structure throughout whole rodent and rabbit fetal hearts, focusing on remodeling associated with intrauterine growth restriction15. They showed that the great advantage of PB X-PCI, as compared to micro-computed tomography (micro-CT), is that it provides a better contrast between soft cardiac tissues than classical X-ray absorption imaging.In recent years, X-ray computed tomography using synchrotron radiation has emerged and has been validated for imaging of different cardiac pathologies by assessing native intact animal heart models, as well as ex vivo human fetal hearts, and transmural samples of adult human hearts, both normal and disease-affected 24. At HR, even some properties of the vascular walls can be appreciated.In this study, we have shown that PB X-PCI allows for multiscale quantification of the precise regional and transmural extension of an MI, from organ to cellular level. At the macroscale, it offers the quantification of global cardiac remodeling, such as wall thickness, myocardial mass and cavity volumes, as well as the visualization of the coronary arterial and venous tree, enabling the precise identification of the location of the left coronary artery occlusion. While global remodeling in the setting of an MI is well understood, the whole heart macro-vascular assessment offered by PB X-PCI allows new avenues to explore. For example, the adaptive response and regeneration of the vasculature can be clearly seen from the increased vascular branching and the presence of enlarged thin wall vessels in the area of the MI. These large vessels were described before using histology and their overall effect studied by MRI, but PB X-PCI allows the direct visualization and quantification in the whole 3D infarct area where both the arterial as well as the venous branches can be studied without the need for contrast agentsfibers”) in 3D—an important component of cardiac architecture that might be affected by different cardiac conditions, such as MI. However, compared to the size of cardiomyocyte, DT-MRI has a limited resolution  and specifically assesses diffusivity in water-containing structures, which might not make it the ideal modality to investigate scarred or highly fibrotic tissue or when assessing intracellular matrix remodeling. Additionally, the visual representations of fiber-tracks obtained by tractography do not directly show all local properties and are affected by imaging artefacts26.At the mesoscale, specific magnetic resonance techniques, such as diffusion tensor imaging (DT-MRI) and tractography, have been used to characterize in vivo and ex vivo the transmural course of the orientation of cardiomyocyte aggregates  myocardial regions, however more pronounced in the former area33.Using classical histopathology approaches, it was shown that despite a large increase in collagen density, the organization is maintained in the core of infarction in both acute and chronic MI. While collagen is clearly synthesized in the infarction, its orientation  is influenced by mechanical loading directionAs can be seen from Fig. In summary, in this paper we have shown that PB X-PCI offers a powerful research tool to study tissue remodeling following an MI using a whole heart, 3D, non-destructive, non-staining or contrast-based technique, feasible for the quantification of myocardial remodeling at whole-organ, tissue, vascular as well as cellular level in ex vivo model of ischemic heart disease.40.Synchrotrons are large scale facilities with limited access due to high competition for the available time slots. Although this currently limits the amount of studies that can be performed, there is a clear technical development pathway towards using PB X-PCI based on laboratory X-ray sources or alternative laser-electron beam setups. Micro-CTs with X-PCI capabilities can be expected in the near futureAlso, while studies on imaging beating hearts (Langendorff and in-vivo) with X-PCI are underway, the current research was performed on static, ex-vivo hearts thus lacking direct correlative function assessment, and lacking direct comparison with in vivo methods.Limited number of animal models of disease and one control animal hinder the validation power of this study, however the aim was primarily to show the comprehensive potential of the method in the setting of ischemic heart disease pathological processes.Finally, the current field-of-view of most synchrotron imaging beamlines only allows to study small  specimens given that scan time importantly increases when stitched acquisitions need to be performed.41. Rats were sacrificed after 2 weeks, the hearts were excised, and immersed in formalin. Rats were euthanized with an anaesthetic overload  and subsequent exsanguination. For this experiment 4 rats with induced MI, and 1 control healthy rat were used. Online Supplementary methods explain in more detail animal handling.Post-MI remodeling was recapitulated in a well-established rodent model. A transmural MI was induced by left coronary artery ligation through a left thoracotomy in 8 to 11 week-old Wistar male rats Animal care and experimentation conformed to the European Union (Directive 2010/63/UE) and Spanish guidelines (RD 53/2013) for experiments involving animals. This study was approved by the local animal research ethics committee “Comité de Ética de Experimentación Animal (CEEA)” (CEEA 68/5435). The study planning, design, implementation and reporting was performed in compliance with ARRIVE guidelines.7. Briefly, the sample is fully illuminated by the X-ray beam and the microscope is placed at a certain distance from the sample in order to allow for interference patterns to form, which will induce PB contrast enhancement, especially on the interface between different tissues. In our case, a monochromatic beam with an energy of 20 keV and two configurations were used. First, a LR configuration is chosen to image the whole heart at 5.8 µm effective pixel size, with a sample-detector distance of 333 cm, using a LuAG:Ce 300 µm scintillator  and a PCO.Edge 4.2 CMOS detector . The resulting dataset is used for navigation of regions of interest to be imaged with a HR setup  and a PCO.Edge 5.5 CMOS detector ), and for offline assessment of whole organ remodeling, cardiomyocytes orientation analysis, and vasculature visualization7.Synchrotron radiation-based X-PCI image acquisition was carried out at the TOMCAT beamline (X02DA) of the Swiss Light Source . The samples were placed in dedicated tubes with degassed deionized water as medium to reduce the chance of bubble formation. The samples were then placed on the stage for acquisition with a multi-scale PB X-PCI setup43.When the sample is too large to fit fully in the field of view, several overlapping scans have to be acquired and stitched a posteriori. The acquired projections are reconstructed using the Gridrec algorithm both in absorption and applying the single distance phase retrieval method developed by Paganin45.Fiji, an open-source platform for biological-image analysis, was used to analyze and visualize gross anatomical features, as well as induced histopathological remodeling by myocardial infarction Pre-processing of the LR datasets, such as contrast and brightness enhancement, was performed to ease the process of feature detection.46.Then, a semi-automatic, whole heart segmentation was performed on the LR datasets using Ilastik to obtain first a rough segmentation, followed by smoothing by an in-house algorithm implemented in MATLAB (R2018b)In order to calculate the LV myocardial and cavity volumes, the epicardial and endocardial borders of the LV were manually delineated in some short-axis image slices of the LR datasets from the apex to the base. Then a 3D interpolation was performed to obtain the whole LV mask using a custom algorithm implemented in MATLAB from which both LV myocardial and cavity volumes were quantified.47. Every segment was assessed for myocardial damage and categorized in three categories, defined as: 1. Transmural MI: the whole segment is scarred, 2. peri-MI: segments immediately adjacent to the infarcted area, with no signs of scarring, 3. contralateral segments: segments directly opposite to the infarcted ones, with no signs of loss of myocardium.For the detailed regional analysis of structural myocardial changes, a 45-segment myocardial model was usedFor each of the segments, LV myocardial thickness was also automatically calculated by computing the Euclidean distance transform of the binary LV mask using a custom algorithm implemented in MATLAB.49.The high resolution achieved by PB X-PCI allowed identifying and analyzing individual cardiomyocytes in the HR datasets, that were segmented and their CSA was quantified using open-source software (Fiji-Image J and 3D Slicer)In our cardiomyocyte analysis, we included two post-MI and the control hearts. Cardiomyocytes were analyzed in sub-volumes sized 551.2 µm × 551.2 µm × 260 µm (length × width × height) of the HR datasets. In post-MI hearts, cardiomyocytes in the area of infarction (including preserved cells adjoining the fibrotic post-MI tissue), as well as in the non-affected myocardium were analyzed. The infarcted area was part of the anterior wall, while the non-affected area analyzed was located in the septum. The same corresponding areas were also quantified in the control rat heart. Two sub-volumes were selected per area, one closer to the endocardium, and the other closer to the epicardium. Individual cardiomyocytes were segmented by manual delineation. Then CSA calculation was performed in Fiji-ImageJ and expressed as the median value with interquartile ranges of measurements of 10 cells per sub-volume.16. Briefly, for each image voxel, the gradient in x, y and z directions was computed using a central difference algorithm. Then, the ST in each image voxel was obtained as the cross product of gradient vectors , which is in matrix notation:The orientation of the local cardiomyocyte aggregates (often referred to as ‘fibers’) was assessed on LR datasets using a custom structure tensor (ST) based algorithm implemented in MATLABi). The eigenvector with the smallest eigenvalue , and the two regression coefficients β1 and β0, and the R2 (linearity) coefficient of the linear fitting were obtained. β1 represents the total HA gradient over the myocardial wall while β0 is the intercept term.Cardiomyocyte aggregates orientation analysis and quantification was performed across the 45 LV myocardial segments. Transmural profiles (from endo- to epicardium or right-side endocardium) of the HAs in all of the LV segments were obtained to see how HA of cardiomyocyte aggregates changes along the ventricular wall. Linear regression fitting of the transmural profiles of the HA was done  within a neighborhood of size of 200 µm3. The MDI ranges between 0 and 1, with larger values indicating highly organized cardiomyocytes (insignificant disarray) whereas lower values of MDI denote a greater loss of cardiomyocytes organization (high degree of disarray) .Local myocardial disarray was quantified by the calculation of the MDI as proposed recently by Garcia-Canadilla P et al.49. The resulting 3D coronary artery tree was visualized using Seg3D and used for the identification of the exact location of the left coronary artery occlusion50. Furthermore, the vascular branching was identified and visualized in the area of MI.PB X-PCI images show enough tissue contrast to identify vessels without the need for X-ray contrast agents. On the LR datasets the ostia of the coronary arteries were identified at the level of aortic valve, and a detailed segmentation of main coronary arteries and its main branches was performed in 3DSlicerFollowing the PB X-PCI imaging of the intact hearts, a ‘gold-standard’ histopathological analysis was performed for comparison with the PB X-PCI images, obtained at both the cellular and organ level. The hearts were cut, embedded in paraffin and sectioned with a microtome into 4 µm slices that were mounted on glass slides and stained using hematoxylin and eosin dyes. Furthermore, Mallory's trichrome and Gömöri's dyes were used to better discern mature collagen (presumably rich in collagen type I) and reticular fibers. The tissue slides were imaged using light microscopy with 0.55 × and 20 × magnification (approximately 2.2 and 0.7 µm point-to-point resolution respectively). Furthermore, images from glass slides were digitized using the microscope camera  and NanoZoomer 2.0 RS .Normality of data was tested with a Shapiro-Wilks test, adequate for a small number of samples. Normally distributed continuous variables were expressed as means with standard deviation, while non-normally distributed continuous variables were expressed as medians with interquartile ranges. Comparison between two groups was done using a two-tailed Student’s T-test, while comparisons between multiple groups were done using a non-parametric Kruskal Wallis test. For all statistical tests the alpha level was determined at 0.05. Statistical analysis was performed using STATA .Supplementary Information 1.Supplementary Video 1.Supplementary Video 2.Supplementary Video 3.


