Infarction Registry Research Articles

DNAzyme loaded nano-niosomes attenuate myocardial ischemia/reperfusion injury by targeting apoptosis, inflammation in a NF-κB dependent mechanism.

Although DNAzymes have been found to reduce injury after myocardial ischemia/reperfusion (MI/R), their efficiency have been limited due to rapid degradation in vivo. Thus, this study was conducted to extend their half-life by encapsulation into nano‑niosomes and examine their cardioprotective effects in a rat model of myocardial infarction (MI). In order to synthesize nano‑niosomes, surface active agent film hydration method was used. Characterization of nano‑niosomes was performed using the atomic force microscopy (AFM). In order to establish MI/R model in rats, left anterior descending coronary artery (LAD) was ligated for 30min. A single dose (150µL) of drug formulations was injected into the infarcted region. The cardiac function was evaluated using echocardiography. The expression of pro-inflammatory cytokines, apoptotic factors, and nuclear factor-κB (NF-κB) were evaluated using Western blot and immunohistochemistry, respectively. Particle size of only nano-niosomes was in the range of 60-90nm, while a shift to 70-110nm was seen after DNAzyme encapsulation. MI rats treated with DNAzyme‑loaded nano‑niosomes could markedly reduce Bax, caspase3, TNF-α, IL-1β, and NF-κB as well as increase Bcl-2 compared to only MI/R group. Collectively, our finding show that nano‑niosomes can be considered excellent drug delivery platforms to extend half-life and stability of DNAzyme, when it is used to reduce myocardial I/R injury.

Intravenously Administered Human Umbilical Cord-Derived Mesenchymal Stem Cell (HucMSC) Improves Cardiac Performance following Infarction via Immune Modulation.

Overactive inflammatory responses contribute to progressive cardiac dysfunction after myocardial infarction (MI). Mesenchymal stem cell (MSC) has generated significant interest as potent immune modulators that can regulate excessive immune responses. We hypothesized that intravenous (iv) administration of human umbilical cord-derived MSC (HucMSC) exerts systemic and local anti-inflammation effects, leading to improved heart function after MI. In murine MI models, we confirmed that single iv administration of HucMSC (30 × 104) improved cardiac performance and prevented adverse remodeling after MI. A small proportion of HucMSC is trafficked to the heart, preferentially in the infarcted region. HucMSC administration increased CD3+ T cell proportion in the periphery while decreased T cell proportion in both infarcted heart and mediastinal lymph nodes (med-LN) at 7-day post-MI, indicating a systematic and local T cell interchange mediated by HucMSC. The inhibitory effects of HucMSC on T cell infiltration in the infarcted heart and med-LN sustained to 21-day post-MI. Our findings suggested that iv administration of HucMSC fostered systemic and local immunomodulatory effects that contributed to the improvement of cardiac performance after MI.

Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway

BackgroundExtracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV.MethodsMSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo.ResultsMSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01–0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05–0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05–0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy.ConclusionsWe uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Conductive Hydrogel Patches with High Elasticity and Fatigue Resistance for Cardiac Microenvironment Remodeling.

Remodeling the conductive zone to assist normal myocardial contraction and relaxation during myocardial fibrosis has become the primary concern of myocardial infarction (MI) regeneration. Herein, we report an unbreakable and self-recoverable hyaluronic acid conductive cardiac patch for MI treatment, which can maintain structural integrity under mechanical load and integrate mechanical and electrical conduction and biological cues to restore cardiac electrical conduction and diastolic contraction function. Using the free carboxyl groups and aldehyde groups in the hydrogel system, excellent adhesion properties are achieved in the interface between the myocardial patch and the tissue, which can be closely integrated with the rabbit myocardial tissue, reducing the need for suture. Interestingly, the hydrogel patch exhibits sensitive conductivity (ΔR/R0 ≈ 2.5) for 100 cycles and mechanical stability for 500 continuous loading cycles without collapse, which allows the patch to withstand mechanical damage caused by sustained contraction and relaxation of the myocardial tissue. Moreover, considering the oxidative stress state caused by excessive ROS in the MI area, we incorporated Rg1 into the hydrogel to improve the abnormal myocardial microenvironment, which achieved more than 80% free radicalscavenging efficiency in the local infarcted region and promoted myocardial reconstruction. Overall, these Rg1-loaded conductive hydrogels with highly elastic fatigue resistance have great potential in restoring the abnormal electrical conduction pathway and promoting the myocardial microenvironment, thereby repairing the heart and improving the cardiac function.

