Healthy Myocardium Research Articles

Late iodine enhancement quantification by computed tomography: a comparison study against cardiac magnetic resonance imaging

Abstract Introduction Cardiac computed tomography (CT) has emerged as a promising alternative to cardiac magnetic resonance (CMR) for myocardial characterization. However, the quantification of late iodine enhancement (LIE) and its threshold values have not been previously reported. The Full Width Half Maximum (FWHM) technique established a cut-off value of 50% of the maximum intensity signal to quantify late gadolinium enhancement (LGE) in CMR. Nevertheless, the distinction between healthy and fibrotic myocardium in CT is less pronounced, prompting the need for specific threshold values for accurate quantification of LIE with this technique. Purpose Our primary aim was to validate and determine the optimal cut-off values for quantifying LIE using cardiac CT. Methods We included consecutive patients who underwent both LIE and LGE within a period of less than 2 months. Late enhancement quantification was performed using a commercially available software (figure 1). The FWHM technique was applied for LGE quantification. Various signal density cut-off values (70%, 75%, 80%, 85%, and 90%) were explored for LIE quantification. The total myocardial mass, total scar mass and scar proportion were calculated. The Intraclass Correlation Coefficient (ICC) was computed for each of the specified cut-off values. Results From November 2022 to February 2024, 58 patients underwent cardiac CT with LIE. Among them, 17 patients (48 (33;59) years; 13 (68,4%) male) had concomitant LGE and were included in the final analysis. The most common indication for CT was myocardial infarction with non-obstructive coronary arteries (52,9%). The total myocardial mass by CT was 108.83 ± 21.69 g, while the total myocardial mass by CMR was 100.33 ± 25.19 g. The ICC between both techniques was good (0.78, p=0.001). A cut-off value of 75% for the CT showed the strongest correlation with the CMR, both for total scar mass and scar proportion. Total scar mass was 9.43 ± 8.29 g for CT and 10.7 ± 8.46 g for CMR, with an ICC of 0.68 (p=0.01). Scar proportion was 9.97 ± 8.26% for CT and 11.09 ± 9% for CMR, showing a good correlation (ICC 0.73, p=0.006). Conclusion Late iodine enhancement quantification by cardiac computed tomography is feasible. A signal density threshold of 75% showed the strongest correlation with the cardiac magnetic resonance.Example of late iodine enhancement

Magnetic resonance reveals early lipid deposition in murine prediabetes as predictive marker for cardiovascular injury

People with diabetes have an increased cardiovascular risk and a poorer outcome after myocardial infarction (MI). However, the exact underlying mechanisms are still unclear, as is the question of which non-invasive measures could be used to predict the altered risk for the patient at early stages of the disease and adapt personalized treatment. Here, we used a holistic magnetic resonance approach to monitor longitudinally not only the main target heart, but also liver, peripheral/skeletal muscle, bone marrow, and hematopoiesis during disease development and subsequent MI. In prediabetic mice, we found a strong accumulation of lipids in all organs which preceded even a significant whole-body weight gain. Intramyocellular lipids (IMCLs) were most sensitive to reveal in vivo very early alterations in tissue properties during the prediabetic state. Subsequent induction of MI led to a persistent impairment of contractile function in septal/posterior segments of prediabetic hearts which correlated with their lipid load prior MI. At the same time, prediabetic cardiomyocytes exhibited sarcomere function at its limit resulting in overload and lower compensatory contractility of the healthy myocardium after MI. In summary, we identified IMCLs as very early marker in murine prediabetes and together with the cardiac lipid load as predictive for the functional outcome after MI.

MRI Accurately Visualizes RF Ablation Delivery Targeted to MRI-Defined Arrhythmia Substrates in the Left Ventricle.