Valvular heart disease (VHD) is a major cause of morbidity and mortality worldwide which with the population aging in the Western world has resulted in a 45% concurrent increase in non-rheumatic VHD . VHD posOur understanding of VHD is rapidly evolving expand the framework more broadly by considering the consequences of VHD into cardiac structure, function and remodeling. All of this has been sped along by the adoption of a multi-modality imaging (MMI) approach. While echocardiography remains the cornerstone for the initial diagnosis and evaluation, the modern heart valve specialist must also be versed in additional imaging modalities, which can aid in the diagnosis, patient selection and treatment planning. This comprehensive evaluation in VHD provided by cardiac imaging is essential in diagnosis and mechanism of valve dysfunction, severity quantification, procedural selection, intra-procedural guidance, and follow up for outcome and complications. This Frontiers topic collection collates some exemplars of recent advances in multimodality imaging and provides the clinician with the knowledge to deliver an individualized approach to their patients with VHD.Guzzetti et al. update us on the nuances of assessing patients with low-gradient AS. In this situation transthoracic echocardiography (TTE) is the foundation of assessment; MMI has an increasing role to play to appreciate current paradigm that AS is a disease of valve and myocardium. They evaluate the established role of cardiac computed tomography (CCT) for valve calcification quantification, and the evolving role cardiac magnetic resonance imaging (CMR) for the myocardial assessment for detecting those who may benefit from current non-guideline-based intervention.Discordance between aortic stenosis (AS) severity and gradients are not uncommon, occurring in up to 40% of patients. Sharma et al. describe the role of echocardiography in assessment with the growing role of CMR for reliable, reproducible chamber assessment, providing optimal multi-modality assessment to improve the outcome of these patients.The management of AS has been radically changed since the advent of transcatheter aortic valve replacement (TAVR). Experience and success in this field has spurred on research into mitral valve intervention where there is a vast burden of morbidity but limited evidence base. The advent of MitraClip  and its Salvatore et al. examine the current evidence base for selecting and monitoring the optimal candidate for transcatheter edge-to-edge repair (TEER) with MitraClip device . They highlight the evolving role of stress echocardiography being a valuable tool to optimize timing of intervention, and of cardiac magnetic resonance (CMR) in the comprehensive evaluation of SMR severity, and myocardial fibrosis  is a rapidly progressing field, with TMVR increasingly used for failed mitral prosthesis , as well as valve-in-ring, and valve-in-MAC . Additionally, paravalvular leak (PVL) closure—both of surgical and percutaneous prostheses—is an increasing indication for transcatheter intervention. TMVR and PVL are complex anatomically and physiologically, and therefore require multi-modality imaging at all stages to define anatomy and mechanism, procedural planning, and intraprocedural guidance. Tayal et al. investigate the evolving application of multimodality to patients with mitral valve prolapse (MVP) and risk of ventricular arrhythmia. A disease entity described by Barlow , where CMR can offer not only precise ventricular assessment but also accurate quantification of the MR severity—particularly important in asymptomatic patients. Echocardiography, predominantly 3D transesophageal echocardiography, is the established benchmark but with the advent of 4D flow CMR, the multi-directional and dimensional regurgitation in MR can now be fully appreciated and quantified. 4D CMR involves phase contrast acquisition with velocity encoding in three-dimensions and time resolved. This systematic review compares 4D CMR to established echo techniques and older 2D CMR methods adding a reliable and reproducible technique in what can be a difficult surveillance and timing of intervention process.While CMR is now the gold standard for myocardial volumes, function and myocardial scar, its utility in the hemodynamic assessment of VHD is becoming increasingly evident. Cave et al. describe how 4D flow can visualize and quantify the eccentric aortic flow in BAV patients and link this to the risk of developing aortopathy. They highlight recent insights into the flow dynamics of the various surgical techniques and devices available in this population .4D flow by CMR is additionally providing insight into the mechanism of aortopathy in the bicuspid aortic valve (BAV) disease, the most common congenital lesion. BAV confers a chronic elevated risk of aortic dissection even after valve intervention (which 50% of patients require in their lifetime). We believe that this collection of multi-modality imaging applications in valvular heart disease offers the reader a contemporary range of exciting exemplars in this rapidly progressing field. Incorporation of multi-modality imaging provides valuable insights into mechanisms, which should be part for future randomized control trial to improve the outcomes of patients burdened with VHD. We hope that this collection will stimulate clinicians utilize an integrative approach to VHD in their practice.This Editorial was conceived and written by all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


After 15 years from its advent in the clinical field, coronary computed tomography (CCTA) is now widely considered as the best first-step test in patients with low-to-moderate pre-test probability of coronary artery disease. Technological innovation was of pivotal importance for the extensive clinical and scientific interest in CCTA. Recently, the advent of last generation wide-coverage CT scans paved the way for new clinical applications of this technique beyond coronary arteries anatomy evaluation. More precisely, both biventricular volume and systolic function quantification and myocardial fibrosis identification appeared to be feasible with last generation CT. In the present review we would focus on potential applications of cardiac computed tomography (CCT), beyond CCTA, for a comprehensive assessment patients with newly diagnosed cardiomyopathy, from technical requirements to novel clinical applications. Multimodality imaging has recently gained a pivotal role in the management of cardiovascular disease, and the diagnostic work-up of cardiomyopathies, in order to define the different phenotypes, was deeply influenced by the recent introduction of advanced cardiovascular imaging modalities, such as cardiac magnetic resonance (CMR) . Even ifIn the DANAMI-3-DEFER CMR substudy , 181 of The present review will focus on potential applications of CCT for a comprehensive assessment of patients with newly diagnosed cardiomyopathy, from the well-validated evaluation of coronary anatomy to novel potential clinical applications.In the diagnostic pathway of dilated cardiomyopathy (DCM) of unknown etiology, the identification of patients with ischemic heart disease (IHD) is pivotal . DespiteIn 2012, Malagò et al. reported optimal imaging quality focused on cardiac vein anatomy evaluation in a consecutive cohort of patients (301 subjects) who previously underwent CCT for coronary anatomy evaluation and were retrospectively evaluated for cardiac vein mapping . Of inteTake-home message:Cardiac computed tomography is indicated in patients with DCM of unknown etiology to rule out IHD as an alternative to ICA- Cardiac computed tomography for coronary anatomy evaluation provides concomitant cardiac vein mapping in patients with HFrEF- Besides the well-validated and widely recognized role of CCT as a non-invasive tool for coronary anatomy evaluation, clinical and research interest is focusing on the potential application of CCT for a comprehensive cardiac assessment.In 2004, Juergens et al. reported a very early experience of left ventricular volumes and systolic function evaluation with 4-slices CT compared with CMR in 30 subjects showing a good correlation between the two techniques . SimilarDespite several reports on the feasibility and accuracy of CCT for biventricular systolic function evaluation, its clinical application is limited mainly due to the elevated radiation dose up to 18–20 mSv with old-generation CT scans , 31. IndRecently, the myocardial strain has been proposed as a promising tool for the evaluation of left and right ventricular function, especially in patients with HF and preserved ejection fraction (HFpEF). Even if echocardiography remains the most used technique for myocardial global and regional strain evaluation, both cardiac MRI  and, morpost hoc analysis for biventricular volume and systolic function is not feasible if CT scan acquisition was focused on coronary anatomy evaluation. All these points are now limiting the clinical use of CCT for the evaluation of biventricular function. However, the promising role of CCT for the evaluation of biventricular function is confirmed by the inclusion of this technique as a potential alternative to CMR in several consensus documents oncardiomyopathies  elevated radiation dose; (2) higher dose of contrast medium is usually administered for biventricular balanced contrast opacification during the entire images acquisition; (3) a opathies , 36.Recently, the advent in the clinical field of new generation CT scans, from dual-source scanners to wide detectors enabling the entire heart volume to be covered in one beat, represents an interesting opportunity to overcome previous limitations of CCT. Moreover, new generation CT scans are characterized by a reduction in gantry rotation time that is associated with increase temporal resolution improving end-systolic/end-diastolic phase identification .Results from the E PLURIBUS study  will sooBeyond myocardial function evaluation, myocardial fibrosis identification is widely considered to have a significant prognostic value. In 2016, a meta-analysis including 19 studies and 2,850 patients for a total of 423 arrhythmic events  supporteOn the contrary, the recently described capability of CCT to identify the presence of myocardial fibrosis needs a dedicated acquisition protocol . The patOne of the first reports of exploring the assessment of myocardial viability was described in a small experimental study involving 17 animals (10 dogs and 7 pigs) in which an accurate identification and quantification of myocardial fibrosis by CT vs. postmortem autopsy evaluation was demonstrated .In 2005, a first-in-human study enrolled 28 consecutive patients with a previous history of myocardial infarction who underwent both CMR and CCT with late CT scan for myocardial fibrosis evaluation ; using 1k = 0.89; P = 0.001) with ICA and CMR for etiological classification of LVD. For what concern myocardial fibrosis identification only two patients had false-negative results at CCT vs. CMR, possibly caused by the poor image quality and low signal-to-noise ratio. However, an overall very good accuracy  for the identification of fibrosis by CCT was reported.In 2008, le Polain de Waroux et al. enrolled 71 consecutive patients with new-onset of left ventricular dysfunction (LVD) who underwent ICA, CMR, and CCT with myocardial fibrosis evaluation ; on a pe2 in CCT vs. 2.9 ± 2.4 cm2 in CMR; of interest, authors reported that the relative intensity ratio between normal remote myocardium and area of myocardial fibrosis in CT was 1.8 ± 0.3  technology permits contemporary use of different tube potential enabling tissue characterization with extracellular volume (ECV) estimation that is considered a myocardial fibrosis equivalent when evaluation with CMR. More precisely, in 2020, Ohta et al. reported that strong correlations were seen between CT-ECV and MR-ECV at postcontrast CT images in 23 patients . SimilarTake-home messages:Biventricular volume and systolic function analysis are feasible and accurate with CCT.