Myocardial Infarction Model Research Articles

Factors influencing the return to the professional activity in patients hospitalized for myocardial infarction: a single centre experience - pilot study.

Cardiovascular diseases, with myocardial infarction (MI) on the leading position, remain a serious health care issue and socio-economic burden. Nevertheless, factors influencing the return of patients to the professional activity are not fully understood. Cardiac rehabilitation may have a positive impact on the return to professional activity after MI. However, no study among participants in the comprehensive care after myocardial infarction (CCMI) model (in Polish: "KOS-zawał") evaluated this issue so far. The aim of the study was to evaluate factors influencing the return to work and duration of the sick leave after MI among patients who participated in the CCMI in a single reference cardiology centre in Poland. In total, 144 patients were screened retrospectively. Out of them, 105 were included in the analysis. All patients were treated with direct percutaneous coronary intervention according to current European Society of Cardiology guidelines and participated in cardiac rehabilitation within the CCMI program, therefore had been provided optimal and modern therapeutic approach. Data was collected based on patients' medical records and information furnished by the insurer. Out of 105 patients analysed, 93 (88,6%) returned to work. A positive predictor of returning to work was male sex. Predictors of a prolonged return to work were older age and female sex. Completing rehabilitation, anthropometric factors, biochemical factors or results of post-MI echocardiographic examination did not influence the return to professional activity. A relatively large percentage of patients after MI and in the CCMI program returns to professional activity. Main factors of prolonged sick leave are older age and female sex. Med Pr Work Health Saf. 2024;75(6).

Potential cardioprotective effect of paroxetine against ventricular remodeling in an animal model of myocardial infarction: a comparative study

BackgroundPost-myocardial infarction (MI) remodeling involves various structural and functional changes, such as inflammation and fibrosis. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is linked to the progression of cardiovascular diseases, including myocardial infarction. The inhibitory effects of paroxetine on GRK2 are recognized, yet its protective effect on post-MI remodeling has not been elucidated. Here, we investigated the cardioprotective effect of paroxetine in an animal model of MI, focusing on post-MI cardiac remodeling and comparing its effect to a β-blocker and an angiotensin receptor antagonist.MethodsAlbino Wistar rats were divided into five groups (control; untreated MI; and MI pre-treated with either paroxetine, metoprolol, or irbesartan). MI was induced using isoproterenol (100 mg.kg−1) on days 16 and 17. Cardioprotective effects were determined by assessing markers of cardiac injury, histopathology, inflammation, oxidative stress, and fibrosis. Statistical analysis performed using a one-way analysis of variance, followed by an appropriate post hoc test, the differences between the groups were considered significant when the (P < 0.05).ResultsParoxetine significantly attenuated cardiac injury biomarkers including serum Tn-I and CK-MB levels. In terms of cardiac remodeling, paroxetine significantly reduced the relative HW/BW index and the plasms FGF23 level. Furthermore, it modulated markers of fibrosis, inflammation, and oxidative stress.ConclusionThe current findings suggest that pre-treatment with paroxetine may exert a beneficial effect that protects against post-MI remodeling, including modulating fibrotic, inflammatory, and angiogenesis-related factors. Therefore, the current findings show the promising role of paroxetine as a cardioprotective that attenuates post-MI remodeling processes.

An antioxidant nanozyme for targeted cardiac fibrosis therapy post myocardial infarction