Investigate the capacity of MRI to evaluate efficacy of radiofrequency (RF) ablations delivered to MRI-defined arrhythmogenic substrates. Baseline MRI was performed at 3T including 3D LGE in a swine model of chronic myocardial infarct (N=8). MRI-derived maps of scar and heterogeneous tissue channels (HTCs) were generated using ADAS 3D. Animals underwent electroanatomic mapping and ablation of the left ventricle in CARTO3, guided by MRI-derived scar maps. Post-ablation MRI (in vivo at 3T in 5/8 animals; ex vivo at 1.5T in 3/8) included 3D native T1-weighted IR-SPGR (TI=700-800ms) to visualize RF lesions. T1-derived RF lesions were compared against excised tissue. The locations of T1-derived RF lesions were compared against CARTO ablation tags, and segment-wise sensitivity and specificity of lesion detection were calculated within the AHA 17-segment model. RF lesions were clearly visualized in HTCs, scar, and myocardium. Ablation patterns delivered in CARTO matched T1-derived RF lesion patterns with high sensitivity (88.9%) and specificity (94.7%), and were closely matched in registered MR-EP data sets, with a displacement of 5.4 ±3.8mm (N=152 ablation tags). Integrating MRI into ablative procedures for RF lesion assessment is feasible. Patterns of RF lesions created using a standard 3D EAM system are accurately reflected by MRI visualization in healthy myocardium, scar, and HTCs comprising the MRI-defined arrhythmia substrate. MRI visualization of RF lesions can provide near-immediate (<24h) assessment of ablation, potentially indicating whether critical MRI-defined ventricular tachycardia substrates have been adequately ablated.

Impact of cardiac patch alignment on restoring post-infarct ventricular function.

Acute myocardial infarction (MI) leads to a loss of cardiac function which, following adverse ventricular remodeling (AVR), can ultimately result in heart failure. Tissue-engineered contractile patches placed over the infarct offer potential for restoring cardiac function and reducing AVR. In this computational study, we investigate how improvement of pump function depends on the orientation of the cardiac patch and the fibers therein relative to the left ventricle (LV). Additionally, we examine how model outcome depends on the choice of material properties for healthy and infarct tissue. In a finite element model of LV mechanics, an infarction was induced by eliminating active stress generation and increasing passive tissue stiffness in a region comprising 15% of the LV wall volume. The cardiac patch was modeled as a rectangular piece of healthy myocardium with a volume of 25% of the infarcted tissue. The orientation of the patch was varied from 0 to relative to the circumferential plane. The infarct reduced stroke work by 34% compared to the healthy heart. Optimal patch support was achieved when the patch was oriented parallel to the subepicardial fiber direction, restoring 9% of lost functionality. Typically, about one-third of the total recovery was attributed to the patch, while the remainder resulted from restored functionality in native myocardium adjacent to the infarct. The patch contributes to cardiac function through two mechanisms. A contribution of tissue in the patch and an increased contribution of native tissue, due to favorable changes in mechanical boundary conditions.

Hypoxic-Normoxic Crosstalk Activates Pro-Inflammatory Signaling in Human Cardiac Fibroblasts and Myocytes in a Post-Infarct Myocardium on a Chip.

Myocardial infarctions locally deprive myocardium of oxygenated blood and cause immediate cardiac myocyte necrosis. Irreparable myocardium is then replaced with a scar through a dynamic repair process that is an interplay between hypoxic cells of the infarct zone and normoxic cells of adjacent healthy myocardium. In many cases, unresolved inflammation or fibrosis occurs for reasons that are incompletely understood, increasing the risk of heart failure. Crosstalk between hypoxic and normoxic cardiac cells is hypothesized to regulate mechanisms of repair after a myocardial infarction. To test this hypothesis, microfluidic devices are fabricated on 3D printed templates for co-culturing hypoxic and normoxic cardiac cells. This system demonstrates that hypoxia drives human cardiac fibroblasts toward glycolysis and a pro-fibrotic phenotype, similar to the anti-inflammatory phase of wound healing. Co-culture with normoxic fibroblasts uniquely upregulates pro-inflammatory signaling in hypoxic fibroblasts, including increased secretion of tumor necrosis factor alpha (TNF-α). In co-culture with hypoxic fibroblasts, normoxic human induced pluripotent stem cell (hiPSC)-derived cardiac myocytes also increase pro-inflammatory signaling, including upregulation of interleukin 6 (IL-6) family signaling pathway and increased expression of IL-6 receptor. Together, these data suggest that crosstalk between hypoxic fibroblasts and normoxic cardiac cells uniquely activates phenotypes that resemble the initial pro-inflammatory phase of post-infarct wound healing.