- Myocardial fibrosis assessment is feasible with CT, even if a low contrast-to-noise ratio limits diagnostic accuracy vs. CMR.- For both the myocardial fibrosis and biventricular function assessment with CT, dedicate acquisition protocol is needed with an increase in radiation dose and iodinated contrast amount administration, limiting their clinical use to those patients with CMR contraindication.- In the next future, technological advances may further expand the clinical application of non-coronary CCT evaluation.- As previously outlined, a dedicated acquisition protocol for comprehensive evaluation of myocardial fibrosis and biventricular volumes and function is needed; it is important to underline that coronary anatomy analysis is feasible using the same imaging dataset. More precisely, biventricular volumes and function are evaluated using imaging acquired at the first pass contrast angiographic phase, the same used for coronary evaluation. What differs from traditional CCTA is the total volume of contrast needed (at least 1.5 ml/kg for function and fibrosis vs. <1 ml/kg for coronary anatomy) and the need for biventricular opacification, that may cause, in rare cases, artifacts on the mid-portion of the right coronary artery. On the other side, the need for contrast medium bolus for optimal angiographic evaluation of coronary vessels has been indicated as a potential cause to mild, but significative, overestimation of right ventricular end-diastolic volume (RVEDV); to reduce discrepancies vs. CMR in RVEDV quantification, contrast injection at lower infusion rate has been proposed, but this approach would make coronary stenosis not evaluable. Overall, high priority should be given to coronary anatomy evaluation as this is the most important and validated CCTapplication.For what concerns myocardial fibrosis evaluation, the late post-contrast acquisition is needed without a significative increase in radiation dose. It should be underlined that, especially in patients with DCM, where a higher dose of contrast medium is needed to evaluate coronary anatomy, adding a late post-contrast scan could be proposed on a regular basis; on the contrary, this is not true for biventricular volumes and function evaluation for which the need of entire cardiac cycle acquisition is associated with a significative increase in radiation dose.Finally, it should be underlined that all these advanced uses of cardiac CT are strictly dependent on the availability of the last generation CT; indeed, 64-slice CT technology is suboptimal especially for biventricular volumes and function analysis and is associated with very high radiation dose , prohibitive especially when serial evaluation at follow-up is needed.Several clinical fields may benefit from a wider application of CCT beyond coronary anatomy evaluation, even if extensive supporting data are still to come. The unique capability of CCT to evaluate both coronary and myocardial anatomy may support its use in the evaluation of patients with HCM. In this setting, beyond the analysis of myocardial thickness and fibrosis, CCT may provide an accurate evaluation of the concomitant presence of coronary artery disease; more precisely, in a previous study including 60 patients with HCM , CCT proAccurate analysis of the right ventricle is of the utmost importance in patients with suspected arrhythmogenic cardiomyopathy (AC); even if validated cut-offs for AC diagnosis are still missing, the presence of right ventricular bulging and/or right ventricular dilation or systolic dysfunction could be identified with CCT. However, it should be underlined that previous reports suggested a mild, but significative, overestimation of right ventricular diastolic volume with CT vs. CMR , possiblFor what concerns myocardial tissue analysis, one of the most promising clinical applications of CCT is the evaluation of anatomical substrate in patients with unstable ventricular arrhythmias and possible indications to transcatheter ablation. In this setting, identification of myocardial arrhythmic substrate by CMR has been demonstrated to improve procedural outcome ; unfortuApart from this advanced application, CCT should be considered in clinical practice for biventricular volume and function analysis and myocardial fibrosis identification when CMR is contraindicated and TTE is inconclusive. This approach is supported by guidelines and consensus documents previously published , 36, 61.Despite promising results from CCT, nowadays, CMR remains the gold standard for biventricular volume and function quantification and for myocardial tissue characterization, as several technical reasons limit CCT clinical application for non-coronary evaluation. First, the temporal resolution of CCT is lower when compared with CMR. Second, CCT analysis is associated with non-negligible radiation dose ; this is of particular concern in young patients who may undergo serial CCT during follow-up and for which cumulative radiation dose would result to be prohibitive. Moreover, the diagnostic accuracy of CCT for myocardial fibrosis evaluation is lower when compared to CMR due to a lower signal-to-noise ratio.These limitations could be overcome in the future if further technological advances, especially in the field of artificial intelligence, should be applied in clinical practice .When CMR is contraindicated and TTE results to be inconclusive, CCT may be considered in clinical practice as an alternative to CMR during diagnostic evaluation of patients with cardiomyopathies . AdequatEC and SM wrote the first draft of the manuscript. GM, AF, AA, EMe, and FR performed literature research and data evaluation. EMa, CG, ZL, MG, AB, RM, and CMG performed manuscript and figure editing and revision. CC, VC, MP, DA, and GP provided expert revision and supervision. All authors contributed to the article and approved the submitted version.Centro Cardiologico Monzino will cover publication fees.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hypertrophic cardiomyopathy (HCM) related myocardial vascular remodelling may lead to the reduction of myocardial blood supply and a subsequent progressive loss of cardiac function. This process has been difficult to observe and thus their connection remains unclear. Here we used non-invasive myocardial blood flow sensitive CMR to show an impairment of resting myocardial perfusion in a mouse model of naturally occurring HCM.Mybpc3 and Myh7 and bears the key features of human HCM. The C57BL/6 J (B6) was used as a reference strain. Mice with either B6 or D2 backgrounds  underwent cine-CMR for functional assessment at 9.4 T. Left ventricular (LV) wall thickness was measured in end diastolic phase by cine-CMR. Quantitative myocardial perfusion maps  were acquired from arterial spin labelling (cine ASL-CMR) at rest. Myocardial perfusion values were measured by delineating different regions of interest based on the LV segmentation model in the mid ventricle of the LV myocardium. Directly after the CMR, the mouse hearts were removed for histological assessments to confirm the incidence of myocardial interstitial fibrosis (n = 8 in each group) and small vessel remodelling such as vessel density (n = 6 in each group) and perivascular fibrosis (n = 8 in each group).We used a mouse model  that spontaneously carries variants in the two most susceptible HCM genes—p < 0.001; female: D2 LV wall thickness = 1.0 ± 0.1 mm vs B6 LV wall thickness = 0.8 ± 0.1 mm, p < 0.01). The resting global myocardial perfusion  was lower in D2 than in B6 mice . This myocardial microvascular dysfunction was observed and associated with a reduction in regional MBF, mainly in the interventricular septal and inferior areas of the myocardium. Immunofluorescence revealed a lower number of vessel densities in D2 than in B6 . Myocardial collagen volume fraction (CVF) was significantly higher in D2 LV versus B6 LV mice . Furthermore, a higher ratio of perivascular fibrosis (PFR) was found in D2 than in B6 mice .LV hypertrophy was more pronounced in D2 than in B6 mice (male: D2 LV wall thickness = 1.3 ± 0.1 mm vs B6 LV wall thickness = 1.0 ± 0.0 mm, Our work describes an imaging marker using cine ASL-CMR with a potential to monitor vascular and myocardial remodelling in HCM. MYBPC3) [MYH7) [Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac genetic disease with an estimated population prevalence of HCM ranging from 1:200 to 1:500 individuals . Sudden MYBPC3)  and β-my) [MYH7) . Aberran) [MYH7) . The myo) [MYH7) , 12. Whi) [MYH7) , at pres) [MYH7) . CMR can) [MYH7) , but mon) [MYH7) . Here weMicrovascular dysfunction in HCM patients has been proposed as a strong predictor of clinical outcomes and mortality risk , but theLocal myocardial blood volume and blood flow are important indicators of changes in micro-perfusion . Recent We hypothesize that vascular dysregulation caused by hypertrophy or excessive collagen deposits may contribute to the microstructural changes in HCM and cause the reduction. Using a mouse model that closely reflects human HCM, we quantified the amount of blood delivered to myocardial tissue per unit time using myocardial blood flow (MBF) CMR based on the labelling of arterial proton spins , 25. UnlMybpc3 and Myh7 and bears the key features of human HCM [All animal studies were approved by the Berlin State review board at the ‘’Landesamt für Gesundheit und Soziales ’’. Genetic variants that potentially cause