Experimental Myocardial Infarction Research Articles

Thioredoxin 2 protects mice against experimental myocardial infarction

Graphical abstract Experimental Myocardial infarction (MI) using ligation procedure induces cardiac dysfunction, high level of ROS, inflammation, apoptosis, fibrosis and cardiomyocyte (CM) loss. AAV overexpressing human Trx-2, specifically in CM mitochondria improves mouse cardiac function, reduces the size of cardiac infarct, increases the expression of cardiac anti-inflammatory markers, reduces apoptosis and oxidative stress. However, it does not increase CM proliferation. Abstract Introduction and objective Myocardial infarction (MI), which in general results from complications of atherosclerosis, is characterized by high inflammation and cardiomyocytes (CMs) apoptosis and by major loss of CMs. Regeneration of these lost CMs represents a major challenge for MI therapy. The increase of mitochondrial reactive oxygen species (ROS) is involved in cell cycle arrest which can be restarted by hypoxia or in the presence of ROS scavengers. Among ROS scavengers, mitochondrial thioredoxin 2 (Trx-2), an important antioxidant protein, could play a role in the CMs renewal. Method In this study, we investigated the effect of Trx-2 on mouse heart after an experimental MI. Results Trx-2 improves mouse cardiac function, reduces cardiac infarction size and increases the expression of cardiac anti-inflammatory markers. In addition, it reduces apoptosis and oxidative stress in heart tissue of mice after MI but it does not increase CM proliferation in cell culture or in heart tissue. Conclusion Mitochondrial Trx-2 effectively protects against heart infarction, likely via the reduction of oxidative stress, inflammation and apoptosis but not through CM renewal. Significance statement The current study unveils the complexities of MI and highlights mitochondrial Trx-2 role. Post-MI, marked by inflammation, CM apoptosis and significant CM loss. Trx-2 emerges as a vital protector. Its intervention improves mouse cardiac function, reduces infarction size and fosters an anti-inflammatory environment. By uncovering these mechanisms, the study suggests potential therapeutic strategies for oxidative stress, inflammation and apoptosis in MI, positioning Trx-2 as a promising candidate for future cardiac interventions.

Macrophage mediators and mechanisms in cardiovascular disease.

Macrophages are major players in myocardial infarction (MI) and atherosclerosis, two major cardiovascular diseases (CVD). Atherosclerosis is caused by the buildup of cholesterol-rich lipoproteins in blood vessels, causing inflammation, vascular injury, and plaque formation. Plaque rupture or erosion can cause thrombus formation resulting in inadequate blood flow to the heart muscle and MI. Inflammation, particularly driven by macrophages, plays a central role in both atherosclerosis and MI. Recent integrative approaches of single-cell analysis-based classifications in both murine and human atherosclerosis as well as experimental MI showed overlap in origin, diversity, and function of macrophages in the aorta and the heart. We here discuss differences and communalities between macrophages in the heart and aorta at steady state and in atherosclerosis or upon MI. We focus on markers, mediators, and functional states of macrophage subpopulations. Recent trials testing anti-inflammatory agents show a major benefit in reducing the inflammatory burden of CVD patients, but highlight a necessity for a broader understanding of immune cell ontogeny and heterogeneity in CVD. The novel insights into macrophage biology in CVD represent exciting opportunities for the development of novel treatment strategies against CVD.

Peracute Myocardial Infarction: Features of the Influence of α2-Adrenoreceptor Stimulation on the Isolated Heart.

We performed a comparative analysis of the effect of α2-adrenoreceptor stimulation on the performance of Langendorff-isolated heart from rats with experimental myocardial infarction in the acute stage and sham-operated animals (control). In animals with peracute myocardial infarction, different agonist concentrations (clonidine, 10-6 and 10-9 M) produced a multidirectional effect on the left-ventricular developed pressure and speed and time parameters of heart contractility. In control rats, both concentrations of the agonist added to the perfused solution reduced contraction force. Clonidine in a concentration of 10-6 M reduced HR in both groups and in a concentration of 10-9 M, it decreased HR in control rats and caused multidirectional changes in rats with myocardial infarction. The coronary flow decreased in all series of experiments.

The Role of Arterial Elasticity in Determining the Degree of Chronic Heart Failure in Myocardial Infarction.