SARS-CoV-2 pathogenesis in an angiotensin II–induced heart-on-a-chip disease model and extracellular vesicle screening

Adverse cardiac outcomes in COVID-19 patients, particularly those with preexisting cardiac disease, motivate the development of human cell-based organ-on-a-chip models to recapitulate cardiac injury and dysfunction and for screening of cardioprotective therapeutics. Here, we developed a heart-on-a-chip model to study the pathogenesis of SARS-CoV-2 in healthy myocardium established from human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and a cardiac dysfunction model, mimicking aspects of preexisting hypertensive disease induced by angiotensin II (Ang II). We recapitulated cytopathic features of SARS-CoV-2-induced cardiac damage, including progressively impaired contractile function and calcium handling, apoptosis, and sarcomere disarray. SARS-CoV-2 presence in Ang II-treated hearts-on-a-chip decreased contractile force with earlier onset of contractile dysfunction and profoundly enhanced inflammatory cytokines compared to SARS-CoV-2 alone. Toward the development of potential therapeutics, we evaluated the cardioprotective effects of extracellular vesicles (EVs) from human iPSC which alleviated the impairment of contractile force, decreased apoptosis, reduced the disruption of sarcomeric proteins, and enhanced beta-oxidation gene expression. Viral load was not affected by either Ang II or EV treatment. We identified MicroRNAs miR-20a-5p and miR-19a-3p as potential mediators of cardioprotective effects of these EVs.

Personalized evaluation of the passive myocardium in ischemic cardiomyopathy via computational modeling using Bayesian optimization.

Biomechanics-based patient-specific modeling is a promising approach that has proved invaluable for its clinical potential to assess the adversities caused by ischemic heart disease (IHD). In the present study, we propose a framework to find the passive material properties of the myocardium and the unloaded shape of cardiac ventricles simultaneously in patients diagnosed with ischemic cardiomyopathy (ICM). This was achieved by minimizing the difference between the simulated andthe target end-diastolic pressure-volume relationships (EDPVRs) using black-box Bayesian optimization, based on the finite element analysis (FEA). End-diastolic (ED) biventricular geometry and the location of the ischemia were determined from cardiac magnetic resonance (CMR) imaging. We employed our pipeline to model the cardiac ventricles of three patients aged between 57 and 66years, with and without the inclusion of valves. An excellent agreement between the simulated and thetarget EDPVRs has been reached. Our results revealed that the incorporation of valvular springs typically leads to lower hyperelastic parameters for both healthy and ischemic myocardium, as well as a higher fiber Green strain in the viable regions compared to models without valvular stiffness. Furthermore, the addition of valve-related effects did not result in significant changes in myofiber stress after optimization. We concluded that more accurate results could be obtained when cardiac valves were considered in modeling ventricles. The present novel and practical methodology paves the way for developing digital twins of ischemic cardiac ventricles, providing a non-invasive assessment for designing optimal personalized therapies in precision medicine.