myocardial functional changes were previously reported . We useduman HCM . The C57All in vivo CMR measurements were performed on a 9.4 T small animal CMR system . Anesthesia of mice was induced using 3% isoflurane  in 500 mL/min medical air and 500 mL/min oxygen and was maintained at 0.5 to 1.0% isoflurane after the induction. During CMR examinations, it was important to maintain hemodynamic stability to avoid confounding interference with the imaging results. During cine ASL-CMR scans, oxygen was given at a dose of at least 800 mL/min to avoid hypoxia. Core body temperature was maintained at 36 ± 0.5 °C using a heated water tubing system. Heart rates, respiration rates and core body temperature were closely monitored using a remote monitoring system .2, matrix size = 192 × 384, slice thickness = 0.8 mm, with a temporal resolution of 16 images per cardiac cycle [For the high-fidelity approaches for CMR in mice, image acquisition was conducted using a cryogenically-cooled radiofrequency (RF) transceiver antenna . To obtain a stack of cardiac short axis (SAX) views covering the whole mouse heart, 9–10 slices were consecutively acquired using a self-gated bright-blood cine . Image acquisition was gated upon detection of the ECG’s R-wave. Quantitative image analysis and calculation of perfusion maps were performed using in-house developed analysis tools built in the Interactive Data Language (IDL). After averaging the steady-state cine repetitions from successive cardiac cycles, regional perfusion was analyzed using a ventricular segmentation model [The cineASL technique used is described in detail elsewhere , 30. Thion model . The bor2, matrix size = 500 × 336, slice thickness = 0.3 mm, in-plane spatial resolution = 30 µm).Following in vivo CMR, mice were perfused with 4% PFA. Fixed ex vivo hearts (n = 2 from each group for illustration) were imaged with high spatial resolution to check for the presence of myocardial hypertrophy and disarray . This step arrested the cardiac cycle during diastole. Heart tissue were post fixed in 4% PFA solution and then dehydrated. Fixed hearts were either cryopreserved in a 30% sucrose-PBS solution for at least 3 days at 4 °C or embedded with paraffin. Cryopreserved hearts were then embedded in OCT , frozen on dry ice, and stored in − 80 °C until sectioning. For tissue sectioning, 10 µm cross-sections of hearts were cryo-sectioned using a cryostat microtome  starting from the apex. Four µm paraffin sections of heart were prepared using a microtome .For detecting myocardial microvasculature, heart sections were analyzed using immunofluorescence (IF) staining methods. Briefly, 10 µm cryo-preserved sections were mounted on glass slides. For blocking the unspecific bindings, tissue sections were treated with a blocking solution containing 10% normal donkey serum , 4% fetal bovine serum , 0.2% Triton X-100 in PBS for 3 h at room temperature. Heart tissue sections from entire mid-ventricular short-axis sections were then incubated with Alexa Fluor 488 conjugated Isolectin B4  diluted in 0.01 M PBS with 5% NDS over night at 4 °C. After washing in freshly prepared PBS with 2.5% NDS, the nuclei were stained with Hoechst 33,342 (Sigma-Aldrich). The presence of fluorescent stained cells was determined by observation on a microscope . Quantifications of Isolectin B4 + vessels were performed in 10 random fields captured under 200 magnifications. All image processing was then performed using ImageJ  and Adobe Illustrator . The captured images were carefully screened. Blurred images were excluded from the quantification. For quantification, small vessel density in myocardium was analyzed using ImageJ software plugins (vessel density) in five random microscopic fields in the whole myocardium and expressed as percentage .To determine the interstitial collagen   and perihttp://www.rstudio.com/) or GraphPad Prism 5 . The graphs were generated by GraphPad Prism 5. The comparison between B6 and D2 mice in diastolic and systolic cardiac phases were analyzed using one-way ANOVA. The sampling frequency was further tested for normality using Kolmogorov–Smirnov test. A low K-S statistic value represent with a high p-value indicate that data is normally distributed. Statistical difference of MBF by sex or cardiac phases between groups were further tested using factorial analysis of variance  followed by post-hoc Turkey HSD (Honestly Significant Difference). The Spearman's rank correlation coefficient was used for testing the strength of the correlation between LV thickness and global MBF. Capillary density (%), CVF (%) and PFR (%) from B6 and D2 were compared using t-test followed by Mann Whitney test. All data are presented as mean ± SD. The differences were considered statistically significant at *P < 0.05; **P < 0.01; and ***P < 0.001.All data analyses of the cardiac physiological measurements using CMR and histopathology were performed by reviewers blinded to the mouse genetic makeup. Experimental analysis and statistics were conducted in R studio  , whereas in D2 mice it was significantly lower in the end-systolic than in the end-diastolic phases . Lateral and anterior regions did not show significant MBF difference.Based on the segmentation model Fig. a, we ana+ vessels in D2 than in B6 mouse myocardium . Furthermore, we also observed higher ratio of perivascular fibrosis in D2 mice versus B6 mice . Microscopic characteristics revealed the relation of perfusion deficit with both perivascular and interstitial fibrosis.To visualize the myocardial fibrosis precisely, we performed collagen staining to indicate the exact position of fibrosis within the LV Fig. c. MyocarIn this study, we demonstrate that cine ASL-CMR is capable of detecting changes in myocardial perfusion that are correlated to a reduction in small vessel density in the myocardium. The reduced myocardial perfusion provides an indication for microvascular dysfunction in HCM. The myocardial perfusion deficiency is correlated with LVH and associated with myocardial fibrosis and loss of small vessel densities, features which are presumably mediated by the genetic variants commonly found in HCM. We analysed the global as well as the regional differences of MBF based on the cardiac segmentation model. However, motion artefacts have been recognized as a limiting factor for the precise detection of myocardial regional differences. These artefacts can be induced by myocardial contraction/relaxation, by respiratory motion causing a shift a in the chest wall and the diaphragm, by susceptibility changes due to motion of the heart–lung or heart–liver interface or by non-uniform regionally motion patterns (different twist and strain) of the heart . AnotherEn route to non-contrast myocardial perfusion imaging such as ASL-CMR, more studies are needed to prove that both methods are equally relevant for clinical applications [Subclinical myocardial remodelling dictates the progression of HCM, but currently diagnosis and treatment of the disease are restricted to measurements of myocardial hypertrophy. Diagnosing microvascular dysfunction has been a challenge. Standard tests used to diagnose coronary artery disease are not designed to detect small vessel disease, so a better understanding of the factors associated with microvascular dysfunction and its relation to the development of HCM would represent a major step toward earlier diagnosis and better management of the disease. Our results can partially explain previous findings showing that HCM patients have lower myocardial blood volume than healthy counterparts . In the ications .Although a number of post-mortem studies have demonstrated marked impairment of the coronary microcirculation in the absence of significant coronary lesions in HCM patients , 38, theClassically, HCM is characterized by varying degrees of LVH with a preserved or sometimes even increased LVEF . Our datBlood flow through small vessels in the myocardium is influenced by changes in myocardial tissue pressure during heartbeats. Most myocardial perfusion occurs during the diastolic heart phase, when the myocardial pressure is low . It may The accuracy of this non-invasive MBF measurement using cineASL has already been validated against the more common FAIR Look-Locker Gradient Echo technique, which was in turn validated against fluorescent microspheres . The varSex differences are known in several facets of cardiac physiology . Sex difWhile we observed the sex differences in end-diastolic MBF in D2 mice but not in other experimental groups, this observation might be attributed to the small sample size used, which is a recognized limitation of our study. We are therefore unable to comment on the exact sex influence that might exist with perfusion abnormalities. To address this scientific question future work will need to incorporate a larger sample size. The cardiac function and MBF measurements were not derived from the same group of mice. Notably, the physiological effects of anaesthesia during CMR have to be minimized. Consequently, we have designed the CMR measurement protocol such that the total duration of an individual in vivo experiment does not exceed a maximum of 60 min. Therefore all measurements were performed in the same time window.We noted that MBF values in mice found in this study are higher when compared with published findings , 58, 59.Mybpc3 or Myh7 point mutations need to be pursued, as does the relation between oxygen consumption and myocardial perfusion in HCM.Our study did not tackle the influence of single genetic mutations. Therefore, the specific effects of 1, T2 and T2*) and ASL, we can observe how CMR biomarkers change over time, and how these changes can predict later disease outcomes.To tackle the diastolic dysfunction, we did not include myocardial strain measurements in our study because we would like to first emphasize the early microstructural change such as vascular deficiency in HCM. MR tagging can be useful for detecting changes in myocardial strain in the mouse heart. We anticipate including this approach into our future studies. Our preliminary results provide the basis for future investigations of the entire disease course, including the early disease phase when the pathological changes are subtle. Then by performing a comprehensive protocol of CMR measurements including parametric mapping (TWe used state-of-the-art in vivo CMR to evaluate microstructure and functional changes in mice with HCM genetic variants. We have demonstrated that small vessel dysfunction is present in these HCM variants in association with myocardial fibrosis. Our work thus suggests that more research on MBF as an imaging marker with a potential to monitor early myocardial microvascular remodelling is relevant in the field.