Effect of biomaterial stiffness on cardiac mechanics in a biventricular infarcted rat heart model with microstructural representation of in situ intramyocardial injectate.

Intramyocardial delivery of biomaterials is a promising concept for treating myocardial infarction. The delivered biomaterial provides mechanical support and attenuates wall thinning and elevated wall stress in the infarct region. This study aimed at developing a biventricular finite element model of an infarcted rat heart with a microstructural representation of an in situ biomaterial injectate, and a parametric investigation of the effect of the injectate stiffness on the cardiac mechanics. A three-dimensional subject-specific biventricular finite element model of a rat heart with left ventricular infarct and microstructurally dispersed biomaterial delivered 1 week after infarct induction was developed from ex vivo microcomputed tomography data. The volumetric mesh density varied between 303 mm-3 in the myocardium and 3852 mm-3 in the injectate region due to the microstructural intramyocardial dispersion. Parametric simulations were conducted with the injectate's elastic modulus varying from 4.1 to 405,900 kPa, and myocardial and injectate strains were recorded. With increasing injectate stiffness, the end-diastolic median myocardial fibre and cross-fibre strain decreased in magnitude from 3.6% to 1.1% and from -6.0% to -2.9%, respectively. At end-systole, the myocardial fibre and cross-fibre strain decreased in magnitude from -20.4% to -11.8% and from 6.5% to 4.6%, respectively. In the injectate, the maximum and minimum principal strains decreased in magnitude from 5.4% to 0.001% and from -5.4% to -0.001%, respectively, at end-diastole and from 38.5% to 0.06% and from -39.0% to -0.06%, respectively, at end-systole. With the microstructural injectate geometry, the developed subject-specific cardiac finite element model offers potential for extension to cellular injectates and in silico studies of mechanotransduction and therapeutic signalling in the infarcted heart with an infarct animal model extensively used in preclinical research.

Recent Advances in the Pathophysiological Role of Neutrophils and Macrophages following Acute Myocardial Infarction

Acute Myocardial Infarction (AMI) is one of the leading causes of death in the world, and immune cells such as neutrophils and macrophages are implicated in its pathophysiology. Despite decades of research, there is much debate on the roles of these immune cells, however, new concepts are emerging. This review summaries the recent advances in our understanding of the involvement of neutrophils and macrophages in post-AMI cardiac healing. Recently, neutrophils and monocytes were found to begin their phenotypical transformation in the bone marrow following an AMI, before migration to the infarct region. Novel cytokines and feedback loops have been identified in coordinating the process of immune cell recruitment to the heart post-AMI including subsets of pro- and anti-inflammatory neutrophils and new pathways of WNT signalling that alter macrophage phenotypes to a pro-inflammatory phenotype. There is also an interplay between these cells during regulation of immune cell migration as neutrophils are involved in polarising macrophages toward a reparative archetype that promotes clearance of apoptotic cells and cellular debris. Resident macrophages in the pericardial cavity also showed a cardioprotective role which may have important implications in cardiac surgeries that involve removal of the pericardium.

A Matrix-Metalloproteinase-Responsive Hydrogel System for Modulating the Immune Microenvironment in Myocardial Infarction.