Myocardial inflammation after elective percutaneous coronary intervention

ObjectiveIt is well established that inflammation plays a central role in the sequelae of percutaneous coronary intervention (PCI). Most of the studies to date have focused on the inflammatory reaction affecting the vessel wall after angioplasty. However, there are data to suggest that the main foci of inflammation are in fact in the myocardium beyond the vessel wall. The main aim of our study was to investigate the myocardial inflammation after elective, uncomplicated angioplasty with cardiovascular magnetic resonance (CMR) enhanced by ultrasmall superparamagnetic particles of iron oxide (USPIO) and also blood biomarkers. This is the first study to report such findings after elective angioplasty. MethodsWe assessed patients undergoing elective angioplasty for stable angina with USPIO-enhanced CMR two weeks after the procedure and compared the results with those of healthy volunteers who constituted the control group. We excluded patients with previous myocardial infarction, previous PCI, or any significant inflammatory condition. All patients also underwent blood biomarker testing at baseline (pre-PCI), 4 h, and two weeks later. ResultsA total of five patients and three controls were scanned. There was a small absolute increase, although statistically insignificant, in R2∗ values in the PCI area compared with either remote myocardium from the same patient (PCI area [left anterior descending artery (LAD)] vs remote myocardium [circumflex area]: 19.3 ± 10.8 vs 9.2 ± 7.9, p = 0.1) or healthy myocardium from healthy volunteers (PCI area [LAD] vs healthy myocardium [LAD]: 19.3 ± 10.8 vs 12.2 ± 4.0, p = 0.2). PTX3 and IL-6 were the only biomarkers that changed significantly from baseline to 4 h and 2 weeks. Both biomarkers peaked at 4 h. ConclusionWe used USPIO-enhanced CMR for the first time to assess myocardial inflammation after elective, uncomplicated PCI. We have demonstrated a small numerical increase in inflammation, which was not statistically significant. This study opens the way for future studies to use this method as a means to target inflammation.

Human cardiomyocyte derived extracellular vesicles regulate cardiac fibroblast activation through miR-24

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondazione Leonardo Introduction Cardiovascular diseases are associated with increase in interstitial fibrosis due to cardiac fibroblast (CF) activation into myofibroblast leading to the secretion and deposition of extracellular matrix (ECM). The intricate functional activation of these processes is not well understood, especially concerning the contribution of the microenvironment. One of the most important mechanisms of paracrine communication are due to Extracellular vesicles (EVs). EVs are cell-released nanoparticles carrying proteins, lipids, and nucleic acids, particularly miRs. To note, previous transcriptomic analysis of healthy human heart demonstrated that miR24-3p is one of the most abundant miRs [1], suggesting an important role associated with its expression. Aim of the work Here we aim to investigate the role of miR24-3p as regulator of cardiac fibroblast activation, focusing on healthy and pathological conditions. Materials and methods Bioinformatic analysis of open-data, single-cell RNA sequencing from heart tissue was conducted to assess the expression of miR24-3p and its specific targets in both healthy and infarcted myocardium. To explore the functional role of miR24-3p, loss- and gain-of-function experiments were performed by transfecting cardiac fibroblasts (CF) with specific antimiR or mimic oligonucleotides, respectively. In investigating the influence of cardiomyocytes (CM) on CF regulation, extracellular vesicles (EVs) from human-induced pluripotent stem cell-derived CM were isolated and utilized in in vitro experiments. The expression levels of miRNA24-3p were also evaluated in the plasma of healthy individuals and patients who had experienced myocardial infarction. Finally, cardiac slices from human tissue were employed as ex-vivo microtissues to functionally validate the in vitro findings. Results RealTime analysis of CF, CM and cardiac endothelial cells (EC) revealed a CM specific expression of miR24-3p, not only at cellular level but also in EVs. Upregulation of miR24-3p in CF was able to significantly reduce protein expression of FURIN, CYCLD1 and SMAD4, resulting in decrease of CF activation and ECM secretion. Interestingly, treatment of CF with CM-EVs recapitulate miR24-3p transfection, while EVs derived from hypoxia cultured CM (MI-like) does not. RNAScope and ddPCR analysis on human cardiac slice cultured under hypoxia conditions confirmed decrease in miR24-3p expression upon induction of stress. Ultimately, a significant decrease in miR24-3p in circulating serum EVs of MI patients’ was observed. Conclusions These data demonstrate the role of miR24-3p in CF regulation through the paracrine activity mediated by CM-EVs. Further analysis, including the use of a 3D human heart microtissue, will confirm the mechanism of cross-talk between CM and CF.