The deterioration of hepatorenal function due to worsening congestion is relatively common in acute heart failure and carries an independent adverse prognosis. In some patients, the risk of proarrhythmia is increased due to impaired drug metabolism. We described a patient with acute heart failure, polymorphic ventricular tachycardia (VT), and ventricular fibrillation episodes while receiving loading doses of amiodarone for atrial fibrillation. The occurrence of arrhythmia at the background therapy with a relatively safe antiarrhythmic drug in the settings of moderate cardiac, renal, and borderline liver functional impairment demonstrates that careful evaluation of liver and renal function is mandatory for the prevention of proarrhythmia. Premature ventricular complexes, runs of nonsustained ventricular tachycardia (NSVT), and sustained ventricular tachycardia (VT) are common in patients with left ventricular (LV) dysfunction. They may be consequences of structural heart disease and may contribute to increased mortality risk. Optimized medical therapy for heart failure and amiodarone initiation are recommended in patients with LV dysfunction and VT . AmiodarThe polymorphic VT torsades de pointes (TdP) is considered a proarrhythmia typically associated with amiodarone treatment. It has been observed in one-third of all proarrhythmic events in patients treated with this drug . PhysiciА woman in her late 70s presented to the ED with chest discomfort and dyspnea with onset а few hours before presentation. She had a history of hypertension controlled by antihypertensive therapy, anemia, and stage IV renal disease. She was discharged from another hospital’s surgical clinic nearly one week earlier after being conservatively treated for ileus. She had undergone surgical resection of a benign tumor of the stomach more than five years ago. She was diagnosed with anemia in the surgical clinic. Following a transfusion of homologous blood, her hemoglobin was 99 g/L. She reported tightness in the chest and palpitations, and we detected paroxysmal atrial fibrillation, which necessitated amiodarone therapy. Her thyroid gland test results were within the reference range. The patient was discharged from the surgical clinic on therapy with amiodarone , bisoprolol , and ramipril 5 mg (twice). In our ED, she presented with orthopnea, pale skin, a blood pressure of 165/70 mmHg, and a pulse rate of 50 beats per minute (bpm). On cardiac auscultation, we noted muffled heart sounds and clear lungs. The serial electrocardiographic (ECG) records at admission showed sinus bradycardia with a ventricular rate of 47-54 bpm, prolongation in the corresponding QTc interval (462 to 508 msec), and runs of polymorphic NSVT . The patient received magnesium, and the rate and rhythm control medications were stopped. During the first few hours of her stay in the ICU, the patient had a ventricular fibrillation (VF) episode that necessitated an electric shock. Temporary transvenous pacing of her heart at 80 bpm was started to prevent future episodes of VT associated with prolonged QT in the setting of bradycardia. Her laboratory test results showed normal hemoglobin (128-131 g/L), leukocytosis , renal dysfunction , total bilirubin of 18.6 mmol/L, marginally low potassium levels (3.5 mmol/L), and elevated cardiac-specific troponin I (50.5-56.5 ng/L). The initial echocardiographic examination showed moderately reduced LV EF (32%), global hypokinesia, severe mitral regurgitation (MR) and tricuspid regurgitation (TR), LV hypertrophy (13 mm), and marginally enlarged right ventricle . Cardiac catheterization and coronary angiography were performed due to suspicion of significant obstructive coronary disease and her recently diagnosed heart failure. The invasive study results confirmed some echocardiographic findings, including reduced EF (38%), global LV hypokinesia, severe MR and moderate TR, and LV end-diastolic pressure of 23 mmHg. Atherosclerotic plaques causing minor stenoses were found in all coronary arteries. A second echocardiographic study a few days later revealed mild MR and TR and 38% EF. The patient was informed on evidence-based therapy that can prevent the risk of sudden cardiac death: implantable cardioverter-defibrillator (ICD), which she declined. Given her persistent bradycardia, previous atrial fibrillation, and heart failure episodes, a permanent pacemaker was implanted and programmed to pace the heart at a rate of 70 bpm. The patient was released on therapy with bisoprolol 5+2.5 mg, furosemide 40 mg daily, spironolactone 25 mg once daily, magnesium aspartate tetrahydrate three times daily (500 mg), and pantoprazole 40 mg. She was assigned additional clinical examinations for anemia detected immediately before the current hospital admission.The patient remained without symptomatic episodes of arrhythmia, presented with NYHA class II symptoms of heart failure, and was without anemia, according to laboratory findings at the end of the 28-month follow-up. Prophylaxis with anticoagulant medication has been initiated.In this patient case, the evidence for proarrhythmia is the accumulation of several risk factors contributing to proarrhythmia: female sex, lost electrolyte balance , bradycardia, and structural heart disease ,6. The pThe occurrence of VA coincided with the effects of amiodarone on cardiac repolarization. These effects appear late-within at least 10 days of initiation . The detEpisodes of marked QT interval prolongation and VA also may frequently occur because of acute myocardial ischemia (80%) and less often in patients with advanced conduction system disease (heart block) and cardiomyopathy . We exclNo renal side effects have been described concerning amiodarone therapy . The detThe prophylactic insertion of a pacemaker to maintain a relatively high rate of 70-80 bpm, withdrawal of antiarrhythmic medication and magnesium, and potassium replenishment are appropriate acute treatments of TdP . ICD theAnother treatment approach, catheter ablation for VA in dilative cardiomyopathy is now increasingly used either primarily and/or combined with automatic anti-tachycardia devices and beta-blockers . The difPrevious studies have reported varying results of the acute success of polymorphic VT ablation . HoweverIt is also important that transient conduction abnormalities could follow a radiofrequency procedure ,20. The Renal and liver congestion are common pathologic consequences of ventricular dysfunction in heart failure. The condition could be associated with impaired hepatic metabolism of amiodarone and risk of proarrhythmia. The evaluation and control of liver and renal function, as factors for proarrhythmia, are mandatory in the treatment of heart failure.


Patients with a TAPSE/sPAP lower than 0.25 mm/mmHg had worse prognosis, with log-rank test p = 0.001. the echocardiographic estimation of TAPSE/sPAP offers an easy, reliable, non-invasive prognostic parameter for the comprehensive assessment of hemodynamic adaptation in PAH patients.In response to an increased afterload in pulmonary arterial hypertension (PAH), the right ventricle (RV) adapts by remodeling and increasing contractility. The idea of coupling refers to maintaining a relatively constant relationship between ventricular contractility and afterload. Twenty-eight stable PAH patients (mean age 49.5 ± 15.5 years) were enrolled into the study. The follow-up time of this study was 58 months, and the combined endpoint (CEP) was defined as death or clinical deterioration. We used echo TAPSE as a surrogate of RV contractility and estimated systolic pulmonary artery pressure (sPAP) reflecting RV afterload. Ventricular–arterial coupling was evaluated by the ratio between these two parameters (TAPSE/sPAP). In the PAH group, the mean pulmonary artery pressure (mPAP) was 47.29 ± 15.3 mmHg. The mean echo-estimated TAPSE/sPAP was 0.34 ± 0.19 mm/mmHg and was comparable in value and prognostic usefulness to the parameter derived from magnetic resonance and catheterization . Patients who had CEP ( Pulmonary arterial hypertension (PAH) is a rare disease that causes increased pulmonary vascular resistance (PVR) and elevated pulmonary arterial pressures (PAPs). This often leads to heart failure and premature death . Due to When the RV becomes overloaded in PAH, it mostly adapts to the increased afterload by increasing contractility according to Frank–Starling law. However, with the depletion of systolic function, the RV becomes uncoupled from pulmonary circulation and dilates to preserve flow output . The besIn this study, we aimed to (1) verify the relationship between the echo-derived RV–arterial coupling surrogate, TAPSE/sPAP ratio, and hemodynamic parameters obtained from right heart catheterization (RHC) and magnetic resonance imaging (MRI) in PAH patients, and (2) investigate whether the echocardiographic TAPSE/sPAP ratio has prognostic significance in PAH patients.This paper presents an echo-focused analysis (with 58 months of follow-up observation) of a PAH group enrolled to the project, with a grant entitled “The role of PET/MRI hybrid imaging in assessment of pulmonary arterial hypertension patients”, of which partial results were previously published ,10,11.Into the study we enrolled twenty-eight clinically stable PAH patients. Pre-capillary pulmonary hypertension was confirmed by RHC (mean pulmonary artery pressure (mPAP) ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg). According to European guidelines [The clinical follow-up lasted 58 months. Death, WHO class worsening, and hospitalization due to pulmonary hypertension or right heart failure (requiring therapy with intravenous diuretics) were used as a combined clinical endpoint (CEP) for Kaplan–Meier analysis .The study was approved by the local Bioethics Committee. All patients gave written, informed consent for participating in the study, including the taking and storage of blood samples. The study complied with the Declaration of Helsinki.2) and of the estimated central venous pressure obtained by inferior cava vein diameter and collapsibility [Echocardiographic examinations were performed in both study and control groups. Tricuspid annular plane systolic excursion (TAPSE) was obtained by M-mode imaging in the apical four-chamber view centered on the right ventricle. It was defined as the difference between the displacement of the RV lateral annulus from end-diastole to end-systole. The echo estimation of the sPAP (RVSP/esPAP) (reflecting RV afterload) was based on the sum of the peak velocity of tricuspid regurgitation  was performed using a Swan–Ganz catheter with standard technique , and durCardiac magnetic resonance imaging is the gold standard noninvasive method for RV functional assessment. We used MRI scans to obtain TAPSE as a reference method to echo TAPSE . MRI imat-test was used for continuous data and a χ2 test was used for categorical variables. Spearman’s correlation coefficient was used to examine the relationship between