Injectable hydrogels carrying therapeutic factors to modulate the infarct immune microenvironment show great potential in the treatment of myocardial infarction (MI). However, conventional injectable hydrogels release therapeutic factors in an uncontrolled manner, which leads to poor treatment efficacy and acute side effects on normal tissues. Inthiswork, a matrix metalloproteinase (MMP)2/9-responsive hydrogel system (MPGC4) is developed, considering the characteristics of the post-MI microenvironment. MPGC4 consists of tetra-poly(ethylene glycol) (PEG) hydrogels and a composite gene nanocarrier (CTL4) that is composed of carbon dots (CDots) coupled with interleukin-4 plasmid DNA via electrostatic interactions. MPGC4 can be automatically triggered to release CTL4 on demand after MI to regulate the infarct immune microenvironment. In addition, due to the photoluminescence properties of CDots, a large amount of viscoelastic MPGC4 is found to be retained in situ after injection into the infarct region without leakage. The in vitro results demonstrate that CTL4 promotes proinflammatory M1 macrophage polarization to the anti-inflammatory M2 subtype and contributes to cardiomyocyte survival through macrophage transition. In a rat model of MI, MPGC4 clears MMPs and precisely targets CTL4 to the infarcted region. In particular, MPGC4 improves cardiac function by modulating macrophage transition to reduce early inflammatory responses and proangiogenic activity.

Therapeutic Hypothermia Inhibits Hypoxia‐Induced Cardiomyocyte Apoptosis Via the MiR‐483‐3p/Cdk9 Axis

Background Therapeutic hypothermia has a beneficial effect on cardiac function after acute myocardial infarction, but the exact mechanism is still unclear. Recent research has suggested that microRNAs participate in acute myocardial infarction to regulate cardiomyocyte survival. This study aimed to explore the ability of hypothermia-regulated microRNA-483-3p (miR-483-3p) to inhibit hypoxia-induced myocardial infarction. Methods and Results Primary cardiomyocytes were cultured under hypoxia at 32 °C to mimic therapeutic hypothermia, and the differentially expressed microRNAs were determined by RNA sequencing. Therapeutic hypothermia recovered hypoxia-induced increases in apoptosis, decreases in ATP levels, and decreases in miR-483-3p expression. Overexpression of miR-483-3p exhibited effects similar to those of therapeutic hypothermia on hypoxia in the treatment of cardiomyocytes to associate with maintaining the mitochondrial membrane potential, and cyclin-dependent kinase 9 (Cdk9) was identified as a target gene with downregulated expression by miR-483-3p. Knockdown of Cdk9 also promoted cardiac survival, ATP production, and mitochondrial membrane potential stability under hypoxia. In vivo, the expression of miR-483-3p and Cdk9 was tested in the cardiac tissue of the mice with acute myocardial infarction, and the expression of miR-483-3p decreased and Cdk9 increased in the region of myocardial infarction. However, miR-483-3p was overexpressed with lentivirus, which suppressed apoptosis, infarct size (miR-483-3p,22.00±4.04% versus negative control,28.57±5.44%, P<0.05), and Cdk9 expression to improve cardiac contractility. Conclusions MiR-483-3p antagonizes hypoxia, leading to cardiomyocyte injury by targeting Cdk9, which is a new mechanism of therapeutic hypothermia.

Association Between Weight Status and Rate of Cognitive Decline: China Health and Nutrition Survey 1997-2018.

There is a close relationship between weight status and cognitive impairment in older adults. This study examined the association between weight status and the trajectory of cognitive decline over time in a population-based cohort of older adults in China. We used data from adults aged ≥55 years participating in the China health and nutrition survey (1997-2018). Underweight (body mass index [BMI] ≤ 18.5 kg/m2), normal weight (18.5-23 kg/m2), overweight (23-27.5 kg/m2), and obesity (BMI ≥ 27.5 kg/m2) were defined using the World Health Organization Asian cutpoints. Global cognition was estimated every 2-4years through a face-to-face interview using a modified telephone interview for cognitive status (scores 0-27). The association between BMI and the rate of global cognitive decline, using a restricted cubic spline for age and age category, was examined with linear mixed-effects models accounting for correlation within communities and individuals. We included 5 992 adults (53% female participants, mean age of 62 at baseline). We found differences in the adjusted rate of global cognitive decline by weight status (p = .01 in the cubic spline model). Models were adjusted for sex, marital status, current employment status, income, region, urbanization, education status, birth cohort, leisure activity, smoking status, and self-reported diagnosis of hypertension, diabetes, or Myocardial Infarction (MI)/stroke. In addition, significant declines by age in global cognitive function were found for all weight status categories except individuals with obesity. In a cohort of adults in China, cognitive decline trajectory differed by weight status. Aslower rate of change was observed in participants classified as having obesity.

