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.

A Computational Pipeline for Patient-Specific Prediction of the Postoperative Mitral Valve Functional State.

While mitral valve (MV) repair remains the preferred clinical option for mitral regurgitation (MR) treatment, long-term outcomes remain suboptimal and difficult to predict. Furthermore, pre-operative optimization is complicated by the heterogeneity of MR presentations and the multiplicity of potential repair configurations. In the present work, we established a patient-specific MV computational pipeline based strictly on standard-of-care pre-operative imaging data to quantitatively predict the post-repair MV functional state. First, we established human mitral valve chordae tendinae (MVCT) geometric characteristics obtained from five CT-imaged excised human hearts. From these data, we developed a finite-element model of the full patient-specific MV apparatus that included MVCT papillary muscle origins obtained from both the in vitro study and the pre-operative three-dimensional echocardiography images. To functionally tune the patient-specific MV mechanical behavior, we simulated pre-operative MV closure and iteratively updated the leaflet and MVCT prestrains to minimize the mismatch between the simulated and target end-systolic geometries. Using the resultant fully calibrated MV model, we simulated undersized ring annuloplasty (URA) by defining the annular geometry directly from the ring geometry. In three human cases, the postoperative geometries were predicted to 1 mm of the target, and the MV leaflet strain fields demonstrated close agreement with noninvasive strain estimation technique targets. Interestingly, our model predicted increased posterior leaflet tethering after URA in two recurrent patients, which is the likely driver of long-term MV repair failure. In summary, the present pipeline was able to predict postoperative outcomes from pre-operative clinical data alone. This approach can thus lay the foundation for optimal tailored surgical planning for more durable repair, as well as development of mitral valve digital twins.

Magnetic susceptibility and R2* of myocardial reperfusion injury at 3T and 7T.

PURPOSE: Magnetic susceptibility (Δχ) alterations have shown association with myocardial infarction (MI) iron deposition, yet there remains limited understanding of the relationship between relaxation rates and susceptibility or the effect of magnetic field strength. Hence, Δχ and R2∗ in MI were compared at 3T and 7T. METHODS: Subacute MI was induced by coronary artery ligation in male Yorkshire swine. 3D multiecho gradient echo imaging was performed at 1-week postinfarction at 3T and 7T. Quantitative susceptibility mapping images were reconstructed using a morphology-enabled dipole inversion. R2∗ maps and quantitative susceptibility mapping were generated to assess the relationship between R2∗ , Δχ, and field strength. Infarct histopathology was investigated. RESULTS: Magnetic susceptibility was not significantly different across field strengths (7T: 126.8 ± 41.7 ppb; 3T: 110.2 ± 21.0 ppb, P = NS), unlike R2∗ (7T: 247.0 ± 14.8 Hz; 3T: 106.1 ± 6.5 Hz, P < .001). Additionally, infarct Δχ and R2∗ were significantly higher than remote myocardium. Magnetic susceptibility at 7T versus 3T had a significant association (ß = 1.02, R2 = 0.82, P < .001), as did R2∗ (ß = 2.35, R2 = 0.98, P < .001). Infarct pathophysiology and iron deposition were detected through histology and compared with imaging findings. CONCLUSION: R2∗ showed dependence and Δχ showed independence of field strength. Histology validated the presence of iron and supported imaging findings.

Altered Responsiveness to TGFß and BMP and Increased CD45+ Cell Presence in Mitral Valves Are Unique Features of Ischemic Mitral Regurgitation.

[Figure: see text].

A Contemporary Look at Biomechanical Models of Myocardium.

Understanding and predicting the mechanical behavior of myocardium under healthy and pathophysiological conditions are vital to developing novel cardiac therapies and promoting personalized interventions. Within the past 30 years, various constitutive models have been proposed for the passive mechanical behavior of myocardium. These models cover a broad range of mathematical forms, microstructural observations, and specific test conditions to which they are fitted. We present a critical review of these models, covering both phenomenological and structural approaches, and their relations to the underlying structure and function of myocardium. We further explore the experimental and numerical techniques used to identify the model parameters. Next, we provide a brief overview of continuum-level electromechanical models of myocardium, with a focus on the methods used to integrate the active and passive components of myocardial behavior. We conclude by pointing to future directions in the areas of optimal form as well as new approaches for constitutive modeling of myocardium.

