Using Diffusion Tensor Imaging to Depict Changes After Matured Pluripotent Stem Cell-Derived Cardiomyocytes Transplantation.

BACKGROUND: Novel treatment strategies are needed to improve the structure and function in the myocardium post infarction. In vitro-matured pluripotent stem cell-derived cardiomyocytes (PSC-CMs), have been shown to be a promising regenerative strategy. We hypothesized that mature PSC-CMs will have anisotropic structure and improved cell alignment when compared to immature PSC-CMs using magnetic resonance imaging (MRI) in a guinea pig model of cardiac injury. METHODS: Guinea pigs (n=16) were cryoinjured on day -10, followed by transplantation of either 108 polydimethylsiloxane-matured PSC-CMs (PDMS, n=6) or 108 immature tissue culture plastic-generated PSC-CMs (TCP, n=6) on day 0. Vehicle (sham-treated) subjects were injected with a pro-survival cocktail devoid of cells (n=4), while healthy controls (n=4) did not undergo cryoinjury or treatment. Animals were sacrificed on either day +14 or day +28 post transplantation. Animals were imaged ex vivo on a 7T Bruker MRI. A 3D Diffusion Tensor Imaging sequence was used to quantify structure via fractional anisotropy (FA), mean diffusivity (MD) and myocyte alignment measured by the standard deviation of the transverse angle (TA). RESULTS: MD and FA of mature PDMS grafts demonstrated anisotropy that were not significantly different than the healthy control hearts (MD=1.1 ± 0.12 ×10-3 mm2/s vs. 0.93 ± 0.01 ×10-3 mm2/s, p=0.4 and FA=0.22±0.05 vs. 0.26±0.001, p=0.5). Immature TCP grafts exhibited significantly higher MD than the healthy control (1.3 ± 0.08 ×10-3 mm2/s, p<0.05) and significantly lower FA than the control (0.12±0.02, p< 0.05) but were not different from mature PDMS grafts in this small cohort. TA of healthy controls showed low variability and were not significantly different than mature PDMS grafts (p=0.4) while immature TCP grafts were significantly different (p<0.001). DISCUSSION: DTI parameters of mature graft tissue trended towards that of the healthy myocardium, indicating the grafted cardiomyocytes may have a similar phenotype to healthy tissue. Contrast-enhanced MR images corresponded well to histological staining, demonstrating a non-invasive method of localizing the repopulated cardiomyocytes within the scar. CONCLUSIONS: The DTI measures within graft tissue were indicative of anisotropic structure, and showed greater myocyte organization compared to the scarred territory. These findings show that MRI is a valuable tool to assess structural impacts of regenerative therapies.

Evaluating a novel accelerated free-breathing late gadolinium enhancement imaging sequence for assessment of myocardial injury.

INTRODUCTION: Cardiac magnetic resonance imaging (MRI), including late gadolinium enhancement (LGE), plays an important role in the diagnosis and prognostication of ischemic and non-ischemic myocardial injury. Conventional LGE sequences require patients to perform multiple breath-holds and require long acquisition times. In this study, we compare image quality and assessment of myocardial LGE using an accelerated free-breathing sequence to the conventional standard-of-care sequence. METHODS: In this prospective cohort study, a total of 41 patients post Coronavirus 2019 (COVID-19) infection were included. Studies were performed on a 1.5 Tesla scanner with LGE imaging acquired using a conventional inversion recovery rapid gradient echo (conventional LGE) sequence followed by the novel accelerated free-breathing (FB-LGE) sequence. Image quality was visually scored (ordinal scale from 1 to 5) and compared between conventional and free-breathing sequences using the Wilcoxon rank sum test. Presence of per-segment LGE was identified according to the American Heart Association 16-segment myocardial model and compared across both conventional LGE and FB-LGE sequences using a two-sided chi-square test. The perpatient LGE extent was also evaluated using both sequences and compared using the Wilcoxon rank sum test. Interobserver variability in detection of per-segment LGE and per-patient LGE extent was evaluated using Cohen's kappa statistic and interclass correlation (ICC), respectively. RESULTS: The mean acquisition time for the FB-LGE sequence was 17 s compared to 413 s for the conventional LGE sequence (P < 0.001). Assessment of image quality was similar between both sequences (P = 0.19). There were no statistically significant differences in LGE assessed using the FB-LGE versus conventional LGE on a per-segment (P = 0.42) and per-patient (P = 0.06) basis. Interobserver variability in LGE assessment for FB-LGE was good for per-segment (= 0.71) and per-patient extent (ICC = 0.92) analyses. CONCLUSIONS: The accelerated FB-LGE sequence performed comparably to the conventional standard-of-care LGE sequence in a cohort of patients post COVID-19 infection in a fraction of the time and without the need for breath-holding. Such a sequence could impact clinical practice by increasing cardiac MRI throughput and accessibility for frail or acutely ill patients unable to perform breath-holding.