Abstract TP194: The FLAIR Signal Intensity Ratio Predicts Early Neurologic Deterioration For Small Subcortical Infarcts

Introduction: Early neurologic deterioration (END) occurs in nearly 40% of small subcortical infarct (SSI), with the majority occurring as a byproduct of completion of the initial infarct leading to significant morbidity. Presently there is not a robust predictive radiographic biomarker for END from SSI. The fluid-attenuated inversion recovery signal intensity ratio (FLAIR-SIR) ≥ 1.15 was shown to aid in differentiation of completed infarcts from those with penumbra allowing in identifying those that may benefit from alteplase. We aimed to use the FLAIR-SIR as a biomarker for predicting END from SSI. We hypothesized that those with a higher FLAIR-SIR had less risk of developing END due to completion of infarct. Methods: We retrospectively enrolled individuals who were seen at the Rhode Island Hospital between 2019 and 2022. Those included had a radiographic diagnosis of a SSI per STRIVE criteria. The primary outcome was END diagnosed as ≥ 2-point increase in NIH Stroke Scale score within 24 hours of admission. The primary exposure was FLAIR-SIR, defined as the ratio of ipsilateral FLAIR intensity within the region of infarct divided by the FLAIR of the contralateral identical anatomical location. Standard descriptive and unadjusted regression analyses were used. Results: A total of 195 individuals were included with a mean age 68 (± 13) years, and 59.5% (116/195) being male. END was identified in 3.6% (7/195). The mean overall FLAIR-SIR was 1.26 (± 0.30) with a mean of 1.26 (± 0.34) for those without END and 1.07 (± 0.25) for those with END ( p = 0.66). Using Youden’s J index for FLAIR-SIR, the optimal cutoff was determined to be ≤ 1.15. For a FLAIR-SIR ≤ 1.15, unadjusted Cox regression finds a hazard ratio of 4.1 (95%CI 0.79 - 21.1, p = 0.092) for END within 24 hours. Conclusions: FLAIR-SIR measurement above 1.15 may serve as a radiographic predictor of less risk of END amongst SSI. Our findings corroborate prior studies identifying 1.15 as a threshold for at-risk and completed SSI and should receive thrombolytics to minimize risk of END. Future studies are needed to increase power and confirm our findings.

Abstract 12: Higher Blood Pressure Trajectories After Endovascular Thrombectomy Are Associated With Cerebral Edema Development