Aim To study the left ventricular (LV) contractile and pumping function during the recovery phase following ligation of the anterior descending coronary artery (CA).Material and methods Cardiodynamic parameters were studied in Wistar rats 2-4 weeks after experimental myocardial infarction (MI). MI was induced by ligation of the anterior descending CA under zoletil anesthesia. LV catheterization was performed with a standard FTH-1912B-8018 PV catheter inserted into the LV through the right carotid artery.Results After the induction of MI, the mortality rate of animals was 50%. Survived animals developed significant LV dilatation and a decrease in ejection fraction (EF) by an average of 31%. However, major indexes of the pumping function, including minute volume, heart work, and maximum ejection velocity, were within a normal range whereas the maximum filling velocity was almost doubled. Approximately 50% of hearts with dilated LV had normal EF, delayed relaxation, and increased LV diastolic pressure, which qualified this group as a diastolic dysfunction group. The systolic dysfunction group with EF less than 50% of normal had similar values of myocardial contractility and relaxation but differed from the diastolic dysfunction group in more than 50% reduced maximum LV ejection velocity and 1.7 times increased elasticity of the arterial wall. A close inverse correlation was found between these values (r= -0.91).Conclusion The study results showed that, with a similar myocardial contractile function, the cardiac pumping function is determined by the elasticity of the aortic wall. Therefore, restriction of reactive fibrosis during MI is an important task of modern cardiology.

Thioredoxin-1 and its mimetic peptide improve systolic cardiac function and remodeling after myocardial infarction.

Myocardial infarction (MI) is characterized by a significant loss of cardiomyocytes (CMs), and it is suggested that reactive oxygen species (ROS) are involved in cell cycle arrest, leading to impaired CM renewal. Thioredoxin-1 (Trx-1) scavenges ROS and may play a role in restoring CM renewal. However, the truncated form of Trx-1, Trx-80, can compromise its efficacy by exerting antagonistic effects. Therefore, a Trx-1 mimetic peptide called CB3 was tested as an alternative way to restore CMs. This study aimed to investigate the effects of Trx-1, Trx-80, and CB3 on mice with experimental MI and study the underlying mechanism of CB3 on CMs. Mouse cardiac parameters were quantified by echocardiography, and infarction size and fibrosis determined using Trichrome and Picro-Sirius Red staining. The study found that Trx-1 and CB3 improved mouse cardiac function, reduced the size of cardiac infarct and fibrosis, and decreased the expression of cardiac inflammatory markers. Furthermore, CB3 polarized macrophages into M2 phenotype, reduced apoptosis and oxidative stress after MI, and increased CM proliferation in cell culture and invivo. CB3 effectively protected against myocardial infarction and could represent a new class of compounds for treating MI.

Differential expression and implication of m6A methylation in mice with experimental myocardial infarction

Objective: To define differentially expressed N6-adenylate methylation (m6A) genes in the myocardial tissue of mice with myocardial infarction (MI) and explore its potential impact on the pathological process of MI. Methods: The random number table method was used to divide the eighteen SPF C57BL/6J male mice aged from 8 to 10 weeks into MI group (MI group, n=9) and control group (control group, n=9). Modified m6A genes from the myocardial tissue were detected via methylated RNA immunoprecipitation with the next generation sequencing (MeRIP-seq). We explored methylation modified characteristics, verified mRNA expression and m6A modified level by bioinformatics analysis, qPCR and MeRIP-qPCR. Results: The Heatmap revealed that 901 differentially modified m6A genes between MI and control group, of which 537 genes were upregulated, and 364 genes were downregulated. The principal component analysis affirmed that two groups could be distinguished significantly in terms of m6A gene modification. The characteristic sequence of m6A modification was GGACU and mainly concentrated in the coding sequence. According to the conjoint analysis with RNA-seq and MeRIP-seq, 119 genes expressed simultaneous m6A modification difference and mRNA expression difference. The Venn diagram exhibited the positive and negative correlation between m6A modification and mRNA expression. Besides, the GO enrichment analysis indicated that the genes with m6A differential modification in MI group were mainly involved in heart development and other processes. qPCR verified that Gbp6 was up-regulated, while Dnaja1 and Dnajb1 were down-regulated. MeRIP-qPCR revealed that the m6A modification level of Hspa1b was downregulated. Conclusion: Myocardial infarction induces differential modification of m6A in the mice model. In addition, the genes with m6A modification may be affected by methylation related enzymes, thus participating the pathogenesis of MI by regulating apoptosis and inflammation.