The excessive release of reactive oxygen species (ROS) after myocardial infarction (MI) disrupts the natural healing process, leading to cardiac fibrosis and compromising patient prognosis. However, the clinical application of many antioxidant drugs for MI treatment is hindered by their poor antioxidant efficacy and inability to specifically target the heart. Here we developed a tannic acid-modified MnO2 nanozyme (named MnO2@TA), which can achieve cardiac targeting to inhibit post-MI fibrosis and enhance cardiac function. Specifically, the MnO2@TA nanozyme, endowed with superoxide dismutase (SOD) and catalase (CAT) activities, effectively scavenges ROS, suppressing fibroblast activation and mitigating cardiac fibrosis without affecting cardiac repair. Notably, the incorporation of TA improves the nanozyme’s affinity for the elastin and collagen-rich extracellular matrix in cardiac tissues, significantly increasing its retention and uptake within the heart and thereby enhancing its anti-fibrotic efficacy. In a murine myocardial infarction model, MnO2@TA demonstrates remarkable cardiac protection and safety, significantly improving cardiac function while attenuating cardiac fibrosis. This study presents a valuable reference for clinical research aimed at inhibiting cardiac fibrosis and advancing myocardial infarction treatments.Graphical

Ischemia-Induced Expression Status of Cofilin 1, CRSP2, HSP90, HSP27, and IL-8 in Epicardial Adipose Tissue and Single Cell Transcriptomic Profiling of Stromal Cells.

Epicardial adipose tissue (EAT) is a rich source of EAT-derived stromal cells (EATDS) which possess regenerative potential. CRSP2, HSP27, IL8, HSP90 and Cofilin 1 were detected in the secretome of left ventricular stromal cells under ischemia challenge. However, the association of these genes in the EAT and EATDS remain understudied. We aim to assess the status of cofilin 1, CRSP2, HSP27, IL8 and HSP90 in the EAT of myocardial infarction (MI) and Coronary Artery Bypass Graft (CABG) swine models and in vitro stimulated ischemic EATDS. Expression status of these proteins in EAT were assessed by immunostaining and in EATDS using qRT-PCR, immunostaining, and Western blot. EATDS phenotyping was performed using sc-RNAseq analysis. Cofilin 1 was increased while the other four genes were decreased in the CABG. IL8 and HSP90 were increased while CRSP2, HSP27 and cofilin 1 were decreased in the MI group. Similar trend was displayed in the expression of these genes in EATDS. Additionally, EATDS displayed versatile phenotypes at single cell resolution based on the differential expression of various gene signatures. The findings revealed novel insights into EAT/EATDS biology and further understanding regarding the EATDS sub-phenotypes would open novel avenues in translational cardiology.

Knockdown of KLF6 ameliorates myocardial infarction by regulating autophagy via transcriptional regulation of PTTG1.

Krüppel-like factor 6 (KLF6) knockdown provides protection against kidney ischemia/reperfusion (I/R) injury and ischemic stroke. However, it is unclear whether it plays a role in myocardial infarction (MI) remains unknown. Here, the expression of KLF6 was analyzed using the GEO database and determined in patients with MI. The impact of KLF6 knockdown was further confirmed in in vivo and >in vitro models of MI. The interaction between KLF6 and PTTG1 was also evaluated. According to the GEO database, KLF6 expression was found to be upregulated in mouse hearts after MI compared to sham-operated mice. The upregulation of KLF6 in hearts from mice post-MI and in patients with MI was confirmed. KLF6 knockdown was found to alleviate myocardial injury, diminish infarct size, and suppress apoptosis and autophagy in mice with MI. Additionally, inactivation of the AMPK/mTOR signaling was observed after KLF6 knockdown in mice with MI. In an in vitro model of MI, knockdown of KLF6 increased cell survival and inhibited autophagy through the AMPK/mTOR pathway. Additionally, KLF6 interacted with the promoter of PTTG1 and negatively regulated its expression. Knockdown of PTTG1 abolished the function of KLF6 knockdown in vitro. This study demonstrates the protective effect of KLF6 knockdown against MI, which is attributed to the elevation of PTTG1 expression and inhibition of the AMPK/mTOR pathway. These findings provide a novel insight into MI treatment.

Single cell transcriptomics profiling of the stromal cells in the pathologic association of ribosomal proteins in the ischemic myocardium and epicardial fat.