Introduction: High blood pressure after endovascular thrombectomy (EVT) can cause cerebral hyperemia and disrupt the blood-brain barrier. However, its role in cerebral edema development is incompletely understood. In this study, we examined the relationship between post-EVT systolic blood pressure (SBP) trajectories and cerebral edema. Methods: We prospectively enrolled patients with large-vessel occlusion stroke who underwent EVT. Cerebrospinal fluid (CSF) volume was measured using a deep-learning algorithm on CT images at baseline, 24 hours, and 72 hours after stroke. The ratio of CSF volumes between hemispheres was calculated. Automated segmentation of infarct regions on follow-up scans was used to measure net water uptake (NWU), the ratio of density within infarcted tissue relative to the mirrored contralateral region. Latent variable mixture modeling (LVMM) divided patients into SBP trajectory groups during the first 72 hours post-EVT (Fig. 1A). Measures of edema (change in CSF ratio, NWU) were compared between groups. Results: One hundred patients (mean age 70 ± 16, mean NIHSS 15) were analyzed. Edema was assessed by a gradual increase in NWU (20.5, 27.0) at 24 and 72 hours, respectively, and by a reduction in CSF ratio (0.95, 0.78, 0.68) in the affected hemisphere at baseline, 24 hours, and 72 hours, respectively. LVMM identified five SBP trajectories. Higher SBP trajectories were associated with higher NWU (Fig. 1B) but not lower CSF ratio at 24 hours (p&lt;0.001 and p=0.343, respectively). After adjusting for age, admission NIHSS, and TICI score, the moderate-to-high and high-to-moderate trajectory groups were independently associated with higher NWU (aOR 11.40, 95% CI 2.14-20.66) and (aOR 10.97, 95% CI 0.12-21.82), relative to the low and moderate groups. Conclusions: Higher SBP trajectories are associated with an increase in NWU post-EVT. NWU is a promising radiographic biomarker for measuring cerebral edema during the early phase after stroke.

Prognosis of ischemic stroke predicted by machine learning based on multi-modal MRI radiomics.

Increased risk of stroke is highly associated with psychiatric disorders. We aimed to conduct the machine learning model based on multi-modal magnetic resonance imaging (MRI) radiomics predicting the prognosis of ischemic stroke. This study retrospectively analyzed 148 patients with acute ischemic stroke due to anterior circulation artery occlusion. Based on the modified Rankin Scale (mRS) score, patients were divided into good (mRS ≤ 2) and poor (mRS > 2) outcome groups. Segmentation of the infarct region was performed by manually outlining a mask of the lesion on diffusion-weighted images (DWI) using MRIcron software. The apparent diffusion coefficient (ADC), fluid decay inversion recoverage (FLAIR), susceptibility weighted imaging (SWI) and T1-weighted (T1w) images were aligned to the DWI images and the radiomic features within the lesion area were extracted for each image modality. The calculations were done using pyradiomics software and a total of 4,744 stroke-related imaging features were automatically calculated. Next, feature selection based on recursive feature elimination was used for each modality and three radiomic features were extracted from each modality plus one feature from the lesion mask, for a total of 16 radiomic features. At last, five machine learning (ML) models were trained and tested to predict stroke prognosis, calculate the received operating characteristic (ROC) curves and other parameters, evaluate the performance of the models and validate their predictive efficacy by five-fold cross-validation. Sixteen radiomic features were selected to construct the ML models for prognostic classification. By five-fold cross-validation, light gradient boosting machine (LightGBM) model-based muti-modal MRI radiomic features performed best in binary prognostic classification with accuracy of 0.831, sensitivity of 0.739, specificity of 0.902, F1-score of 0.788 and an area under the curve (AUC) of 0.902. The ML models based on muti-modal MRI radiomics are of high value for predicting clinical outcomes in acute stroke patients.

Distribution of intraperitoneally administered deuterium-labeled water in aquaporin-4-knockout mouse brain after middle cerebral artery occlusion.

As the movement of water in the brain is known to be involved in neural activity and various brain pathologies, the ability to assess water dynamics in the brain will be important for the understanding of brain function and the diagnosis and treatment of brain diseases. Aquaporin-4 (AQP4) is a membrane channel protein that is highly expressed in brain astrocytes and is important for the movement of water molecules in the brain. In this study, we investigated the contribution of AQP4 to brain water dynamics by administering deuterium-labeled water (D2O) intraperitoneally to wild-type and AQP4 knockout (AQP4-ko) mice that had undergone surgical occlusion of the middle cerebral artery (MCA). Water dynamics in the infarct region and on either side of the anterior cerebral artery (ACA) was monitored with proton-density-weighted imaging (PDWI) performed on a 7T animal MRI. D2O caused a negative signal change quickly after administration. The AQP4-ko mice showed a delay of the time-to-minimum in both the contralateral and ipsilateral ACA regions compared to wild-type mice. Also, only the AQP4- ko mice showed a delay of the time-to-minimum in the ipsilateral ACA region compared to the contralateral side. In only the wild-type mice, the signal minimum in the ipsilateral ACA region was higher than that in the contralateral ACA region. In the infarct region, the signal attenuation was slower for the AQP4-ko mice in comparison to the wild-type mice. These results suggest that AQP4 loss affects water dynamics in the ACA region not only in the infarct region. Dynamic PDWI after D2O administration may be a useful tool for showing the effects of AQP4 in vivo.