two continuous variables. Receiver operator characteristic curves (ROCs) were plotted to determine the area under the curve (AUC) and the sensitivity and specificity of the optimal cut-offs. To investigate the occurrence of clinical endpoints, the Kaplan–Meier method with the log-rank test was implemented; p < 0.05 was deemed statistically significant. A statistical software package, STATA13 (USA), was used for the analysis.The data are expressed as a mean ± standard deviation (SD) or median (interquartile range) in the case of variables with non-normal distribution (Kolmogorov–Smirnov test). The Student’s n = 19; connective tissue diseases n = 4; associated with congenital small/coincidental defects n = 5). The control group consisted of twelve healthy volunteers, matched for age and sex . Five patients (17%) were incident cases, while the rest of the study group were prevalent and receiving PAH-specific treatment at the time of study. Most of them were in the WHO functional class III  and the majority of patients were women . General groups characteristics are presented in The study group consisted of twenty-eight PAH patients, with the mean age 49.5 ± 15.5 years , r = 0.86, p < 0.001. In addition, MRI-derived TAPSE values correlated well with echo TAPSE, r = 0.92, p < 0.001.In the PAH group, RV dimensions were significantly higher than in the control group, . The LV p < 0.01. This ratio was comparable to the ratio obtained with a use of MRI (TAPSE) and RHC (sPAP); as shown in the Bland–Altman plot in The echo-estimated RV ventricular–arterial coupling surrogate parameter (echo TAPSE/sPAP) was 0.35 ± 0.20 and 1.51 ± 0.22 in the control group, p < 0.001), as shown in p < 0.001) and positively with cardiac index . Moreover, the echo TAPSE/sPAP ratio also correlated with other MRI parameters—right ventricle ejection fraction, r = 0.51, p = 0.01, as shown in p = 0.004); and with RV mass index  in PAH. Echo TAPSE/sPAP significantly correlated with the non-echo ratio of TAPSE (MRI)/sPAP (RHC)—r = 0.75, p < 0.005. We did not observe significant correlations of TAPSE/sPAP ratio with other PAH prognostic factors, e.g., 6MWT distance or BNP levels.We observed that echo TAPSE/sPAP positively correlated with RHC-derived parameters—inversely with the mPAP . After 58 months’ follow-up, six patients died, and fifteen patients had WHO class worsening with hospitalization . The mean time to clinical worsening was 27.16 ± 20.21 months.We analyzed parameters in PAH subjects who had met the combined endpoint—CEP , Patients who reached CEP had a significantly higher echo mPAP and lower TAPSE .Interestingly, the TAPSE/sPAP ratio was significantly lower in CEP+ patients  and revealed the cut-off value −0.25 mm/mmHg. Patients with an echo TAPSE/sPAP lower than 0.25 mm/mmHg had worse prognosis, with log-rank test p = 0.001, as shown in ROC analysis confirmed the role of TAPSE/sPAP in predicting CEP (AUC 0.72 (95% CI 0.61–0.92), p = 0.43).Furthermore, ROC analysis revealed that TAPSE and sPAP alone (from echo or MRI) had a lower prediction of CEP than when presented as a ratio (according to the coupling idea), as shown in In our study, we confirmed that the simplified, echocardiographic approach of estimating RV–arterial coupling in PAH patients—the TAPSE/sPAP ratio—could be very useful in patient evaluation, even at bedside. It is linked with long-term prognosis and significantly correlates with the hemodynamic parameters of the RV from MRI and RHC.The idea of coupling is based on the relationship between ventricular contractility and afterload. In case of elevated pulmonary vascular resistance , RV systolic function and afterload are adequately coupled; however, with a further chronic increase in afterload, the RV becomes unable to proportionally enhance its contractility, leading to progressive right heart failure ,17.Still, the most accurate protocol for obtaining RV–arterial coupling is direct (invasive) measurement of pressure–volume loops ,4. DespiIn our study, we validated echo TAPSE/sPAP versus MRI- and RHC-derived parameters. As expected, the echo TAPSE/sPAP ratio strongly correlated with the hemodynamic afterload-dependent parameters, e.g., PVR or the cardiac index, which have been separately related to outcome in patients with PAH ,19. The It is noteworthy that echo, MRI and invasive measurements were performed during the baseline visit (at stable state of PAH patients), and we observed significant correlations between those parameters . This coIt has to be mentioned that our study group consisted mostly of patients with idiopathic PAH in WHO III class with severely deteriorated pulmonary hemodynamics . The TAPSE/sPAP ratio was low overall, and therefore, we cannot directly transfer our results to patients with less severe PAH. On the other hand, patients with the lowest TAPSE/sPAP values at baseline had a worse prognosis. This could help in risk stratification by detecting the group of PAH patients who need therapy escalation in a shorter period of time. We are aware that sPAP is an imperfect measure of RV afterload. By definition, it combines components of both vascular resistance and pulmonary venous congestion , and a bThere are also limitations on a use of TAPSE as a measure of RV systolic function. TAPSE provides information on the longitudinal motion of the chamber (which reflects contractility), but it is highly angle- and operator-dependent . In the TAPSE is also an afterload-dependent parameter and itself is an important predictor of poor outcome in PAH ,22. On tThe proposed echocardiographic estimation of RV ventricular–arterial coupling offers a potential easy, reliable and non-invasive prognostic parameter for the more comprehensive assessment of hemodynamic adaptation in patients with pulmonary arterial hypertension, even at bedside. It is significantly related with other invasive measurements or MRI-derived parameters. Identifying PAH patients with a nearly uncoupled right ventricle before clinical deterioration may be crucial to determining their prognosis.


Reduced ventricular longitudinal shortening measured by atrioventricular plane displacement (AVPD) and global longitudinal strain (GLS) are prognostic markers in heart disease. This study aims to determine if AVPD and GLS with cardiovascular magnetic resonance (CMR) are independent predictors of cardiovascular (CV) and all-cause death also in heart failure with reduced ejection fraction (HFrEF). Patients (n = 287) were examined with CMR and AVPD, GLS, ventricular volumes, myocardial fibrosis/scar were measured. Follow-up was 5 years with cause of death retrieved from a national registry. Forty CV and 60 all-cause deaths occurred and CV non-survivors had a lower AVPD  and worse GLS . Kaplan–Meier analyses displayed increased survival for patients in the highest AVPD- and GLS-tertiles vs. the lowest tertiles . AVPD and GLS showed in univariate analysis a hazard ratio (HR) of 1.30 (per-mm-decrease) and 1.19 (per-%-decrease) for CV death. Mean AVPD and GLS were independent predictors of all-cause death (HR = 1.24 per-mm-decrease and 1.15 per-%-decrease), but only AVPD showed incremental value over age, sex, body-mass-index, EF, etiology and fibrosis/scar for CV death . Ventricular longitudinal shortening remains independently prognostic for death in HFrEF even after adjusting for well-known clinical risk factors. Reduced ventricular longitudinal shortening has been associated with progressive HF4, and it has been shown to be an earlier and more sensitive marker for contractile dysfunction than the commonly-used ejection fraction (EF)6. Patients with preserved EF can exhibit reduced longitudinal shortening8, illustrating a disadvantage of using EF as the sole marker of ventricular function. Additionally, experimental data show that subendocardial damage elicits isolated reductions in ventricular longitudinal shortening irrespective of EF9. Therefore, there could be advantages in considering longitudinal function when assessing cardiac function, rather than relying solely on common measurements such as EF.Heart failure (HF) is a debilitating condition that affected an estimated 6.5 million Americans over the age of 20 in 2012, and the prevalence is projected to increase 46% by 2030, making HF a major challenge for the health-care system10 and global longitudinal strain (GLS)11. AVPD measures the average distance the atrioventricular (AV) plane moves towards the apex and is the major contributor to ventricular emptying and concomitantly to atrial filling during systole12. GLS is another well-known marker of ventricular longitudinal shortening13, and is a measure of the average segmental myocardial deformation. While AVPD and GLS are both measures of longitudinal shortening, the two cannot be used interchangeably16.Ventricular longitudinal shortening can be measured by atrioventricular plane displacement (AVPD)19. They are predictors of major adverse cardiac events and all-cause mortality in outpatients referred for clinical cardiac magnetic resonance (CMR)20, for patients with EF below 50%22 and for patients with hypertension16. However, it is not known whether selective assessment of ventricular longitudinal shortening in heart failure patients with reduced ejection fraction (HFrEF) adds prognostic value, since these patients are already known to have poor prognosis. Ventricular longitudinal shortening measurements are not presently included in standard clinical assessment of heart failure patients24 undergoing echocardiography or CMR. Clarifying the potential added benefit of ventricular longitudinal shortening over commonly-used parameters could aid in the clinical assessment of heart failure patients.Both AVPD and GLS are reduced in patients with HF22. Moreover, different methods for assessment of ventricular longitudinal shortening have been used. The earliest studies on the prognostic value of AVPD using echocardiography measured AVPD in several positions27. Later studies using CMR focused on a single point in the lateral21 or septal wall28, or normalized AVPD to cardiac length3. While regional longitudinal strain is already known to be related to outcome30, it is unknown whether the prognostic value of AVPD is influenced by the location of the AVPD measurements in heart failure patients. This may in part explain why there is no recommended or standardized position for measuring AVPD using CMR imaging. However, six points encompassing the left ventricular AV-plane are available for analysis when using the three standard long-axis views in CMR.Previous studies have reported differences in the prognostic value of ventricular longitudinal shortening that can be explained by differences between populations and follow-up periodsTherefore, the primary aim of this study was to assess the prognostic value of ventricular longitudinal shortening variables as independent predictors of cardiovascular (CV) and all-cause death in a cohort of patients with HFrEF. Secondly, this study