Sustenance of ischemia in the surviving cardiac tissue following myocardial infarction (MI) elicits a proinflammatory milieu resulting in subsequent pathological episodes. Also, the activation and release of ribosomal proteins under ischemic insults have been unveiled; however, their extra ribosomal functions are unknown. We identified the ribosomal proteins including RPL10A, RPL14, RPL30, RPS18, FAU-40 (RPS30), and RPSA (Laminin Receptor, LR) in the vesicles of ischemia challenged epicardial adipose tissue derived stromal cells (EATDS). The present study aimed to assess the association of these proteins in the epicardial adipose tissues (EAT) and left ventricular (LV) myocardium and isolated stromal cells (EATDS and LVSCs) from hyperlipidemic (HL), MI and coronary artery bypass graft (CABG) swine models. The findings revealed an upregulation of RPL10A, RPL14, RPL30, RPS18, RPS30, and RPSA in the LV tissues of CABG and HL swine with a concomitant reduction in the MI group. RPS30 displayed similar upregulation in EAT, whereas the expression of other ribosomal proteins was not significantly altered. Additionally, the ischemic LVSCs and EATDS displayed altered expression status of these genes compared to the control. Also, the RPS18 + , RPL30 + and RPSA + LVSCs favored ischemia and revealed similar anti-inflammatory and regenerative sub-phenotypes reflecting the protective/survival mechanisms. Further understanding regarding the underlying molecular mechanisms and functions of these ribosomal proteins offers immense translational opportunities in the better management of ischemic cardiac complications.

A Body-Temperature-Triggered In Situ Softening Peripheral Nerve Electrode for Chronic Robust Neuromodulation.

Implantable peripheral nerve electrodes are crucial for monitoring health and alleviating symptoms of chronic diseases. Advanced compliant electrodes have been developed because of their biomechanical compatibility. However, these mechanically tissue-like electrodes suffer from unmanageable operating forces, leading to high risks of nerve injury and fragile electrode-tissue interfaces. Here, a peripheral nerve electrode is developed that simultaneously fulfills the criteria of body temperature softening and tissue-like modulus (less than 0.8MPa at 37°C) after implantation. The central core is altered from the tri-arm crosslinker to the star-branched monomer to kill two birds (close the translation temperature to 37°C and decrease the modulus after implantation) with one stone. Furthermore, the decreased interfacial impedance (325.1±46.9Ω at 1kHz) and increased charge storage capacity (111.2±5.8mCcm-2) are achieved by an in situ electrografted conductive polymer on the strain-insensitive conductive network of Au nanotubes. The electrodes are readily wrapped around nerves and applied for long-term stimulation in vivo with minimal inflammation. Neuromodulation experiments demonstrate their potential clinical utility, including vagus nerve stimulation in rats to suppress seizures and alleviation of cardiac remodeling in a canine model of myocardial infarction.

A Vaccine Against Fibroblast Activation Protein Improves Murine Cardiac Fibrosis by Preventing the Accumulation of Myofibroblasts.

Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis. We coadministered a FAP peptide vaccine with a CpG K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues. We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; P=4.59×10-3) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm2; FAP vaccine versus angiotensin II and phenylephrine control; P=6.67×10-3). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models. Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.

Development and internal validation of time-to-event risk prediction models for major medical complications within 30 days after elective colectomy.