Impact of myocardial phenotype on atrioventricular delay optimization at rest and during exercise: insights from a virtual patient study

Abstract Background The usefulness of atrioventricular delay (AVD) optimization in cardiac resynchronization therapy (CRT) for heart failure (HF) patients with left bundle branch block (LBBB) and reduced left ventricular ejection fraction (LVEF) is still debated. Yet, studies have not explored the role of non-electrical myocardial disease substrates in determining optimal AVD settings among patients. Purpose We first hypothesized that acute response to AVD optimization might be modulated by various myocardial disease substrates. Furthermore, we hypothesized that cardiac function is more sensitive to changes in AV coupling during exercise and that this sensitivity is also modulated by underlying myocardial disease substrates. Methods We used the CircAdapt model of the human heart and circulation to simulate different types of LV remodeling that can be found in CRT candidates. First, an LBBB-like pattern of mechanical activation was imposed by delaying LV free wall (LVFW) and interventricular septal (IVS) activation relative to right ventricular free wall activation. Then, two types of LV remodeling were simulated by LV dilation with preserved or impaired myocardial contractility, resulting in LVEF &amp;lt;35%. To investigate the effect of diastolic dysfunction, we increased passive myocardial stiffness of the IVS and LVFW on both substrates with LV remodeling until a mean left atrial pressure (mLAP) of 14 mmHg was reached. CRT was simulated by resynchronizing IVS and LVFW. AVD optimization was conducted by gradually reducing the paced AVD from 220 ms to 40 ms in steps of 20 ms. In each simulation, the optimal paced AVD at rest (cardiac output (CO) and heart rate (HR) of 4.2 L/min and 80 bpm, respectively) was assessed using stroke volume (SV) and mLAP which is used as a measure of LV filling pressure. To investigate the relative effect of these myocardial phenotypes during AVD optimization under exercise, CO and HR were increased step-wise. Results The gain in SV by AVD optimization was larger in the simulations with healthy myocardium than in those with hypo-contractile and stiff myocardium (Figure 1: top-row). However, mLAP was comparably decreased by AVD optimization in healthy and diseased myocardium (Figure 1: bottom row). During exercise, the optimum AVD shifted to shorter values (Figure 2: top-row), and mLAP was much more sensitive to AVD, particularly in the presence of hypo-contractile and stiff myocardium (Figure 2: bottom row). Conclusion Virtual patient simulations show that both myocardial hypocontractility and stiffness dampen the effect of AVD optimization on SV. Furthermore, simulations suggest that patients benefit more from AVD optimization during exercise than during resting conditions. These mechanistic insights may help to gain more benefit from AVD optimization for patients undergoing CRT.AVD optimization at restAVD optimization during exercise

Exploration of peak frequency mapping for ventricular tachycardia ablation. Identification of critical isthmus zones during substrate mapping

Abstract Background/Introduction The ability to classify and differentiate between near field and far-field components of intracardiac signals is a key element in identifying critical arrhythmogenic substrate during ventricular tachycardia (VT) ablation. Near Field algorithms based on omnipolar electrograms enable detection and automation of true localised signals providing unique insights into substrate characteristics. This novel feature identifies localised signal peak frequency (PF) which can be displayed across different voltage ranges. Purpose/Aims The significance of PF mapping in the context of VT ablation is limited and its utility in the identification of the critical diastolic isthmus zone (IZ) is not known. The aim of this study is to explore the utilisation of PF mapping during VT ablation and evaluate whether significant differences in PF occur within areas of interest and critical components of the VT circuit during substrate mapping. Methods All patients underwent VT ablation using the EnSite™ X mapping system with the HDGrid omnipolar mapping catheter. Only cases with both high density sinus rhythm (SR) substrate maps and VT activation maps with clear identification of the IZ were included. VT activation and propagation maps were generated and the diastolic IZ was superimposed onto the SR substrate map. PF analysis was performed retrospectively. Surface area, omnipolar voltage and PF of the maps were measured in the SR substrate maps and co-localised with the critical IZ of the VT circuit as identified in the VT activation maps. Analysis of PF was conducted across different voltage ranges: healthy myocardium (&amp;gt;1.5mV), scar (1.5-0.5mV) and dense scar (0.5-0.1mV). Sensitivity and specificity measurements were made within segments of the IZ and non-isthmus zones and depicted as ROC curves. Results 55 patients underwent VT ablation over a 12-month period, with a total of 18 fulfilling the inclusion criteria. Mean age was 70 (±12.5years) with an average ejection fraction of 36%. The overall PF of the SR substrate maps was 121.85±26.85 Hz, compared to 162.22±46.22Hz within the IZ (p=0.002). Within the low voltage scar region, the overall PF was 120.86±33.24Hz compared to 188.32±81.36Hz within the IZ (p=0.003). No significant difference in PF was observed within healthy myocardium (112.70±52.06 Hz) compared to components of the IZ within the &amp;gt;1.5mV range (157.61±136.11Hz), p=0.207. The AUC for PF within the overall substrate map and co-localisation with the IZ was 0.67, and 0.73 within low voltage zones (&amp;lt;1.5mV). Conclusions PF mapping may identify critical components of the VT circuit during SR substrate mapping and its utilisation may compliment established substrate mapping approaches. PF guided ablation strategies require further evaluation in future prospective studies.