aimed to evaluate ventricular longitudinal shortening as a prognostic tool independent of well-known risk markers such as EF and late gadolinium enhancement (LGE). Thirdly, we aimed to evaluate the relative prognostic differences between measuring one point or using several averaged points encircling the AV-plane, for CV and all-cause death in this population.Out of 295 patients with HFrEF undergoing a clinical CMR examination eight patients with poor image quality were excluded and so 287 patients were included for the final analysis . Figure Four patients had insufficient image quality for strain analysis and were excluded, hence GLS could be measured in 283 out of 287 (99%) patients. Ventricular longitudinal shortening was lower in patients (AVPD 7.8 ± 2.4 mm and GLS − 7.5 ± 3.0%) compared with age-matched controls . Patients had larger volumes , smaller stroke volumes (75 ± 22 ml) and EF (26.5 ± 8.0%) than controls . LGE was present in 77% of patients, and out of the LGE positive patients, ICM (74%) was more commonly seen than NICM (26%).The intraobserver variability was 0.5 ± 0.8 mm for AVPD [Intra class correlation (ICC): 0.95 (0.91–0.97)] and 0.2 ± 1.4% for GLS [ICC: 0.90 (0.82–0.95)]. The interobserver variability was 0.2 ± 1.0 mm for AVPD [ICC: 0.92 (0.82–0.95)] and 0.1 ± 1.4% for GLS [ICC: 0.90 (0.82–0.94)]. Bland and Altman-plots are presented in the Almost half (47%) of patients with available New York Heart Association (NYHA) classifications n = 216) were in NYHA III (Table 6 were inThe full follow-up time was median 7.9 years (IQR 5.4–11.7 years) and the first 5-year follow up showed 40 CV deaths and 60 all-cause deaths  = 17.0, p < 0.001) (Table 2(1) = 14.6, p < 0.001) over the clinical risk factors.AVPD persisted as an independent predictor of CV death (HR of 1.33-per-mm-decrease) at the 5-year follow-up when adjusting for well-known clinical risk factors , etiology of decreased EF, LGE presence, EF and EDVi) in multivariate Cox regression analysis  at 5 years. Secondly, AVPD was, unlike GLS, an independent prognostic marker for CV death at 5 years even after adjusting for well-known clinical risk factors such as EF, age, sex, BMI, etiology of decreased EF, presence of LGE and EDVi. Both AVPD and GLS, however, persisted as independent predictors of all-cause death. Thirdly, septal AVPD and mean AVPD resulted in the highest values of HR for CV and all-cause death, indicating that the prognostic value of AVPD is influenced by measurement location. It is not evident that GLS or AVPD would have prognostic importance when the global function measured as EF is severely reduced and the novelty of the present study is showing that ventricular longitudinal shortening retains its independent prognostic value in this patient population.25. The prognostic link between ventricular longitudinal shortening and death was first shown in echocardiography in heart failure patients17 and in patients hospitalized with acute myocardial infarctions31. Our study adds information about the prognostic relationship between AVPD, GLS and death in patients with severe HF, as these latter studies focused on cohorts with less disease severity. Previous CMR studies have investigated mitral annular plane systolic excursion (MAPSE) as a predictor of major adverse cardiovascular events in unselected outpatients referred for clinical CMR (HR 1.34 per-2-mm-decrease)20 and in patients with ST-elevation myocardial infarction (HR 1.20 per-mm-decrease)28. Furthermore, CMR-derived MAPSE has been shown as a predictor of all-cause death in patients with EF < 50% (HR 1.65 per-mm-decrease)21 and in patients with hypertension (HR 1.47 per-mm-decrease)16. While these studies had follow-up times with a span from 1.5 to 5 years, we found HR for AVPD at 5 years in the same range (HR 1.33) in our cohort of patients with severe disease.This study specifically targeted heart failure with severely reduced EF, in which AVPD and GLS are known to already be reducedThere can be several factors responsible for the variations in prognostic values obtained in the previous studies. Firstly, these studies encompassed different populations with different levels of disease severity and mortality. Secondly, the different follow-up time can be a factor. And thirdly, the location of measurement may play a role.22. In these three populations, mean EF ranged from 33 to 59% compared to our population (EF 26.5 ± 8.0%) which could explain the difference in mortality. As the total number of CV and all-cause deaths (n = 40 and n = 60) relative to our population size (n = 287) are higher than previous CMR studies of ventricular longitudinal shortening, our power to perform multivariate modeling is adequate, even though the number of subjects is moderate. Our prognostic values (hazard ratios) are lower than previous CMR studies28, possibly because of the narrow range of AVPD and GLS in our high morbidity and mortality population.At our 5-year follow-up, we had a total mortality of 21% which is about 40% higher than the three studies from Romano et al.The length of follow-up can also affect the prognostic values from ventricular longitudinal shortening variables. Longer follow-up carries more information and could aid in distinguishing prognostic information among groups with small differences. However, longer follow-up times expose the patients to an increasing number of confounding factors that are impossible to adequately control for. The 28, who found the septal point to be of higher predictive value than the lateral point. Rangarajan et al.20, however, did not find the septal position to be a significant predictor of major adverse cardiac events. The reasons for this were not clear to the authors and differs from our results. One methodological difference is that we measured a perpendicular distance from the AV-plane whereas Rangarajan et al. measured the direct route (beeline) of the mitral annular position from ED to ES. The effect of these methodological differences would, however, be expected to be small. In addition to the septal and lateral points, our study suggests that the six single AVPD locations influence the prognostic values in a slightly different way.We found septal AVPD to have the highest HR of the single measurement locations. This is in line with Mayr et al.3 and sometimes also referred to “long-axis shortening”. This is in concordance with the study by Støylen et al.15 showing that normalizing MAPSE to LV length did not adequately adjust for inter-individual size-dependent variability compared to only MAPSE, but rather that the method could add geometric biases.There was a slight insubstantial decrease, in HR by indexing AVPD to LV length in our study. The indexed AVPD is the equivalent of the “long-axis strain” presented by Gjesdal et al. in the Multi-Ethnic study of Atherosclerosis (MESA)34 is contradicted by our results. Longitudinal strain tools have the possibilities of analyzing regional and segmental strain values, something that is advantageous compared to AVPD.In this study, worse GLS was associated with increased CV death rates, higher NYHA class, and was an independent marker for all-cause death. Both AVPD and GLS were independent predictors of CV death for the full follow-up data in . There w.35 found GLS to be a superior prognostic predictor for a composite endpoint compared to MAPSE and EF in STEMI patients within one week of treatment. This may be explained by differences in patient populations and outcome measures between the studies. Additionally, our univariate results for GLS at 5 years was slightly lower but comparable to similar studies in patients with EF < 50% (HR 1.35)22 and dilated cardiomyopathy (HR 1.35)34.In contrast to our results Holzknecht et al36. Our data suggest this effect to be a short-term one since it disappears in the full follow-up data. Hypothetically, hypertension in HFrEF patients might indicate cardiac reserve capacities and a higher tolerance for medical treatments.Of note, the presence of hypertension was associated with a markedly decreased risk of CV death, as also shown by Zarrinkoub et al.Our study adds knowledge to the prognostic link between ventricular longitudinal shortening and death in a patient group with severe systolic dysfunction. In pathophysiological aspects, GLS measures the myocardial deformation throughout the myocardium while AVPD measures the result of that deformation on the AV-plane. The interaction between the AV-plane and atria is the direct measure of atrio-ventricular coupling and thus AVPD have a direct pathophysiological coupling to atrial filling in systole and to ventricular diastolic filling and may enhance the prognostic performance compared to GLS seen in this study.37. This was corroborated by a recent CMR study measuring flow profiles in the pulmonary veins in both controls and heart failure patients38.Ventricular longitudinal shortening reflected in AVPD and GLS causes displacement of blood to the great arteries in systole. While both measurements generally are appraised by their systolic properties, their contribution to filling of the heart is also crucial for the maintenance of cardiac output and may in part explain the strong prognostic information in GLS and especially AVPD. The systolic movement of the mitral and tricuspid valves towards the apex ejects blood into the great arteries while simultaneously causing suction of blood into the atria39 which also helps to understand why ventricular longitudinal shortening would be prognostic in ischemic heart failure.The pathophysiological connection between reduced ventricular longitudinal shortening and deaths related to heart failure is more easily understood than the connection between reduced ventricular longitudinal shortening and myocardial infarction (MI) or arrhythmias. One explanation may be that reduced AVPD and GLS show the effects from ischemic cardiomyopathy and prior ischemic insult. Thus, reduced ventricular longitudinal shortening may reflect damage to the myocardium not recognized by LGE. Of note, extracellular volume quantification was not available in our study population and may have provided prognostic information. Experimental data have shown that reduced AVPD after acute MI yields a concomitant decrease in SV40, and therefore a one-millimeter decrease is a relatively greater reduction at the septal compared to lateral position. This relative difference is important to consider when evaluating results from different outcome studies of ventricular longitudinal shortening for adequate comparisons. This might also be valuable information when choosing which measurements to use for a planned study. For the clinical setting, single-point septal AVPD seems to be a good choice, but a more diligent approach by averaging several measurements reduces the risk of outliers and may decrease variability. As automated post-processing algorithms for AVPD become available, the mean value from several long axis views may be the most