Patients undergoing colectomy are at risk of numerous major complications. However, existing binary risk stratification models do not predict when a patient may be at highest risks of each complication. Accurate prediction of the timing of complications facilitates targeted, resource-efficient monitoring. We sought to develop and internally validate Cox proportional hazards models to predict time-to-complication of major complications within 30 days after elective colectomy. We studied a retrospective cohort from the multicentered American College of Surgeons National Surgical Quality Improvement Program procedure-targeted colectomy dataset. Patients aged 18 years or above, who underwent elective colectomy between January 1, 2014 and December 31, 2019 were included. A priori candidate predictors were selected based on variable availability, literature review, and multidisciplinary team consensus. Outcomes were mortality, hospital readmission, myocardial infarction, cerebral vascular events, pneumonia, venous thromboembolism, acute renal failure, and sepsis or septic shock within 30 days after surgery. The cohort consisted of 132145 patients (mean ± SD age, 61 ± 15 years; 52% females). Complication rates ranged between 0.3% (n = 383) for cardiac arrest and acute renal failure to 5.3% (n = 6986) for bleeding requiring transfusion, with readmission rate of 8.6% (n = 11415). We observed distinct temporal patterns for each complication: the median [quartiles] postoperative day of complication diagnosis ranged from 1 [0, 2] days for bleeding requiring transfusion to 12 [6, 18] days for venous thromboembolism. Models for mortality, myocardial infarction, pneumonia, and renal failure showed good discrimination with a concordance > 0.8, while models for readmission, venous thromboembolism, and sepsis performed poorly with a concordance of 0.6 to 0.7. Models exhibited good calibration but ranges were limited to low probability areas. We developed and internally validated time-to-event prediction models for complications after elective colectomy. Once further validated, the models can facilitate tailored monitoring of high risk patients during high risk periods. Clinicaltrials.gov (NCT05150548; Principal Investigator: Janny Xue Chen Ke, M.D., M.Sc., F.R.C.P.C.; initial posting: November 25, 2021).

Sequential Delivery of Cardioactive Drugs via Microcapped Microneedle Patches for Improved Heart Function in Post Myocardial Infarction Rats

After myocardial infarction, the heart undergoes adverse remodeling characterized by a series of pathological changes, including inflammation, apoptosis, fibrosis, and hypertrophy. In addition to cardiac catheter-based re-establishment of blood flow, patients typically receive multiple medications that aim to address these different mechanisms underlying left ventricular remodeling. The current study aims to establish a versatile multi-drug delivery platform for the controlled and sequential delivery of multiple therapeutic agents in a single treatment. Toward this goal, we generated a microcapped microneedle patch carrying methylprednisolone, interleukin-10, and vascular endothelial growth factor. In vitro characterization demonstrated a time-sequenced release pattern of these drug: methylprednisolone for the first 3 days, interleukin-10 from day 1 to 15, and vascular endothelial growth factor from day 3 to 25. The therapeutic effects of the microneedle patch were evaluated in a rat model of acute myocardial infarction induced by permanent ligation of left anterior descending coronary artery. Heart function was measured using trans-thoracic echocardiography. Heart inflammation, apoptosis, hypertrophy and angiogenesis were evaluated using histology. Our data indicated that, at 28 days after patch transplantation, animals receiving the microneedle patch with sequential release of these three agents showed reduced inflammation, apoptosis and cardiac hypertrophy compared to the animals receiving control patch without sequential release of these agents, which is associated with the improved angiogenesis and heart function. In conclusion, the microneedle patch can be utilized to deliver multiple therapeutic agents in a controlled and sequential manner that aligns with the pathological phases following myocardial infarction. STATEMENT OF SIGNIFICANCE: The post-myocardial infarction heart remodeling is characterized by a series of pathological events including acute inflammation, apoptosis, fibrosis, cardiac hypertrophy, and depressed heart function. In current clinical practice, multiple procedures and drugs given at different time points are necessary to combat these series of pathological events. In this study, we developed a novel microcapped microneedle patch for the controlled sequential delivery of triple cardioprotective drugs aiming to combat acute inflammation and cardiac hypertrophy, and promote angiogenesis. This study presents a comprehensive therapeutic approach, with the microneedle patch addressing multifaceted pathological processes during post-myocardial infarction left ventricular remodeling. This cardiac drug delivery system has the potential to improve patient treatment by delivering drugs in alignment with the series of time-dependent pathological phases following myocardial infarction, ultimately improving clinical outcomes.

Mechanical circulatory support reduces renal sympathetic nerve activity in an ovine model of acute myocardial infarction.