Regulated necrosis pathways: a potential target for ischemic stroke.

Globally, ischemic stroke causes millions of deaths per year. The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region. In the infarct region, cell injuries follow either the regulated pathway involving precise signaling cascades, such as apoptosis and autophagy, or the nonregulated pathway, which is uncontrolled by any molecularly defined effector mechanisms such as necrosis. However, numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic; this type of necrosis is referred to as regulated necrosis. Depending on the signaling pathway, various elements of regulated necrosis contribute to the development of ischemic stroke, such as necroptosis, pyroptosis, ferroptosis, pathanatos, mitochondrial permeability transition pore-mediated necrosis and oncosis. In this review, we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis. We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemia-induced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.

BMAnet: Boundary Mining With Adversarial Learning for Semi-Supervised 2D Myocardial Infarction Segmentation.

Automatic segmentation of myocardial infarction (MI) regions in late gadolinium-enhanced cardiac magnetic resonance images is an essential step in the computed diagnosis of myocardial infarction. Most of the current myocardial infarction region segmentation methods are based on fully supervised deep learning. However, cardiologists' annotation of myocardial infarction regions in cardiac magnetic resonance images during the diagnosis process is time-consuming and expensive. This paper proposes a semi-supervised myocardial infarction segmentation. It consists of two models: 1) a boundary mining model and 2) an adversarial learning model. The boundary mining model can solve the boundary ambiguity problem by enlarging the gap between the foreground and background features, thus segmenting the myocardial infarction region accurately. The adversarial learning model can make the boundary mining model learn from additional unlabeled data by evaluating the segmentation performance and providing pseudo supervision, which significantly increases the robustness of the boundary mining model. We conduct extensive experiments on an in-house myocardial magnetic resonance dataset. The experimental results on six evaluation metrics demonstrate that our method achieves excellent results in myocardial infarction segmentation and outperforms the state-of-the-art semi-supervised methods.

Force oscillations underlying precision grip in humans with lesioned corticospinal tracts

Stability of precision grip depends on the ability to regulate forces applied by the digits. Increased frequency composition and temporal irregularity of oscillations in the force signal are associated with enhanced force stability, which is thought to result from increased voluntary drive along the corticospinal tract (CST). There is limited knowledge of how these oscillations in force output are regulated in the context of dexterous hand movements like precision grip, which are often impaired by CST damage due to stroke. The extent of residual CST volume descending from primary motor cortex may help explain the ability to modulate force oscillations at higher frequencies. Here, stroke survivors with longstanding hand impairment (n = 17) and neurologically-intact controls (n = 14) performed a precision grip task requiring dynamic and isometric muscle contractions to scale and stabilize forces exerted on a sensor by the index finger and thumb. Diffusion spectrum imaging was used to quantify total white matter volume within the residual and intact CSTs of stroke survivors (n = 12) and CSTs of controls (n = 14). White matter volumes within the infarct region and an analogous portion of overlap with the CST, mirrored onto the intact side, were also quantified in stroke survivors. We found reduced ability to stabilize force and more restricted frequency ranges in force oscillations of stroke survivors relative to controls; though, more broadband, irregular output was strongly related to force-stabilizing ability in both groups. The frequency composition and temporal irregularity of force oscillations observed in stroke survivors did not correlate with maximal precision grip force, suggesting that it is not directly related to impaired force-generating capacity. The ratio of residual to intact CST volumes contained within infarct and mirrored compartments was associated with more broadband, irregular force oscillations in stroke survivors. Our findings provide insight into granular aspects of dexterity altered by corticospinal damage and supply preliminary evidence to support that the ability to modulate force oscillations at higher frequencies is explained, at least in part, by residual CST volume in stroke survivors.