robust approach, without being time-consuming, both for prognostic studies and in the clinical setting.By including six AVPD measurement points we could evaluate relative differences in prognostic values. We found that the two septal and mean AVPD measurement points yielded the highest HR while the lateral positions the lowest. One explanation for this is that amplitudes of septal AVPD are inherently smaller than lateral AVPD36. In sum, differences regarding medical therapies are likely to be of minor confounding importance.Since we had a long follow-up time and patients were included between 2003–2015, optimal medical treatment has changed over the inclusion period. Hence, patients diagnosed in the later part of the inclusion period could have received better medical treatment at baseline and this would improve their prognosis. However, there were no significant differences in medications for patients included when comparing three tertiles split by inclusion dates. The medical treatments prescribed at the time of CMR show that most patients had betablockers and RAAS antagonists but only about half received spironolactone. Forty-two % of patients had all three medications at the time of inclusion and we do not have data on changes in medical therapies. Nevertheless, the overall 5-year mortality rate in our study is in the same range (21%) as the reported average survival estimates of congestive HF in Sweden for similar age-groups for years 2006–2010 42. Additionally, the indications of cardio-resynchronizing therapy devices and cardioverter defibrillators has been expanded for HFrEF patients during the last two decades and the survival benefits of these devices are not included in our general models. Of note, as CRT and ICD treatment are commonly used in patients with HFrEF it is of importance to include these patients in prognostic studies.Fifty-six % of the patients were planned for implantable cardioverter-defibrillator (ICD) or cardio-resynchronizing therapy (CRT) implantation. This can affect the prognoses as these devices have been shown to increase survival, especially within ischemic cardiomyopathiesA methodological factor to consider is measurement error. The inter and intra-observer variability were higher in GLS compared to AVPD measurements which could lower the predictive performance of GLS compared to AVPD and in part explain our results.It can be challenging to determine if the cause of death is related to CV disease. HFrEF patients are prone to have or later on acquire other significant comorbidities such as chronic obstructive pulmonary disease, chronic kidney disease or cancer. These comorbidities impact survival, which is the case over a long follow-up time. The cause of fatal arrythmia could primarily originate from non-CV comorbidities rather than decreased longitudinal shortening. Furthermore, it is possible that there are more confounding factors from comorbidities which we haven’t addressed. Nevertheless, CV death as an endpoint yielded consistently higher hazard ratios than all-cause death to the heart failure-associated predictors studied here indicating CV death to be more sensitive to apply in prognostic studies of heart failure. Our data still suggest that measures of ventricular longitudinal shortening can significantly predict survival even when adjusting for well-known risk factors, and the Measures of ventricular longitudinal shortening are important predictors of cardiovascular and all-cause death in patients with HFrEF, and remains independently prognostic even after adjusting for well-known clinical risk factors. AVPD measured in the septum and mean AVPD demonstrated the highest hazard ratio indicating that measurement location can influence the prognostic results. Measurements of AVPD are quick, do not require specialized software, and can be performed at one or several points, and therefore appear to be clinically more favorable than GLS for determining prognosis in patients with HFrEF.Patients with HFrEF undergoing CMR at Lund University Hospital during 2003–2015 were included. All patients gave informed written consent to have their data used for research purposes prior to CMR examination. This study was approved in 2019 by the Swedish National Review Authority, the Swedish National Board of Health and Welfare and conformed to the principles of the Declaration of Helsinki. All methods were carried out in accordance with relevant guidelines and regulations. Previous medical history and cause of death was obtained from the Swedish National Board of Health and Welfare's Cause of Death Registry.43. In short, healthy controls had no history of cardiovascular disease, diabetes or systemic disease, no cardiovascular medication, no hypertension (blood pressure < 140/90 mmHg), and no pathology on electrocardiography or CMR.Patients were included if they had a clinical diagnosis of heart failure and a CMR examination. Indications for CMR examinations were assessments for infarct, fibrosis, ventricular volumes or investigation prior to ICD or CRT. Exclusion criteria were EF above 40% measured from the CMR examination or inadequate image quality. The etiology of decreased EF was divided into ICM or NICM based on patients’ charts and the clinical CMR reports. Information on patient medications, hypertension, diabetes and NYHA classifications were retrospectively obtained from electronic medical records. Twenty age-matched healthy controls recruited from advertisements were included for comparisons, and whose characteristics have previously been published in detailThe primary outcome was cardiovascular death. CV death was defined as death caused by acute myocardial infarction, heart failure or ventricular arrhythmia as stated by the national registry. The secondary outcome was all-cause death.1.5T Philips Achieva 3T Philips Achieva 1.5T Siemens Aera Imaging was performed using three different clinical MRI-scanners:Standard short and long axis cine images  were acquired using steady-state free precession sequences. LGE sequences for infarct assessment were used according to the clinical protocol. Detailed imaging parameters are presented in the http://segment.heiberg.se)44.Left ventricular (LV) volumes and longitudinal measurements were analyzed from cine images using freely-available imaging analysis software . AVPD was defined as the mean displacement of these six LV points. Further, mean AVPD was indexed to LV length, and LV length was defined as the distance from the apex to the point intersecting the AV-plane at a perpendicular angle. The main advantages for using AVPD compared to the commonly used MAPSE are threefold. First, the basal measuring points for AVPD placed at the top of the ventricular muscle vs. at the mitral valve hinge-points for MAPSE provides easier tracking in CMR. Second, the six measuring points encircling the ventricle increases robustness to measurement errors compared to fewer measurement locations often used for MAPSE. Third, the perpendicular distance from an end-diastolic reference plane used for AVPD vs. the direct route often used in MAPSE circumvents possible biases via lateral translation of the ventricle and enables measuring volumes connected to longitudinal pumping. TAPSE was measured as the lateral free-wall displacement in the 4-chamber view. GLS was calculated using feature tracking in each long-axis view. The myocardium was manually delineated in end diastole and tracked semi-automatically and time-resolved over the cardiac cycle. If tracking was inadequate, it was manually adjusted in end diastole and re-tracked. Both AVPD and GLS measurements required at least two long-axis images for inclusion. Left atrial volume was estimated using the area-length method: V = (8/3π) × (Area2ch × Area4ch)/(L), where L is the shortest length from the 2ch or 4ch-view46. Figure AVPD was measured according to previously published methodologyAll included patients had follow-up data obtained from the Swedish National Health and Welfare’s Death Registry. Elapsed time between CMR examination and CV or all-cause death served as input for survival analyses. Patients were censored if they reached the end of the study period (31 December 2019) without an event. Patients who died from other causes were censored from the primary outcome at time of death. Follow-up analysis was performed for the 5-year follow-up, as the prognostic implication is expected to be most important in the first few years after the imaging test. Data from the complete follow-up time is presented in the t test for continuous variables and Chi-square test for categorical values. Intra, and interobserver variability for AVPD and GLS was tested in a subset of 43 patients with bias ± SD according to Bland and Altman47. Intra class correlation with a two-way-random-model was used to assess inter, and intra-observer reliability of the AVPD and GLS measurements.Continuous data are presented as mean ± standard deviation (SD) or median and interquartile range (IQR) according to normal distribution. Normal distribution was assessed by histograms. Categorical variables are presented as absolute numbers and proportion in percentages. Baseline characteristics were compared among equally-numbered AVPD- or GLS-tertiles with analysis of variance (ANOVA) and with least significant difference post-hoc tests. Differences between two groups were tested with Student’s 48. Schoenfeldt residuals plotted against time was used to assess proportional hazards. For the multivariate Cox regressions, a conditional backwards elimination strategy was performed, and a variable was included when p ≤ 0.10. Final predictive models with AVPD and GLS were compared with nested models including the aforementioned risk factors with the LR-test.Cumulative survival probability curves for CV death were assessed using Kaplan–Meier plots. The log-rank test was used for the 5-year follow-up. Cox regression modeling was used for calculation of hazard ratios (HR) of CV and all-cause death. HR are presented with 95% confidence intervals (95% CI). A priori defined well-known clinical risk factors for CV death  and with < 5% missing values were included in a multivariate Cox regression analysis. Multicollinearity between variables was assessed with Pearson’s linear regression coefficient with a cut-off value for inclusion chosen as < 0.8A p-value < 0.05 was considered significant. Statistical analyses were performed using SPSS v.27.0 .The patients gave informed written consent prior to the CMR examination that their data could be used for research purposes. Patients were able to retract their consent at any time. The patients’ data could also be used in retrospective cardiovascular research studies. This study was approved in 2019 by the Swedish Ethical Review Authority, the Swedish National Board of Health and Welfare in an amendment to the original form without new informed consent and conformed to the principles of the Declaration of Helsinki.Supplementary Information.