The use of circulatory assist devices has been shown to improve glomerular filtration rate and reduce the incidence of acute kidney injury in patients following acute cardiac pathology. However, the mechanisms of improvement in kidney function are not clear. We tested the hypothesis that mechanical circulatory support would result in a decrease in directly recorded renal sympathetic nerve activity (RSNA) and mediate the improvement in renal blood flow (RBF) in a setting of acute myocardial infarction (AMI)-induced left ventricular systolic dysfunction. An anaesthetized ovine model was used to induce AMI (n = 8) using injections of microspheres into the left coronary artery in one group. The second group did not undergo embolization (n = 6). The effects of mechanical circulatory support using the Impella CP on directly recorded renal sympathetic nerve activity were examined in these two groups of animals. Injection of microspheres resulted in a drop in mean arterial pressure (MAP) of 21 ± 4mmHg compared to baseline values (p < 0.05; n = 8). This was associated with a 67% increase in renal sympathetic nerve activity (RSNA; from 16 ± 5 to 21 ± 5 spikes/s; p < 0.05; n = 7). Impella CP support significantly increased MAP by 13 ± 1.5mmHg at pump level 8 (p < 0.05) in the AMI group. Incremental pump support resulted in a significant decrease in RSNA (p < 0.05) in both groups. At pump level P8in the AMI group, RSNA was decreased by 21 ± 5.5% compared to pump level P0 when the pump was not on. Our data indicate that the improvement in kidney function following mechanical circulatory support may be mediated in part by renal sympathoinhibition.

Time to rename the “ischemia/reperfusion injury” model to “ischemia/delayed reperfusion injury” model?

Small animals are often used in the preclinical and translational studies. Left coronary artery ligation followed by reperfusion in rats or mice serves as an important myocardial infarction (MI) models resembling the clinical MI cases treated with revascularization. This model is typically referred to as the “ischemia/reperfusion injury (IRI) model.” However, it is not the reperfusion itself but rather the delay in reperfusion following ischemic insult that contributes most significantly to the residual myocardial damage. Therefore, it may be more accurate to rename it the “ischemia/delayed reperfusion injury (IdRI) model.”

Effect of ventricular fibrillation on infarct size after myocardial infarction: a translational study

Ventricular fibrillation (VF)-induced cardiac arrest frequently complicates ST-segment elevation myocardial infarction (STEMI). Although larger infarct sizes (IS) correlate with a higher risk of VF, the influence of VF itself on IS has remained poorly investigated. To address this knowledge gap, we analyzed the effect of VF on IS in patients and two experimental models. From a prospective cohort, 30 STEMI patients with VF were matched 1:2 with STEMI patients without VF on the common determinants of IS. The primary endpoint was IS, assessed using the 48-h area under the curve (AUC) for troponin. We also compared IS in pigs with/without spontaneous VF during STEMI (n = 15/group), and in an isolated rat heart model of myocardial infarction with/without electrically induced VF (n = 7/group). After matching, the patient characteristics, including the area at risk (AR), were similar. IS was 33% lower in the VF group compared to the control group (troponin AUC 1.6 [0.5–3.3] 106 arbitrary units vs. 2.4 [0.9–4.1] 106 arbitrary units; p < 0.05), but infarct scar size (assessed using MRI and ECG) did not differ between the groups at 1 and 6 months. In both experimental models, IS, expressed as a percentage of AR, was lower (p < 0.05) in the VF group than in the control group. When common determinants of IS are comparable, VF occurring prior to myocardial infarction reperfusion appears to be associated with smaller IS. Nevertheless, this finding, observed under specific experimental conditions and in a highly selected group of patients, was not associated with reduced infarct scar size.Registration (HIBISCUS-STEMI cohort): ClinicalTrials.gov NCT05794022.

RNA-Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post-Transcriptional Manner.