Myocardial tissue salvage is correlated with ischemic border region temperature at reperfusion.

OBJECTIVES: Our pilot study investigated the association between region-specific myocardial tissue temperature and tissue salvage using a novel tri-lumen cooling catheter to provide rapid localized cooling directly to the heart in an open-chest porcine model of ischemia-reperfusion. BACKGROUND: Therapeutic hypothermia remains a promising strategy to limit reperfusion injury following myocardial ischemia. METHODS: Large swine underwent 60 min of coronary occlusion followed by 3 hr of reperfusion. Prior to inducing ischemia, six temperature probes were placed directly on the heart, monitoring myocardial temperatures in different locations. Hemodynamic parameters and core temperature were also collected. Approximately 15 min prior to reperfusion, the cooling catheter was inserted via femoral artery and the distal tip advanced proximal to the occluded coronary vessel under fluoroscopic guidance. Autologous blood was pulled from the animal via femoral sheath and delivered through the central lumen of the cooling catheter, delivering at 50 ml/min, 27°C at the distal tip. Cooling was continued for an additional 25 min after reperfusion followed by a 5-min controlled rewarming. Hearts were excised and assessed for infarct size per area at risk. RESULTS: Although cooling catheter performance was consistent throughout the study (38 W), the resulting tissue cooling was not. Our results show a correlation between myocardial tissue salvage and ischemic border region (IBR) temperature at the time of reperfusion (R2 = 0.59, p = 0.027). IBR tissue is the tissue located at the boundary between healthy and ischemic tissues. CONCLUSIONS: Our findings suggest that localized, rapid, short-term myocardial tissue cooling has the potential to limit reperfusion injury in humans.

Quantitative three-dimensional echocardiographic analysis of the bicuspid aortic valve and aortic root: A single modality approach.

BACKGROUND: Patients with bicuspid aortic valves (BAV) are heterogeneous with regard to patterns of root remodeling and valvular dysfunction. Two-dimensional echocardiography is the standard surveillance modality for patients with aortic valve dysfunction. However, ancillary computed tomography or magnetic resonance imaging is often necessary to characterize associated patterns of aortic root pathology. Conversely, the pairing of three-dimensional (3D) echocardiography with novel quantitative modeling techniques allows for a single modality description of the entire root complex. We sought to determine 3D aortic valve and root geometry with this quantitative approach. METHODS: Transesophageal real-time 3D echocardiography was performed in five patients with tricuspid aortic valves (TAV) and in five patients with BAV. No patient had evidence of valvular dysfunction or aortic root pathology. A customized image analysis protocol was used to assess 3D aortic annular, valvular, and root geometry. RESULTS: Annular, sinus and sinotubular junction diameters and areas were similar in both groups. Coaptation length and area were higher in the TAV group (7.25 ± 0.98 mm and 298 ± 118 mm2 , respectively) compared to the BAV group (5.67 ± 1.33 mm and 177 ± 43 mm2 ; P = .07 and P = .01). Cusp surface area to annular area, coaptation height, and the sub- and supravalvular tenting indices did not differ significantly between groups. CONCLUSIONS: Single modality 3D echocardiography-based modeling allows for a quantitative description of the aortic valve and root geometry. This technique together with novel indices will improve our understanding of normal and pathologic geometry in the BAV population and may help to identify geometric predictors of adverse remodeling and guide tailored surgical therapy.

Evoked Compound Action Potentials Reveal Spinal Cord Dorsal Column Neuroanatomy.