Cardiosphere derived cell secretome therapy after experimental myocardial infarction: effects of intracoronary administration on ventricular tachycardia inducibility and cardiac function

Abstract Background Myocardial infarction (MI) carries high risk of sudden cardiac death due to the development of ventricular tachycardia (VT) which is caused by viable myocytes located within the infarct scar tissue [1]. Cardiosphere derived cell secretome (S-CDCs) has been demonstrated to possess antiarrhythmic properties when delivered transendocardially [2]. Further, S-CDCs has been proven to reduce scar size and increase viable myocardial mass in chronic MI [3]. Purpose The objective of this study was to evaluate the effects of an intracoronary (IC) administration of S-CDCs on VT inducibility and cardiac function in a porcine MI model. Methods After obtaining the approval of the Institutional Animal Care and Use Committee, 14 Large White swine were subjected to closed chest MI induction carrying out balloon occlusion of the left anterior descending coronary artery (below the second diagonal branch) for 150 minutes. One month after MI creation, pigs received an IC administration of saline (CON; 5mL; n=7) or S-CDCs (S-CDCs; 9.16 mg of protein in 5mL of saline; n=7). VT inducibility and magnetic resonance (MR) studies were performed pre- and four months post-injection determining ejection fraction (EF), infarct size (IS) and indexed end diastolic and systolic volumes (EDVi, ESVi). Results Before injection VT was inducible in all cases and no differences were observed between groups in any MR-derived parameter (figure). IC infusion was successful in all swine. At four months VT inducibility study revealed lower inducibility rates in S-CDCs compared to CON (57% versus 100%; p=0.05). At this timepoint EF was higher in S-CDCs (35±10% versus 29±10%) although differences between groups were not statistically significant. Conversely, IS was significantly lower in S-CDCs (12±3% versus 16±2% (p=0.03)). Moreover, a trend towards lower ventricular volumes (EDVi: 83±18mL/m² versus 88±29mL/m² and ESVi: 56±20mL/m² versus 64±27mL/m²) was detected in this group. Conclusions The IC administration of S-CDCs suggests a potential reduction on post-MI VT development as well as a beneficial effect on cardiac function. This therapy seems to reduce IS in this porcine MI model.MR derived parameters

Platelet-derived microRNAs play a pivotal role in cardiac remodeling after myocardial ischemia and reperfusion

Abstract Background Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of miRNAs, which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate, that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions. Purpose The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R. Methods and Results Combining an in vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (LSFM, PET&MRI, speckle-tracking echocardiography), in vitro immune cell migration assays and Next-generation deep sequencing analysis of platelet miRNA expression pattern in mice with a MK/platelet-specific knockout of pre-miRNA processing ribonuclease Dicer, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating LV remodeling after myocardial I/R following transient LCA ligation. Disruption of the miRNA processing machinery in platelets by deletion of Dicer resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial ischemia and reperfusion. Worsened cardiac remodeling after myocardial infarction (MI) in mice with a platelet-specific Dicer deletion (Dicer Pf4Δ/PfΔ4) resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at d28 post-MI. Altogether, these observations culminated in an impaired LV function and hampered long-term cardiac recovery after experimental MI and reperfusion therapy. Treatment with the P2Y12 antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in Dicer Pf4Δ/Pf4Δ mice. Conclusions The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial ischemia and reperfusion.

Efficacy of Empagliflozin in the Treatment of Experimental Myocardial Infarction

Introduction. With the emergence of empagliflozin in the pharmaceutical market, there has been an increase in publications on the primary and secondary pharmacodynamics of the drug, and the list of potential indications for the use of this sodium-glucose co-transporter inhibitor is increasing. Hypotheses about pharmacological effects and mechanisms of their implementation are tested both in large-scale clinical studies and in animal experiments.Aim. The purpose of this work was to study the effectiveness of empagliflozin by echocardiographic, histological and molecular biological analyses at the three most significant points of the dynamic transition from acute myocardial infarction to post-infarction chronic heart failure in laboratory male rats.Materials and methods. The experiment was performed on 60 male outbred rats. Myocardial infarction was modeled in narcotic animals by permanent ligation of the left coronary artery. Based on echocardiographic (EchoCG) study data, animals were randomized to two groups: control infarction: untreated pathology group treated with placebo and pathology group treated with empagliflozin 1 mg/kg per os intragastric daily from the first day of the experiment. At 10, 20 and 30 days after the operation, the animals were also subjected to EchoCG testing, and a group of 10 animals from each group were euthanized for histological examination and molecular analysis.Results and discussion. Empagliflozin use in animals after myocardial infarction modeling contributed to a significant increase in myocardial performance on days 10, 20 and 30, reaching a maximum on day 20 (47.58 ± 1.87 %). The drug promotes long-term preservation of the area of damage to the heart muscle with early formation of mature connective tissue, and also increases myocardial resistance to hypoxia by increasing the amount of HIF-1.Conclusion. Based on the studies carried out, it can be concluded that it is possible to use the sodium-glucose cotransporter type 2 empagliflozin in the formation of post-infarction chronic heart failure in the conditions of normoglycemia.