Stimulating cardiomyocyte (CM) dedifferentiation and cell cycle activity (DACCA) is essential for triggering daughter CM formation. In addition to transcriptional processes, RNA-binding proteins (RBPs) are emerging as crucial post-transcriptional players in regulating CM DACCA. However, whether post-transcriptional regulation of CM DACCA by RBPs could effectively trigger daughter CM formation remains unknown. By performing integrated bioinformatic analysis of snRNA-seq data from neonatal and adult hearts, this study identified Hnrnpa1 as a potential RBP regulating CM DACCA. Hnrnpa1 expression decreased significantly during postnatal heart development. With the use of α-MHC-H2B-mCh/CAG-eGFP-anillin transgenic mice, Hnrnpa1 overexpression promoted CM DACCA, thereby triggering daughter CM formation and enhancing cardiac repair after myocardial infarction (MI). In contrast, CRISPR/Cas9 technology is used to generate CM-specific Hnrnpa1 knockout mice. Hnrnpa1 knockout inhibited cardiac regeneration and worsened cardiac function in the neonatal MI model. Nanopore RNA sequencing, RIP assay, IP-MS, MeRIP-qPCR, PAR-CLIP and luciferase reporter experiments showed that Hnrnpa1 induced Mettl3 post-transcriptional splicing to inhibit m6A-dependent Pbx1 and E2F1 degradation, thereby increasing Runx1, Ccne1, Cdk2 and Ccnb2 expression to promote CM DACCA. In conclusion, Hnrnpa1 triggered daughter CM formation by promoting CM DACCA in a post-transcriptional manner, indicating that Hnrnpa1 might serve as a promising target in cardiac repair post-MI.

Cardiomyocyte-derived exosomes promote cardiomyocyte proliferation and neonatal heart regeneration.

Heart regeneration was mainly achieved by intrinsic capacity. Exosomes are crucial in cardiovascular disease, yet their involvement in myocardial regeneration remains underexplored. To understand the role of cardiomyocyte-derived exosomes (CM-Exos) in heart regeneration. We established mouse models of myocardial infarction and apical resection in neonates to investigate the potential benefits of exosomes in response to injury. Rab27a knockout (KO) mice were constructed as an exosome decrease model. Distinct fibrosis appears in the infarcted and resection area in the KO mice 21 days after heart injury. The proliferation marker pH 3, Ki67, and Aurora B were detected 3 days after surgery, which decreased in KO mice compared to WT mice. Intravenous injection of CM-Exos increased cardiomyocyte proliferation and partially restored heart function in KO mice. Rab27a knockdown invitro reduced the expression of pH 3, Ki67, and Aurora B positive cardiomyocytes. However, the supplementation of CM-Exos increased the proliferation of cardiomyocytes. Exosomal miRNA sequencing was subsequently applied, and miR-21-5p was a promising candidate that promoted cardiomyocyte proliferation through its target genes Spry-1 and PDCD4. Intravenous injection of miR-21-5p exhibited similar proliferative effects as CM-Exos. Our results indicate that CM-Exos promotes cardiomyocyte cycle reentry by delivering miR-21-5p, highlighting the endogenous factors of myocardial regeneration.

ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction.

Protein phosphorylation, controlled by protein kinases, is central to regulating various pathophysiological processes, including cardiac systolic function. The dysregulation of protein kinase activity plays a significant role in the pathogenesis of cardiac systolic dysfunction. While cardiac contraction mechanisms are well documented, the mechanisms underlying cardiac diastole remain elusive. This gap persists owing to the historical focus on systolic dysfunction in heart failure research. Recently, heart failure with preserved ejection fraction (HFpEF), an age-related disease characterized by cardiac diastolic dysfunction, has emerged as a major public health concern. However, its underlying mechanism remains unclear. In this study, we investigated cardiac protein kinases by analyzing the gene expression of 518 protein kinases in human tissues. We identified alpha-kinase 2 (ALPK2) as a novel cardiac-specific atypical kinase and generated tamoxifen-inducible, cardiomyocyte-specific Alpk2-knockout mice and Alpk2-overexpressing mice. Alpk2 deficiency did not affect cardiac systolic dysfunction in the myocardial infarction model or the pressure-overload-induced heart failure model. Notably, cardiomyocyte-specific Alpk2 deficiency exacerbated cardiac diastolic dysfunction induced by aging and in the HFpEF model. Conversely, Alpk2 overexpression increased the phosphorylation of tropomyosin 1, a major regulator that binds myosin to actin, and mitigated cardiac stiffness in HFpEF. This study provides novel evidence that ALPK2 represents a potential therapeutic target for cardiac diastolic dysfunction in HFpEF and age-related cardiac impairments.