Impaired coronary microvascular reactivity in youth with bipolar disorder.

BACKGROUND: Cardiovascular disease (CVD) is excessively prevalent and premature in bipolar disorder (BD), even after controlling for traditional cardiovascular risk factors. The increased risk of CVD in BD may be subserved by microvascular dysfunction. We examined coronary microvascular function in relation to youth BD. METHODS: Participants were 86 youth, ages 13-20 years (n = 39 BD, n = 47 controls). Coronary microvascular reactivity (CMVR) was assessed using quantitative T2 magnetic resonance imaging during a validated breathing-paradigm. Quantitative T2 maps were acquired at baseline, following 60-s of hyperventilation, and every 10-s thereafter during a 40-s breath-hold. Left ventricular structure and function were evaluated based on 12-15 short- and long-axis cardiac-gated cine images. A linear mixed-effects model that controlled for age, sex, and body mass index assessed for between-group differences in CMVR (time-by-group interaction). RESULTS: The breathing-paradigm induced a significant time-related increase in T2 relaxation time for all participants (i.e. CMVR; ß = 0.36, p < 0.001). CMVR was significantly lower in BD v. controls (ß = -0.11, p = 0.002). Post-hoc analyses found lower T2 relaxation time in BD youth after 20-, 30-, and 40 s of breath-holding (d = 0.48, d = 0.72, d = 0.91, respectively; all pFDR < 0.01). Gross left ventricular structure and function (e.g. mass, ejection fraction) were within normal ranges and did not differ between groups. CONCLUSION: Youth with BD showed evidence of subclinically impaired coronary microvascular function, despite normal gross cardiac structure and function. These results converge with prior findings in adults with major depressive disorder and post-traumatic stress disorder. Future studies integrating larger samples, prospective follow-up, and blood-based biomarkers are warranted.

Advanced Techniques for Studying Blood Flow.

ARTICLES DISCUSSED: Tang, G. L., Kim, K. J. Laser Doppler perfusion imaging in the mouse hindlimb. Journal of Visualized Experiments. (170), e62012 (2021). Hage, B. D., Truemper, E. J., Bashford, G.R. Functional transcranial Doppler ultrasound for monitoring cerebral blood flow. Journal of Visualized Experiments. (169), e62048 (2021). Baranger, J., Mertens, L., Villemain, O. Blood flow imaging with ultrafast Doppler. Journal of Visualized Experiments. (164), e61838 (2020). Granja, T., de Andrade, S. F., Rodrigues, L. M. Multispectral optoacoustic tomography for functional imaging in vascular research. Journal of Visualized Experiments. (184), e63883 (2022). Goolaub, D. S., Marini, D., Seed, M., Macgowan, C. K. Human fetal blood flow quantification with magnetic resonance imaging and motion compensation. Journal of Visualized Experiments. (167), e61953 (2021).

Low Prevalence of Late Myocardial Injury on Cardiac MRI Following COVID-19 Infection.