Cardiac magnetic resonance - aided ventricular tachycardia substrate ablation

Abstract Objectives To assess feasibility and reliability of Cardiac magnetic resonance (CMR)-derived pixel signal intensity (PSI) maps obtained by Three Dimensional (3D)- Late Gadolinium Enhancement (LGE) images for detecting potential targets for VT substrate ablation procedures. Background Parametric imaging with color-coded PSI maps obtained from pre-ablation 3D LGE -CMR imaging can be used for identification and characterization of arrhythmic abnormal substrate. Recent publications have shown that PSI maps permit visualization of border zone areas inside the scar. Specifically, corridors of viable tissue within the scar connecting healthy myocardium define VT corridors that may be the electrical equivalent of the abnormal conducting channels on the electroanatomical mapping (EAM). Methods 8 patients with scar-dependent monomorphic VTs who underwent 3D-LGE CMR imaging prior to substrate ablation were included in the study. The studies were performed at 1.5T scanner. We obtained two data sets of 3D whole heart LGE imaging with high resolution. Patients underwent two acquisitions: the conventional respiratory navigated, electrocardiographically-gated 3D fast gradient echo (1.3slice thickness, 256x256 matrix acquisition) and the image-navigated isotropic high resolution 3D GE with Dixon water-fat separation. 3D LGE-CMR images were processed with ADAS-VT software to produce a 3-dimensional model of the heart with 10 layers from the endocardium to epicardium and PSI maps color-coded from the LGE data projected to each of the shells (Figure 1). In the LGE-CMR PSI maps, VT corridors were obtained automatically by the ADAS VT software. Subsequently, data were given to the electrophysiologists and merged with the CARTO3 system EAM data obtained for the ablation (Figure2). CMR information was used to facilitate the identification of target ablation sites in the areas identified by CMR as abnormal substrate and radiofrequency was applied in the presence of both a pathological electrogram (EGM) and a VT corridor as identified by CMR. Results There was a 95% agreement between the abnormal conducting channels as detected by abnormal electrograms in the EAM and the VT corridors identified by 3D LGE CMR imaging. In two occasions, there was one VT corridor that did not correlate with abnormal electrograms and was not ablated. The two 3D LGE sequences used for ADAS-VT corridors analysis showed complete agreement in the number and location of VT corridors. Mean acquisition time for 3D LGE imaging was 11±4minutes for the conventional fast gradient echo sequence, and 5±2minutes for the novel 3D self-image navigated LGE sequence. The image quality of 3D LGE was superior with the Dixon fat-water separation. Overall CMR-aided VT ablation reduced the procedural and fluoroscopy time by 40%. Conclusions CMR-aided VT ablation is feasible, reliable and significantly reduces the procedural time.

Myocardial B cells have specific gene expression and predicted interactions in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy.

Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy. We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with arrhythmogenic right ventricular cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis. We identified 1,100 B cells, including naive B cells and plasma cells. Cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interactions; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation. The human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.

Simulated Effects of Acute Left Ventricular Myocardial Infarction on Mitral Regurgitation in an Ovine Model.