Pretreatment with Notoginsenoside R1 enhances the efficacy of neonatal rat mesenchymal stem cell transplantation in model of myocardial infarction through regulating PI3K/Akt/FoxO1 signaling pathways

BackgroundAlthough stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI.MethodsCardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson’s trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively.ResultsNGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H2O2. Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro.ConclusionsNGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways.

Minimally Invasive Transthoracic Intramyocardial Cellular Transplantation Under Echocardiographic Guidance for Myocardial Impairment

Abstract Objective: To explore the approach of minimally invasive transthoracic intramyocardial cellular transplantation under echocardiographic guidance to promote ischemic myocardial repair in a preclinical big-animal study. Methods: Female Guangxi Bama miniature pigs (weight: 25–30 kg) were randomly allocated into the sham group, untreated myocardial infarction (MI) group (MI group), the MI and surgical intramyocardial injection (SIM) group (MI-SIM group), and the MI and transthoracic echocardiography-guided percutaneous intramyocardial injection (TTEPIM) group (MI-TTEPIM group) (n = 4 each) using a lottery method. A swine MI model was established in the 3 groups excluding the sham group, and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) labeled with the herpes simplex virus type-1 thymidine kinase reporter gene (hiPS-CMTK+) were transplanted by SIM in MI-SIM group and TTEPIM in MI-TTEPIM group. The operation time, postoperative recovery time of animals and volume of blood loss were collected for comparison between MI-SIM group and MI-TTEPIM group. 9-(4-[18F] fluoro-3-(hydroxymethyl) butyl) guanine positron emission tomography/computed tomography imaging was performed to track the hiPS-CMTK+ in vivo. Cardiac function and morphology were evaluated by echocardiography. Results: The operation time and postoperative recovery time of MI-TTEPIM group were significantly shorter than those of MI-SIM group ((28.3 ± 3.6) min vs. (97.0 ± 6.7) min, P &lt; 0.001; (1.3 ± 0.3) d vs. (7.5 ± 0.9) d, P &lt; 0.001). MI-TTEPIM also showed significantly lesser volume of blood loss during cell transplantation than MI-SIM group ((4.3 ± 0.8) mL vs. (47.0 ± 4.1) mL, P &lt; 0.001). The transplanted cells could be traced more accurately in vivo in MI-TTEPIM than in MI-SIM. The circumferential strain of intervention region in the MI-TTEPIM group (–25.07% ± 0.27%) was significantly higher than that of the MI-SIM (–20.39% ± 0.67%) and MI groups (–19.68% ± 0.67%), respectively (P &lt; 0.01). Conclusion: A minimally invasive TTEPIM protocol with stem cells for treating the ischemic myocardium was established in this study. Transplantation of hiPS-CMTK+ with this method could promote the recovery of the circumferential strain of the ischemic myocardium. The findings of this study lay a foundation for the clinical transformation of this auxiliary means of treatment in the future.