BACKGROUND: The prevalence of abnormal cardiac magnetic resonance imaging (MRI) findings indicative of myocardial injury in patients who recovered from coronavirus disease 2019 (COVID-19) is currently unclear, with a high variability in the reported prevalence. PURPOSE: To assess the prevalence of myocardial injury after a COVID-19 infection. STUDY TYPE: Prospective, bicentric study. SUBJECTS: Seventy consecutive patients who recovered from COVID-19 and were previously hospitalized. Mean age was 57 years and 39% of the patients were female. Ten healthy controls and a comparator group of 75 nonischemic cardiomyopathy (NICM) patients were employed. FIELD STRENGTH/SEQUENCE: 1.5-T, steady-state free precession (SSFP) gradient-echo sequence, modified Look-Locker inversion recovery sequence with balanced SSFP readout, T2-prepared spiral readout sequence and a T1-weighted inversion recovery fast gradient-echo sequence was acquired ~4-5 months after recovery from COVID-19. ASSESSMENT: The SSFP sequence was utilized for the calculation of left and right ventricular volumes and ejection fractions (LVEF and RVEF) following manual endocardial contouring. T1 and T2 mapping was performed by pixel-wise exponential fitting, and T1 and T2 values were computed by manual contouring of the left ventricular endocardial and epicardial walls. Late gadolinium enhancement (LGE) images were graded qualitatively as LGE present or absent. STATISTICAL TESTS: T-tests and the χ2 or Fisher's exact tests were used to compare continuous and categorical variables respectively between the COVID-19 and NICM groups. Inter-rater agreement was evaluated by the intraclass correlation coefficient for continuous variables and Cohen's kappa test for LGE. RESULTS: Reduced RVEF occurred in 10%, LGE and elevated native T1 in 9%, reduced LVEF in 4%, and elevated T2 in 3% of COVID-19 patients, respectively. Patients with NICM had lower mean LVEF (41.6% ± 6% vs. 60% ± 7%), RVEF (46% ± 5% vs. 61% ± 9%), and a significantly higher prevalence of LGE (27% vs. 9%) when compared to those post-COVID-19. DATA CONCLUSION: Abnormal cardiac MRI findings may show a low prevalence in patients who recovered from COVID-19 and were previously hospitalized. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

A Deep Learning Segmentation Pipeline for Cardiac T1 Mapping Using MRI Relaxation-based Synthetic Contrast Augmentation.

Purpose: To design and evaluate an automated deep learning method for segmentation and analysis of cardiac MRI T1 maps with use of synthetic T1-weighted images for MRI relaxation-based contrast augmentation. Materials and Methods: This retrospective study included MRI scans acquired between 2016 and 2019 from 100 patients (mean age ± SD, 55 years ± 13; 72 men) across various clinical abnormalities with use of a modified Look-Locker inversion recovery, or MOLLI, sequence to quantify native T1 (T1native), postcontrast T1 (T1post), and extracellular volume (ECV). Data were divided into training (n = 60) and internal (n = 40) test subsets. "Synthetic" T1-weighted images were generated from the T1 exponential inversion-recovery signal model at a range of optimal inversion times, yielding high blood-myocardium contrast, and were used for contrast-based image augmentation during training and testing of a convolutional neural network for myocardial segmentation. Automated segmentation, T1, and ECV were compared with experts with use of Dice similarity coefficients (DSCs), correlation coefficients, and Bland-Altman analysis. An external test dataset (n = 147) was used to assess model generalization. Results: Internal testing showed high myocardial DSC relative to experts (0.81 ± 0.08), which was similar to interobserver DSC (0.81 ± 0.08). Automated segmental measurements strongly correlated with experts (T1native, R = 0.87; T1post, R = 0.91; ECV, R = 0.92), which were similar to interobserver correlation (T1native, R = 0.86; T1post, R = 0.94; ECV, R = 0.95). External testing showed strong DSC (0.80 ± 0.09) and T1native correlation (R = 0.88) between automatic and expert analysis. Conclusion: This deep learning method leveraging synthetic contrast augmentation may provide accurate automated T1 and ECV analysis for cardiac MRI data acquired across different abnormalities, centers, scanners, and T1 sequences.Keywords: MRI, Cardiac, Tissue Characterization, Segmentation, Convolutional Neural Network, Deep Learning Algorithms, Machine Learning Algorithms, Supervised Learning Supplemental material is available for this article. © RSNA, 2022.

Augmenting Performance: A Systematic Review of Optical See-Through Head-Mounted Displays in Surgery.