Abstract 14278: 14 Days of Severe, Sustained Normobaric Hypoxic Enhances Left Ventricular Contractility in Patients After Myocardial Infarction

Studies in mice with experimental myocardial infarction revealed, that sustained severe normobaric hypoxia (FiO2=0.07) reactivates cardiomyocyte proliferation and improves left ventricular ejection fraction. Our study aimed to test safety and feasibility in humans and to assess whether hypoxia improves left ventricular contractility in selected patients with myocardial scars following myocardial infarction.Three males, who suffered myocardial infarction 49-126 months prior to study entry, whose capability for hypoxia acclimatization was validated previously and one healthy male control participated in this proof-of-concept study. After preacclimatization we induced severe hypoxia by adding nitrogen until alveolar oxygen partial pressure reached about 35 mmHg. Hypoxia was maintained for 14 consecutive days (FiO2=0.095) and nights (FiO2=0.105). We assessed ventricular function by echocardiographic-derived global longitudinal strain (LVGLS), serum NTproBNP, high-sensitive Troponin I levels, and marker of myocardial repair. Cardiac 18F-FDG-PET-MRI was done at baseline, end of hypoxia exposure, and at 30 days follow-up. LVGLS increased in prior viable myocardium, but also in areas adjacent to the myocardial scar (baseline: -12.57±2.4 %, end of hypoxia: -14.37±2.62% recovery day 3: -14.33±2.72%, 30 days follow-up: -15.2±3.11%, p=0.0182). NTproBNP tended to decrease (baseline: 189±134 pg/ml, end of hypoxia: 127±28 pg/ml, recovery day 3: 114±18 pg/ml, 30 days follow-up: 108±65 pg/ml). These parameters were not affected in the control. MRI-derived left ventricular enddiastolic volume remained unchanged, but end-systolic left ventricular volume decreased in patients (baseline: 108±49 ml, recovery day 3: 92±50 ml, 30 days follow-up: 101±47 ml, p=0.0068). Troponin I remained in the reference range in all participants. The patient with the most pronounced increase in LVGLS revealed a relevant increase in FDG-uptake at the follow-up, which was also observed in areas adjacent to the myocardial scar.Given the small sample size and the selection of patients, our results have to be interpreted with caution. However, the data indicate potentially beneficial hypoxia-mediated effects in selected patients with ischemic heart disease.

Abstract 16744: Antibody Responses to Myocardial Antigens Released in the Context of a Myocardial Infarction

Our study aims to investigate antigen-specific B cell responses after myocardial infarction. Recent research has indicated that B cells and myocardial antibodies may contribute to the development of ischemic heart failure and dampen post-myocardial infarction repair. However, the antigen specificity of these myocardial antibodies remains unknown. To produce high-affinity antibodies, B cells typically undergo multiple rounds of somatic hypermutation and selection processes within the germinal center (GC) reactions of secondary lymphoid organs. Therefore, we sought to characterize the germinal center B cell responses and to examine the repertoire of B cell receptors (BCR) in C57BL/6J mice subjected to experimental myocardial infarction. Flow cytometry analyses showed increased frequencies of GC B cells in infarcted mice at 5 and 14 days post-surgery. However, sham-operated mice also showed similar increase in GC frequencies on day 14 post-surgery. Single-cell RNA/BCR sequencing analyses enabled the identification of GC B cell and plasma cell (antibody secreting) populations expressing unique B cell receptors in infarcted mice that were not found in sham-operated mice. Over time, the number of GC B cells increased accompanied by a progressive clonal expansion, indicating the development of antigen-driven B cell responses. By examining immunoglobulin variable gene rearrangements within single B cells, we identified distinct B cell lineages expressing mutated antigen receptors suggestive of affinity maturation. Selected BCRs of interested were then cloned into immunoglobulin expression vectors and expressed in immortalized human embryonic kidney cells. When incubated with histological myocardial slices, one of these unique BCR expressed showed binding to myocardial antigens. These findings support the notion that myocardial infarction can trigger germinal center B cell responses, which then lead to the production of high-affinity heart-specific antibodies. Moreover, the ‘track-and-clone’ approach herein described could help unraveling the antigen specificity and functional significance of these myocardial antibodies.