Ischemic mitral regurgitation (IMR) occurs from incomplete coaptation of the mitral valve (MV) after myocardial infarction (MI), typically worsened by continued remodeling of the left ventricular (LV). The importance of LV remodeling is clear as IMR is induced by the post-MI dual mechanisms of mitral annular dilation and leaflet tethering from papillary muscle (PM) distension via the MV chordae tendineae (MVCT). However, the detailed etiology of IMR remains poorly understood, in large part due to the complex interactions of the MV and the post-MI LV remodeling processes. Given the patient-specific anatomical complexities of the IMR disease processes, simulation-based approaches represent an ideal approach to improve our understanding of this deadly disease. However, development of patient-specific models of left ventricle-mitral valve (LV-MV) interactions in IMR are complicated by the substantial variability and complexity of the MR etiology itself, making it difficult to extract underlying mechanisms from clinical data alone. To address these shortcomings, we developed a detailed ovine LV-MV finite element (FE) model based on extant comprehensive ovine experimental data. First, an extant ovine LV FE model (Sci. Rep. 2021 Jun 29;11(1):13466) was extended to incorporate the MV using a high fidelity ovine in vivo derived MV leaflet geometry. As it is not currently possible to image the MVCT in vivo, a functionally equivalent MVCT network was developed to create the final LV-MV model. Interestingly, in pilot studies, the MV leaflet strains did not agree well with known in vivo MV leaflet strain fields. We then incorporated previously reported MV leaflet prestrains (J. Biomech. Eng. 2023 Nov 1;145(11):111002) in the simulations. The resulting LV-MV model produced excellent agreement with the known in vivo ovine MV leaflet strains and deformed shapes in the normal state. We then simulated the effects of regional acute infarctions of varying sizes and anatomical locations by shutting down the local myocardial contractility. The remaining healthy (noninfarcted) myocardium mechanical behaviors were maintained, but allowed to adjust their active contractile patterns to maintain the prescribed pressure-volume loop behaviors in the acute post-MI state. For all cases studied, the LV-MV simulation demonstrated excellent agreement with known LV and MV in vivo strains and MV regurgitation orifice areas. Infarct location was shown to play a critical role in resultant MV leaflet strain fields. Specifically, extensional deformations of the posterior leaflets occurred in the posterobasal and laterobasal infarcts, while compressive deformations of the anterior leaflet were observed in the anterobasal infarct. Moreover, the simulated posterobasal infarct induced the largest MV regurgitation orifice area, consistent with experimental observations. The present study is the first detailed LV-MV simulation that reveals the important role of MV leaflet prestrain and functionally equivalent MVCT for accurate predictions of LV-MV interactions. Importantly, the current study further underscored simulation-based methods in understanding MV function as an integral part of the LV.

Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.

Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.

Repeatability of Open-MOLLI: An open-source inversion recovery myocardial T1 mapping sequence for fast prototyping.

To develop an open-source prototype of myocardial T1 mapping (Open-MOLLI) to improve accessibility to cardiac T1 mapping and evaluate its repeatability. With Open-MOLLI, we aim to enable faster implementation and testing of sequence modifications and to facilitate inter-scanner and cross-vendor reproducibility studies. Open-MOLLI is an inversion-recovery sequence using a balanced SSFP (bSSFP) readout, with inversion and triggering schemes based on the 5(3)3 MOLLI sequence, developed in Pulseq. Open-MOLLI and MOLLI sequences were acquired in the ISMRM/NIST phantom and 21 healthy volunteers. In 18 of those subjects, Open-MOLLI and MOLLI were repeated in the same session (test-retest). Phantom T1 values were comparable between methods, specifically for the vial with reference T1 value most similar to healthy myocardium T1 (T1vial3 = 1027 ms): T1MOLLI = 1011 ± 24 ms versus T1Open-MOLLI = 1009 ± 20 ms. In vivo T1 estimates were similar between Open-MOLLI and MOLLI (T1MOLLI = 1004 ± 33 ms vs. T1Open-MOLLI = 998 ± 52 ms), with a mean difference of -17 ms (p = 0.20), despite noisier Open-MOLLI weighted images and maps. Repeatability measures were slightly higher for Open-MOLLI (RCMOLLI = 3.0% vs. RCOpen-MOLLI = 4.4%). The open-source sequence Open-MOLLI can be used for T1 mapping in vivo with similar mean T1 values to the MOLLI method. Open-MOLLI increases the accessibility to cardiac T1 mapping, providing also a base sequence to which further improvements can easily be added and tested.