We conducted a systematic review of recent literature to understand the current challenges in the use of optical see-through head-mounted displays (OST-HMDs) for augmented reality (AR) assisted surgery. Using Google Scholar, 57 relevant articles from 1 January 2021 through 18 March 2022 were identified. Selected articles were then categorized based on a taxonomy that described the required components of an effective AR-based navigation system: data, processing, overlay, view, and validation. Our findings indicated a focus on orthopedic (n=20) and maxillofacial surgeries (n=8). For preoperative input data, computed tomography (CT) (n=34), and surface rendered models (n=39) were most commonly used to represent image information. Virtual content was commonly directly superimposed with the target site (n=47); this was achieved by surface tracking of fiducials (n=30), external tracking (n=16), or manual placement (n=11). Microsoft HoloLens devices (n=24 in 2021, n=7 in 2022) were the most frequently used OST-HMDs; gestures and/or voice (n=32) served as the preferred interaction paradigm. Though promising system accuracy in the order of 2-5 mm has been demonstrated in phantom models, several human factors and technical challenges-perception, ease of use, context, interaction, and occlusion-remain to be addressed prior to widespread adoption of OST-HMD led surgical navigation.

HMD-EgoPose: head-mounted display-based egocentric marker-less tool and hand pose estimation for augmented surgical guidance.

PURPOSE: The success or failure of modern computer-assisted surgery procedures hinges on the precise six-degree-of-freedom (6DoF) position and orientation (pose) estimation of tracked instruments and tissue. In this paper, we present HMD-EgoPose, a single-shot learning-based approach to hand and object pose estimation and demonstrate state-of-the-art performance on a benchmark dataset for monocular red-green-blue (RGB) 6DoF marker-less hand and surgical instrument pose tracking. Further, we reveal the capacity of our HMD-EgoPose framework for performant 6DoF pose estimation on a commercially available optical see-through head-mounted display (OST-HMD) through a low-latency streaming approach. METHODS: Our framework utilized an efficient convolutional neural network (CNN) backbone for multi-scale feature extraction and a set of subnetworks to jointly learn the 6DoF pose representation of the rigid surgical drill instrument and the grasping orientation of the hand of a user. To make our approach accessible to a commercially available OST-HMD, the Microsoft HoloLens 2, we created a pipeline for low-latency video and data communication with a high-performance computing workstation capable of optimized network inference. RESULTS: HMD-EgoPose outperformed current state-of-the-art approaches on a benchmark dataset for surgical tool pose estimation, achieving an average tool 3D vertex error of 11.0 mm on real data and furthering the progress towards a clinically viable marker-free tracking strategy. Through our low-latency streaming approach, we achieved a round trip latency of 199.1 ms for pose estimation and augmented visualization of the tracked model when integrated with the OST-HMD. CONCLUSION: Our single-shot learned approach, which optimized 6DoF pose based on the joint interaction between the hand of a user and a rigid surgical drill, was robust to occlusion and complex surfaces and improved on current state-of-the-art approaches to marker-less tool and hand pose estimation. Further, we presented the feasibility of our approach for 6DoF object tracking on a commercially available OST-HMD.

Head-Mounted Display-Based Augmented Reality for Image-Guided Media Delivery to the Heart: A Preliminary Investigation of Perceptual Accuracy.

By aligning virtual augmentations with real objects, optical see-through head-mounted display (OST-HMD)-based augmented reality (AR) can enhance user-task performance. Our goal was to compare the perceptual accuracy of several visualization paradigms involving an adjacent monitor, or the Microsoft HoloLens 2 OST-HMD, in a targeted task, as well as to assess the feasibility of displaying imaging-derived virtual models aligned with the injured porcine heart. With 10 participants, we performed a user study to quantify and compare the accuracy, speed, and subjective workload of each paradigm in the completion of a point-and-trace task that simulated surgical targeting. To demonstrate the clinical potential of our system, we assessed its use for the visualization of magnetic resonance imaging (MRI)-based anatomical models, aligned with the surgically exposed heart in a motion-arrested open-chest porcine model. Using the HoloLens 2 with alignment of the ground truth target and our display calibration method, users were able to achieve submillimeter accuracy (0.98 mm) and required 1.42 min for calibration in the point-and-trace task. In the porcine study, we observed good spatial agreement between the MRI-models and target surgical site. The use of an OST-HMD led to improved perceptual accuracy and task-completion times in a simulated targeting task.

Effects of B1+ Heterogeneity on Spin Echo-Based Liver Iron Estimates.