Abstract 4137339: Application of PLGA-PEG-PLGA Thermosensitive Hydrogel Loaded with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Ginsenoside Rb3 in the Treatment of Acute Myocardial Infarction

Background: Ginsenoside Rb3 (GSRb3) is a traditional Chinese medicine monomer. We aim to investigate the effects of GSRb3 on the proliferation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and the reparative effects of PLGA-PEG-PLGA thermosensitive hydrogel loaded with hiPSC-CMs and GSRb3 (NP GSRb3 @Gel+iCM) on myocardial infarction (MI). Methods: 1. Western Blot, RT-qPCR, cell immunofluorescence staining, and CCK-8 assays were employed to assess the proliferative effects of different concentrations of GSRb3 on neonatal mouse primary cardiomyocytes (NCMs) and hiPSC-CMs. 2. Transcriptomic gene sequencing technology was utilized to investigate the mRNA expression changes of hiPSC-CMs induced by GSRb3; The NP GSRb3 @Gel+iCM was injected into the left ventricular myocardium of the MI mice; the same volume injections of hiPSC-CMs (iCM group) and PLGA-PEG-PLGA thermosensitive hydrogel loaded with GSRb3 (NP GSRb3 @Gel group) served as control; Additionally, MI model group without additional treatment and sham group were established. 3. At 4 weeks post-MI, echocardiography, Sirius Red/Fast Green staining and immunofluorescence staining were utilized to evaluate the heart function, infarction size and survival rate of transplanted hiPSC-CMs. Results: GSRb3 inhibit the apoptosis of NCMs while promote proliferation of NCMs and hiPSC-CMs significantly. After 4 weeks of treatment, the engraftment rate of hiPSC-CMs in NP GSRb3 @Gel+iCM group (36.7%) was 4.8 times that of iCM group (7.7%); Compared to the MI group, NP GSRb3 @Gel group and iCM group, NP GSRb3 @Gel+iCM group showed significant improvement in cardiac function; The myocardial repair effect in NP GSRb3 @Gel+iCM group was significantly superior to NP GSRb3 @Gel group and iCM group, with a 47% reduction in infarct size compared to MI group, and further reduction in left ventricular anterior wall thickness compared to NP GSRb3 @Gel group and iCM group. Conclusion: GSRb3 promotes the proliferation of hiPSC-CMs both in vitro and in vivo. NP GSRb3 @Gel+iCM significantly increase the engraftment of hiPSC-CMs, promote angiogenesis, reduce infarction size, inhibit left ventricular remodeling and improve cardiac function.

Abstract 4137267: A novel reproducible low-cost model of acute myocardial infarction in swine

Background: Traditional open- and closed-chest methods for inducing acute myocardial infarction (AMI) in pigs typically require extensive and expensive instrumentation, including ventilators and inhalation anesthesia. This study aims to evaluate a reproducible and low-cost model for AMI in pigs using lower hemisternotomy. Methods: Twenty Yorkshire swine (15-20 kg, 45-50 days of age) underwent permanent ligation of the roots of the first and second diagonal branches of the left anterior descending coronary artery. The procedure was performed under intramuscular anesthesia (1ml 0.5mg/kg Zoletil™ and 2ml 10mg/kg xylazine hydrochloride) with spontaneous respiration. Cardiac function was assessed via echocardiography and cardiac PET/MRI scans at 1 and 4 weeks post-MI. Heart tissue was collected for pathological analysis to evaluate the establishment of the AMI model. Results: All animals exhibited ECG changes, including premature ventricular complexes and ST-segment elevation immediately after ligation. No ventricular tachycardia and fibrillation was observed during the operation. No animals (0%) died during infarct creation. The "Skin-to-Skin" procedure time was 18±3.3 minutes. this procedure produced an infarction that occupies ~10% of the left ventricular mass accompanied with the decrease of LV heart function and LV anterior wall thickness 4 weeks post-MI. Conclusions: This novel low-cost technique provides reproducible acute coronary artery occlusion at a selected location with subsequent AMI. It avoids ventilation, inhalation anesthesia, major surgery and does not require expensive instrumentation for intracoronary intervention.