A dual-responsive ratiometric indicator designed for in vivo monitoring of oxidative stress and antioxidant capacity.

The imbalance between oxidative stress and antioxidant capacity is strongly associated with the development of numerous degenerative diseases, including cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. Therefore, monitoring oxidative stress and antioxidant capacity in vivo is crucial for maintaining cellular homeostasis and the stability of the organism's internal environment. Here, we present the findings of our study on DQ1, a dual-responsive indicator designed specifically for imaging H2O2 and NAD(P)H, which are critical indicators of oxidative stress and antioxidant capacity. DQ1 facilitated the colorimetric and fluorescence detection of H2O2 and NAD(P)H in two well-separated channels, exhibiting a detection limit of 1.0 μM for H2O2 and 0.21 nM for NAD(P)H, respectively. Experiments conducted on living cells and zebrafish demonstrated that DQ1 could effectively detect changes in H2O2 and NAD(P)H levels when exposed to exogenous hypoxic conditions and chemical stimuli. Furthermore, the effectiveness of the as-fabricated indicator was investigated in two distinct mouse models: evaluating H2O2 and NAD(P)H levels in myocardial cell dysfunction during acute myocardial infarction and liver tissue damage under trichloroethylene stress conditions. In vivo experiments demonstrated that the levels of the two cardiac biomarkers increase progressively with the development of myocardial infarction, eventually reaching a steady state after 7 days when the damaged cells in the infarcted region become depleted. Moreover, during 14 continuous days of exposure to trichloroethylene, the two biomarkers in liver tissue exhibited a sustained increase, indicating a significant enhancement in intracellular oxidative stress and antioxidant capacity attributed to the mouse liver's robust metabolic capacity. The aforementioned studies underscore the efficacy of DQ1 as a valuable tool for scrutinizing redox states at both the single-cell and biological tissue levels. It presents significant potential for investigating the dynamic alternations in oxidative stress and antioxidant capacity within disease models as the disease progresses, thereby facilitating a more profound comprehension of these processes across various disease models.

In Vivo Longitudinal Monitoring of Cardiac Remodeling in Murine Ischemia Models With Adaptive Bayesian Regularized Cardiac Strain Imaging: Validation Against Histology.

Adaptive Bayesian regularized cardiac strain imaging (ABR-CSI) uses raw radiofrequency signals to estimate myocardial wall contractility as a surrogate measure of relative tissue elasticity incorporating regularization in the Bayesian sense. We determined the feasibility of using ABR-CSI -derived strain for in vivo longitudinal monitoring of cardiac remodeling in a murine ischemic injury model (myocardial infarction [MI] and ischemia-reperfusion [IR]) and validated the findings against ground truth histology. We randomly stratified 30 BALB/CJ mice (17 females, 13 males, median age=10 wk) into three surgical groups (MI=10, IR=12, sham=8) and imaged pre-surgery (baseline) and 1, 2, 7 and 14 d post-surgery using a pre-clinical high-frequency ultrasound system (VisualSonics Vevo 2100). We then used ABR-CSI to estimate end-systolic and peak radial (er) and longitudinal (el) strain estimates. ABR-CSI was found to have the ability to serially monitor non-uniform cardiac remodeling associated with murine MI and IR non-invasively through temporal variation of strain estimates post-surgery. Furthermore, radial end-systole (ES) strain images and segmental strain curves exhibited improved discrimination among infarct, border and remote regions around the myocardium compared with longitudinal strain results. For example, the MI group had significantly lower (Friedman's with Bonferroni-Dunn test, p=0.002) ES er values in the anterior middle (infarcted) region at day 14 (n=9, 9.23 ± 7.39%) compared with the BL group (n=9, 44.32 ± 5.49). In contrast, anterior basal (remote region) mean ES er values did not differ significantly (non-significant Friedman's test, χ2=8.93, p=0.06) at day 14 (n=6, 33.05 ± 6.99%) compared with baseline (n=6, 34.02 ± 6.75%). Histology slides stained with Masson's trichrome (MT) together with a machine learning model (random forest classifier) were used to derive the ground truth cardiac fibrosis parameter termed histology percentage of myocardial fibrosis (PMF). Both radial and longitudinal strain were found to have strong statistically significant correlations with the PMF parameter. However, radial strain had a higher Spearman's correlation value (εresρ=-0.67, n=172, p < 0.001) compared with longitudinal strain (εlesρ=-0.60, n=172, p < 0.001). Overall, the results of this study indicate that ABR-CSI can reliably perform non-invasive detection of infarcted and remote myocardium in small animal studies.