BACKGROUND: Liver iron concentration (LIC) measured by MRI has become the clinical reference standard for managing iron overload in chronically transfused patients. Transverse relaxivity (R2 or R2* ) measurements are converted to LIC units using empirically derived calibration curves. HYPOTHESIS: That flip angle (FA) error due to B1+ spatial heterogeneity causes significant LIC quantitation error. B1+ scale (b1 , [FAactual /FAspecified ]) variation is a major problem at 3 T which could reduce the accuracy of transverse relaxivity measurements. STUDY TYPE: Prospective. POPULATION: Forty-seven subjects with chronic transfusional iron overload undergoing clinically indicated LIC assessment. FIELD STRENGTH/SEQUENCE: 5 T/3 T dual-repetition time B1+ mapping sequence ASSESSMENT: We quantified the average/standard deviation b1 in the right and left lobes of the liver from B1+ maps acquired at 1.5 T and 3 T. The impact of b1 variation on spin echo LIC estimates was determined using a Monte Carlo model. STATISTICAL TESTS: Mean, median, and standard deviation in whole liver and right and left lobes; two-sided t-test between whole-liver b1 means. RESULTS: Average b1 within the liver was 99.3% ± 12.3% at 1.5 T versus 69.6% ± 14.6% at 3 T and was independent of iron burden (P < 0.05). Monte Carlo simulations demonstrated that b1 systematically increased R2 estimates at lower LIC (<~25 mg/g at 1.5 T, <~15 mg/g at 3 T) but flattened or even inverted the R2 -LIC relationship at higher LIC (≥~25 mg/g to 1.5 T, ≥~15 mg/g to 3 T); changes in the R2 -LIC relationship were symmetric with respect to over and under excitation and were similar at 1.5 T and 3 T (for the same R2 value). The R2* -LIC relationship was independent of b1 . CONCLUSION: Spin echo R2 measurement of LIC at 3 T is error-prone without correction for b1 errors. The impact of b1 error on current 1.5 T spin echo-based techniques for LIC quantification is large enough to introduce measurable intersubject variability but the in vivo effect size needs a dedicated validation study. TECHNICAL EFFICACY STAGE: 2.

Myocardial blood flow is the dominant factor influencing cardiac magnetic resonance adenosine stress T2.

Stress imaging identifies ischemic myocardium by comparing hemodynamics during rest and hyperemic stress. Hyperemia affects multiple hemodynamic parameters in myocardium, including myocardial blood flow (MBF), myocardial blood volume (MBV), and venous blood oxygen levels (PvO2 ). Cardiac T2 is sensitive to these changes and therefore is a promising non-contrast option for stress imaging; however, the impact of individual hemodynamic factors on T2 is poorly understood, making the connection from altered T2 to changes within the tissue difficult. To better understand this interplay, we performed T2 mapping and measured various hemodynamic factors independently in healthy pigs at multiple levels of hyperemic stress, induced by different doses of adenosine (0.14-0.56 mg/kg/min). T1 mapping quantified changes in MBV. MBF was assessed with microspheres, and oxygen consumption was determined by the rate pressure product (RPP). Simulations were also run to better characterize individual contributions to T2. Myocardial T2, MBF, oxygen consumption, and MBV all changed to varying extents between each level of adenosine stress (T2 = 37.6-41.8 ms; MBF = 0.48-1.32 mL/min/g; RPP = 6507-4001 bmp*mmHg; maximum percent change in MBV = 1.31%). Multivariable analyses revealed MBF as the dominant influence on T2 during hyperemia (significant ß-values >7). Myocardial oxygen consumption had almost no effect on T2 (ß-values <0.002); since PvO2 is influenced by both oxygen consumption and MBF, PvO2 changes detected by T2 during adenosine stress can be attributed to MBF. Simulations varying PvO2 and MBV confirmed that PvO2 had the strongest influence on T2, but MBV became important at high PvO2 . Together, these data suggest a model where, during adenosine stress, myocardial T2 responds predominantly to changes in MBF, but at high hyperemia MBV is also influential. Thus, changes in adenosine stress T2 can now be interpreted in terms of the physiological changes that led to it, enabling T2 mapping to become a viable non-contrast option to detect ischemic myocardial tissue.

Suspected subclinical myocarditis detected by cardiac magnetic resonance imaging late post COVID-19 recovery.