Fully automated contrast selection of joint bright- and black-blood late gadolinium enhancement imaging for robust myocardial scar assessment

PurposeJoint bright- and black-blood MRI techniques provide improved scar localization and contrast. Black-blood contrast is obtained after the visual selection of an optimal inversion time (TI) which often results in uncertainties, inter- and intra-observer variability and increased workload. In this work, we propose an artificial intelligence-based algorithm to enable fully automated TI selection and simplify myocardial scar imaging. MethodsThe proposed algorithm first localizes the left ventricle using a U-Net architecture. The localized left cavity centroid is extracted and a squared region of interest (“focus box”) is created around the resulting pixel. The focus box is then propagated on each image and the sum of the pixel intensity inside is computed. The smallest sum corresponds to the image with the lowest intensity signal within the blood pool and healthy myocardium, which will provide an ideal scar-to-blood contrast. The image's corresponding TI is considered optimal. The U-Net was trained to segment the epicardium in 177 patients with binary cross-entropy loss. The algorithm was validated retrospectively in 152 patients, and the agreement between the algorithm and two magnetic resonance (MR) operators' prediction of TI values was calculated using the Fleiss' kappa coefficient. Thirty focus box sizes, ranging from 2.3mm2 to 20.3cm2, were tested. Processing times were measured. ResultsThe U-Net's Dice score was 93.0 ± 0.1%. The proposed algorithm extracted TI values in 2.7 ± 0.1 s per patient (vs. 16.0 ± 8.5 s for the operator). An agreement between the algorithm's prediction and the MR operators' prediction was found in 137/152 patients (κ= 0.89), for an optimal focus box of size 2.3cm2. ConclusionThe proposed fully-automated algorithm has potential of reducing uncertainties, variability, and workload inherent to manual approaches with promise for future clinical implementation for joint bright- and black-blood MRI.

Personalized Pressure Conditions and Calibration for a Predictive Computational Model of Coronary and Myocardial Blood Flow

Predictive modeling of hyperemic coronary and myocardial blood flow (MBF) greatly supports diagnosis and prognostic stratification of patients suffering from coronary artery disease (CAD). In this work, we propose a novel strategy, using only readily available clinical data, to build personalized inlet conditions for coronary and MBF models and to achieve an effective calibration for their predictive application to real clinical cases. Experimental data are used to build personalized pressure waveforms at the aortic root, representative of the hyperemic state and adapted to surrogate the systolic contraction, to be used in computational fluid-dynamics analyses. Model calibration to simulate hyperemic flow is performed in a “blinded” way, not requiring any additional exam. Coronary and myocardial flow simulations are performed in eight patients with different clinical conditions to predict FFR and MBF. Realistic pressure waveforms are recovered for all the patients. Consistent pressure distribution, blood velocities in the large arteries, and distribution of MBF in the healthy myocardium are obtained. FFR results show great accuracy with a per-vessel sensitivity and specificity of 100% according to clinical threshold values. Mean MBF shows good agreement with values from stress-CTP, with lower values in patients with diagnosed perfusion defects. The proposed methodology allows us to quantitatively predict FFR and MBF, by the exclusive use of standard measures easily obtainable in a clinical context. This represents a fundamental step to avoid catheter-based exams and stress tests in CAD diagnosis.

Kiosk 6R-FB-09 - Cine Balanced Steady-state FBee Precession Signal Intensity Variations in Healthy Myocardium

Kiosk 6R-FB-09 - Cine Balanced Steady-state FBee Precession Signal Intensity Variations in Healthy Myocardium

Kiosk 4R-TC-11 - Novel Image Navigator Based Isotropic 3D Late Gadolinium Enhancement Sequence Allows Differentiation of Healthy and Diseased Left Atrial Myocardium

Kiosk 4R-TC-11 - Novel Image Navigator Based Isotropic 3D Late Gadolinium Enhancement Sequence Allows Differentiation of Healthy and Diseased Left Atrial Myocardium