INTRODUCTION: The electrically evoked compound action potential (ECAP) is a measure of the response from a population of fibers to an electrical stimulus. ECAPs can be assessed during spinal cord stimulation (SCS) to elucidate the relationship between stimulation, electrophysiological response, and neuromodulation. This has consequences for the design and programming of SCS devices. METHODS: Sheep were implanted with linear epidural SCS leads. After a stimulating pulse, electrodes recorded ECAPs sequentially as they propagated orthodromically or antidromically. After filtering, amplification, and signal processing, ECAP amplitude and dispersion (width) was measured, and conduction velocity was calculated. Similar clinical data was also collected. A single-neuron computer model that simulated large-diameter sensory axons was used to explore and explain the observations. RESULTS: ECAPs, both animal and human, have a triphasic structure, with P1, N1, and P2 peaks. Conduction velocity in sheep was 109 ms-1 , which indicates that the underlying neural population includes fibers of up to 20 µm in diameter. For travel in both directions, propagation distance was associated with decrease in amplitude and increase in dispersion. Importantly, characteristics of these changes shifted abruptly at various positions along the cord. DISCUSSION: ECAP dispersion increases with propagation distance due to the contribution of slow-conducting small-diameter fibers as the signal propagates away from the source. An analysis of the discontinuities in ECAP dispersion changes with propagation revealed that these are due to the termination of smaller-diameter, slower-conducting fibers at corresponding segmental levels. The implications regarding SCS lead placement, toward the goal of maximizing clinical benefit while minimizing side-effects, are discussed. CONFLICT OF INTEREST: John Parker is the founder and CEO of Saluda Medical and holds stock options. Milan Obradovic, Nastaran Hesam Shariati, Dean M. Karantonis, Peter Single, James Laird-Wah, Robert Gorman and Mark Bickerstaff are employees of Saluda Medical with stock options. At the time the data was collected for the study, Prof. Cousins was a paid consultant for Saluda Medical. John Parker, Milan Obradovic, Dean Karantonis, James Laird-Wah, Robert Gorman and Peter Single are co-inventors in one or more patents related to the topics discussed in this work.

Toward predictive modeling of catheter-based pulmonary valve replacement into native right ventricular outflow tracts.

BACKGROUND: Pulmonary insufficiency is a consequence of transannular patch repair in Tetralogy of Fallot (ToF) leading to late morbidity and mortality. Transcatheter native outflow tract pulmonary valve replacement has become a reality. However, predicting a secure, atraumatic implantation of a catheter-based device remains a significant challenge due to the complex and dynamic nature of the right ventricular outflow tract (RVOT). We sought to quantify the differences in compression and volume for actual implants, and those predicted by pre-implant modeling. METHODS: We used custom software to interactively place virtual transcatheter pulmonary valves (TPVs) into RVOT models created from pre-implant and post Harmony valve implant CT scans of 5 ovine surgical models of TOF to quantify and visualize device volume and compression. RESULTS: Virtual device placement visually mimicked actual device placement and allowed for quantification of device volume and radius. On average, simulated proximal and distal device volumes and compression did not vary statistically throughout the cardiac cycle (P = 0.11) but assessment was limited by small sample size. In comparison to actual implants, there was no significant pairwise difference in the proximal third of the device (P > 0.80), but the simulated distal device volume was significantly underestimated relative to actual device implant volume (P = 0.06). CONCLUSIONS: This study demonstrates that pre-implant modeling which assumes a rigid vessel wall may not accurately predict the degree of distal RVOT expansion following actual device placement. We suggest the potential for virtual modeling of TPVR to be a useful adjunct to procedural planning, but further development is needed.

On the simulation of mitral valve function in health, disease, and treatment.

The mitral valve (MV) is the heart valve that regulates blood ?ow between the left atrium and left ventricle (LV). In situations where the MV fails to fully cover the left atrioventricular ori?ce during systole, the resulting regurgitation causes pulmonary congestion, leading to heart failure and/or stroke. The causes of MV insuf?ciency can be either primary (e.g. myxomatous degeneration) where the valvular tissue is organically diseased, or secondary (typically inducded by ischemic cardiomyopathy) termed ischemic mitral regurgitation (IMR), is brought on by adverse LV remodeling. IMR is present in up to 40% of patients and more than doubles the probability of cardiovascular morbidity after 3.5 years. There is now agreement that adjunctive procedures are required to treat IMR caused by lea?et tethering. However, there is no consensus regarding the best procedure. Multicenter registries and randomized trials would be necessary to prove which procedure is superior. Given the number of proposed procedures and the complexity and duration of such studies, it is highly unlikely that IMR procedure optimization will be achieved by prospective clinical trials. There is thus an urgent need for cell and tissue physiologically based quantitative assessments of MV function to better design surgical solutions and associated therapies. Novel computational approaches directed towards optimized surgical repair procedures can substantially reduce the need for such trial-and-error approaches. We present the details of our MV modeling techniques, with an emphasis on what is known and investigated at various length scales.