There is growing evidence of the potential for cardiac involvement in patients who have been infected with COVID-19. In this case study, we present a patient with no history of cardiovascular disease, who was hospitalized for COVID-19 pneumonia and subsequently recovered. Despite normal serum troponin levels and left ventricular structure and function, multi-parametric cardiac magnetic resonance imaging revealed a classic myocarditis-like pattern of injury approximately 6 months after his convalescence. Physicians should be aware of the possibility of late myocardial injury/inflammation in patients with recovered COVID-19, even in the absence of elevated troponin levels and/or left ventricular dysfunction. .

T2-based area-at-risk and edema are influenced by ischemic duration in acute myocardial infarction.

The purpose of our study was to assess whether T2 MRI identifies the infarcted myocardium or the true area-at-risk (AAR) and whether edema is present in the salvageable region following acute myocardial infarction (MI). The study involved a porcine model of MI with a coronary occlusion model of either 60 min or 90 min. Imaging was performed on a 3T MRI pre-occlusion and at day 3 post-MI. Prior-MI, myocardial perfusion territory (MPT) maps were obtained under MRI via direct intracoronary injection of contrast agent. Post-MI, edema extent was quantified by T2 mapping while infarction and microvascular obstruction (MVO) were assessed by late gadolinium enhancement (LGE). Anatomically registered short-axis slices were analyzed for MPT, T2-AAR and infarct areas and T2 relaxation values. Animals were divided into groups with (MVO+) and without MVO (MVO-). T2-AAR area was significantly greater than infarct area in both groups. In the MVO+ group, T2-AAR and MPT were comparable and highly correlated, whereas, in the MVO- group, T2-AAR significantly underestimated MPT without any trend. T2 values in the salvageable myocardium were found to be significantly higher than those in remote myocardium. Our methodology offers the advantage that all images are acquired within the same MRI reference as opposed to complex co-registration with gross pathology. Our study suggests that edema may expand beyond the infarct zone over the entire ischemic bed. T2-AAR may be more clinically relevant than true AAR by perfusion territory since it identifies the "salvageable" myocardium.

Technical Note: Fully automatic segmental relaxometry (FASTR) for cardiac magnetic resonance T1 mapping.

PURPOSE: Cardiac relaxometry techniques, particularly T1 mapping, have recently gained clinical importance in various cardiac pathologies. Myocardial T1 and extracellular volume are usually calculated from manual identification of left ventricular epicardial and endocardial regions. This is a laborious process, particularly for large volume studies. Here we present a fully automated relaxometry framework (FASTR) for segmental analysis of T1 maps (both native and postcontrast) and partition coefficient (λ). METHODS: Patients (N = 11) were imaged postacute myocardial infarction on a 1.5T clinical scanner. The scan protocol involved CINE-SSFP imaging, native, and post-contrast T1 mapping using the Modified Look-Locker Inversion (MOLLI) recovery sequence. FASTR consisted of automatic myocardial segmentation of spatio-temporally coregistered CINE images as an initial guess, followed by refinement of the contours on the T1 maps to derive segmental T1 and λ. T1 and λ were then compared to those obtained from two trained expert observers. RESULTS: Robust endocardial and epicardial contours were achieved on T1 maps despite the presence of infarcted tissue. Relative to experts, FASTR resulted in myocardial Dice coefficients (native T1: 0.752 ± 0.041; postcontrast T1: 0.751 ± 0.057) that were comparable to interobserver Dice (native T1: 0.803 ± 0.045; postcontrast T1: 0.799 ± 0.054). There were strong correlations observed for T1 and λ derived from experts and FASTR (native T1: r = 0.83; postcontrast T1: r = 0.87; λ: r = 0.78; P < 0.0001), which were comparable to inter-expert correlation coefficients (native T1: r = 0.90; postcontrast T1: r = 0.93; λ: r = 0.80; P < 0.0001). CONCLUSIONS: Our fully automated framework, FASTR, can generate accurate myocardial segmentations for native and postcontrast MOLLI T1 analysis without the need for manual intervention. Such a design is appealing for high volume clinical protocols.

Hemorrhage promotes chronic adverse remodeling in acute myocardial infarction: a T1 , T2 and BOLD study.