Effects of Electronic Cigarette Exposure on Myocardial Infarction and No-Reflow, and Cardiac Function in a Rat Model.

We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the sizes of the no-reflow and myocardial infarction regions, and cardiovascular function compared to exposure to purified air and standard cigarette smoke. Sprague Dawley rats (both male and female, 6 weeks old) were successfully exposed to filtered air (n = 32), E-cig with nicotine (E-cig Nic+, n = 26), E-cig without nicotine (E-cig Nic-, n = 26), or standard cigarette smoke (1R6F reference, n = 31). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Exposure to E-cig vapor with or without nicotine or exposure to standard cigarettes did not increase myocardial infarct size or worsen the no-reflow phenomenon. Exposure to E-cig Nic+ reduced the body weight gain, and increased the LV weight normalized to body weight and LV wall thickness and enhanced the collagen deposition within the LV wall. E-cig exposure led to cardiovascular dysfunction, such as reductions in cardiac output, LV positive and negative dp/dt, suggesting a reduction in contractility and relaxation, and increased systemic arterial resistance after coronary artery occlusion and reperfusion in rats compared to air or cigarette exposure. E-cig exposure did not increase myocardial infarct size or worsen the no-reflow phenomenon, but induced deleterious changes in LV structure leading to cardiovascular dysfunction and increased systemic arterial resistance after coronary artery occlusion followed by reperfusion.

Magnetic Resonance Spectroscopy Deep Learning Denoising Using Few in Vivo Data

Magnetic Resonance Spectroscopy (MRS) is a noninvasive tool to reveal metabolic information. One challenge of <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</sup> H-MRS is the low Signal-Noise Ratio (SNR). To improve the SNR, a typical approach is to perform a large number of Signal Averaging (SA). The data acquisition time, however, is proportional to the number of SA accordingly. A complete clinical MRS scan takes approximately 10 minutes in a common setting with the number of SA of 128. Recently, deep learning has been introduced to improve the SNR, but mostly the simulated data were used as the training set. This may hinder the MRS applications since some potential differences, such as acquisition system imperfections, physiological and psychologic conditions may exist between the simulated and <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vivo</i> data. In this paper, a new scheme that purely used repeated samples of realistic data was proposed. A deep learning model, Refusion Long Short-Term Memory (ReLSTM), was designed to learn the mapping from the time domain data with low SNR (24 SA) to the one with high SNR (128 SA). Experiments on the <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vivo</i> brain spectra of 7 healthy, 2 tumor and 1 cerebral infarction region shows that using SA of 24, only 20% of a common setting, the spectra denoised by ReLSTM can provide the estimated concentrations of metabolites with the reliability comparable to those of the high-SNR spectra obtained commonly with 128 SA. Furthermore, compared with the state-of-the-art Low-Rank (LR) denoising method, the ReLSTM achieves lower relative errors and the Cramér-Rao lower bounds in quantifying some important biomarkers. In summary, ReLSTM can perform high-fidelity spectral denoising of the spectra with the fast acquisition (24 SA), which is valuable to MRS clinical studies.