Hemorrhage is recognized as a new independent predictor of adverse outcomes following acute myocardial infarction. However, the mechanisms of its effects are less understood. The aim of our study was to probe the downstream impact of hemorrhage towards chronic remodeling, including inflammation, vasodilator function and matrix alterations in an experimental model of hemorrhage. Myocardial hemorrhage was induced in the porcine heart by intracoronary injection of collagenase. Animals (N = 18) were subjected to coronary occlusion followed by reperfusion in three groups (six/group): 8 min ischemia with hemorrhage (+HEM), 45 min infarction with no hemorrhage (I - HEM) and 45 min infarction with hemorrhage (I + HEM). MRI was performed up to 4 weeks after intervention. Cardiac function, edema (T2 , T1 ), hemorrhage (T2 *), vasodilator function (T2 BOLD), infarction and microvascular obstruction (MVO) and partition coefficient (pre- and post-contrast T1 ) were computed. Hemorrhage was induced only in the +HEM and I + HEM groups on Day 1 (low T2 * values). Infarct size was the greatest in the I + HEM group, while the +HEM group showed no observable infarct. MVO was seen only in the I + HEM group, with a 40% occurrence rate. Function was compromised and ventricular volume was enlarged only in the hemorrhage groups and not in the ischemia-alone group. In the infarct zone, edema and matrix expansion were the greatest in the I + HEM group. In the remote myocardium, T2 elevation and matrix expansion associated with a transient vasodilator dysfunction were observed in the hemorrhage groups but not in the ischemia-alone group. Our study demonstrates that the introduction of myocardial hemorrhage at reperfusion results in greater myocardial damage, upregulated inflammation, chronic adverse remodeling and remote myocardial alterations beyond the effects of the initial ischemic insult. A systematic understanding of the consequences of hemorrhage will potentially aid in the identification of novel therapeutics for high-risk patients progressing towards heart failure.

Action of iron chelator on intramyocardial hemorrhage and cardiac remodeling following acute myocardial infarction.

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia-reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI.

Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate the Infarcted Pig Heart but Induce Ventricular Tachyarrhythmias.

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.

Non-contrast assessment of microvascular integrity using arterial spin labeled cardiovascular magnetic resonance in a porcine model of acute myocardial infarction.

BACKGROUND: Following acute myocardial infarction (AMI), microvascular integrity and function may be compromised as a result of microvascular obstruction (MVO) and vasodilator dysfunction. It has been observed that both infarcted and remote myocardial territories may exhibit impaired myocardial blood flow (MBF) patterns associated with an abnormal vasodilator response. Arterial spin labeled (ASL) CMR is a novel non-contrast technique that can quantitatively measure MBF. This study investigates the feasibility of ASL-CMR to assess MVO and vasodilator response in swine. METHODS: Thirty-one swine were included in this study. Resting ASL-CMR was performed on 24 healthy swine (baseline group). A subset of 13 swine from the baseline group underwent stress ASL-CMR to assess vasodilator response. Fifteen swine were subjected to a 90-min left anterior descending (LAD) coronary artery occlusion followed by reperfusion. Resting ASL-CMR was performed post-AMI at 1-2 days (N = 9, of which 6 were from the baseline group), 1-2 weeks (N = 8, of which 4 were from the day 1-2 group), and 4 weeks (N = 4, of which 2 were from the week 1-2 group). Resting first-pass CMR and late gadolinium enhancement (LGE) were performed post-AMI for reference. RESULTS: At rest, regional MBF and physiological noise measured from ASL-CMR were 1.08 ± 0.62 and 0.15 ± 0.10 ml/g/min, respectively. Regional MBF increased to 1.47 ± 0.62 ml/g/min with dipyridamole vasodilation (P < 0.001). Significant reduction in MBF was found in the infarcted region 1-2 days, 1-2 weeks, and 4 weeks post-AMI compared to baseline (P < 0.03). This was consistent with perfusion deficit seen on first-pass CMR and with MVO seen on LGE. There were no significant differences between measured MBF in the remote regions pre and post-AMI (P > 0.60). CONCLUSIONS: ASL-CMR can assess vasodilator response in healthy swine and detect significant reduction in regional MBF at rest following AMI. ASL-CMR is an alternative to gadolinium-based techniques for assessment of MVO and microvascular integrity within infarcted, as well as salvageable and remote myocardium. This has the potential to provide early indications of adverse remodeling processes post-ischemia.