Myocardial infarction elevates endoplasmic reticulum stress and protein aggregation in heart as well as brain

Cardiovascular diseases, including myocardial infarction (MI), constitute the leading cause of morbidity and mortality worldwide. Protein-aggregate deposition is a hallmark of aging and neurodegeneration. Our previous study reported that aggregation is strikingly elevated in hearts of hypertensive and aged mice; however, no prior study has addressed MI effects on aggregation in heart or brain. Here, we present novel data on heart and brain aggregation in mice following experimental MI, induced by left coronary artery (LCA) ligation. Infarcted and peri-infarcted heart tissue, and whole cerebra, were isolated from mice at sacrifice, 7 days following LCA ligation. Sham-MI mice (identical surgery without ligation) served as controls. We purified detergent-insoluble aggregates from these tissues, and quantified key protein constituents by high-resolution mass spectrometry (LC–MS/MS). Infarct heart tissue had 2.5- to 10-fold more aggregates than non-infarct or sham-MI heart tissue (each P = 0.001). Protein constituents from MI cerebral aggregates overlapped substantially with those from human Alzheimer’s disease brain. Prior injection of mice with mesenchymal stem cell (MSC) exosomes, shown to limit infarct size after LCA ligation, reduced cardiac aggregation ~ 60%, and attenuated markers of endoplasmic reticulum (ER) stress in heart and brain (GRP78, ATF6, P-PERK) by 50–75%. MI also elevated aggregate constituents enriched in Alzheimer’s disease (AD) aggregates, such as proteasomal subunits, heat-shock proteins, complement C3, clusterin/ApoJ, and other apolipoproteins. These data provide novel evidence that aggregation is elevated in mouse hearts and brains after myocardial ischemia, leading to cognitive impairment resembling AD, but can be attenuated by exosomes or drug (CDN1163) interventions that oppose ER stress.

Cardiomyocyte precursors generated by direct reprogramming and molecular beacon selection attenuate ventricular remodeling after experimental myocardial infarction

BackgroundDirect cardiac reprogramming is currently being investigated for the generation of cells with a true cardiomyocyte (CM) phenotype. Based on the original approach of cardiac transcription factor-induced reprogramming of fibroblasts into CM-like cells, various modifications of that strategy have been developed. However, they uniformly suffer from poor reprogramming efficacy and a lack of translational tools for target cell expansion and purification. Therefore, our group has developed a unique approach to generate proliferative cells with a pre-CM phenotype that can be expanded in vitro to yield substantial cell doses.MethodsCardiac fibroblasts were reprogrammed toward CM fate using lentiviral transduction of cardiac transcriptions factors (GATA4, MEF2C, TBX5, and MYOCD). The resulting cellular phenotype was analyzed by RNA sequencing and immunocytology. Live target cells were purified based on intracellular CM marker expression using molecular beacon technology and fluorescence-activated cell sorting. CM commitment was assessed using 5-azacytidine-based differentiation assays and the therapeutic effect was evaluated in a mouse model of acute myocardial infarction using echocardiography and histology. The cellular secretome was analyzed using mass spectrometry.ResultsWe found that proliferative CM precursor-like cells were part of the phenotype spectrum arising during direct reprogramming of fibroblasts toward CMs. These induced CM precursors (iCMPs) expressed CPC- and CM-specific proteins and were selectable via hairpin-shaped oligonucleotide hybridization probes targeting Myh6/7-mRNA–expressing cells. After purification, iCMPs were capable of extensive expansion, with preserved phenotype when under ascorbic acid supplementation, and gave rise to CM-like cells with organized sarcomeres in differentiation assays. When transplanted into infarcted mouse hearts, iCMPs prevented CM loss, attenuated fibrotic scarring, and preserved ventricular function, which can in part be attributed to their substantial secretion of factors with documented beneficial effect on cardiac repair.ConclusionsFibroblast reprogramming combined with molecular beacon-based cell selection yields an iCMP-like cell population with cardioprotective potential. Further studies are needed to elucidate mechanism-of-action and translational potential.Graphical

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1−/−) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3–6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Contrast-enhanced cardiac MRI is superior to non-contrast mapping to predict left ventricular remodeling at 6 months after acute myocardial infarction

ObjectivesParametric mapping constitutes a novel cardiac magnetic resonance (CMR) technique enabling quantitative assessment of pathologic alterations of left ventricular (LV) myocardium. This study aimed to investigate the clinical utility of mapping techniques with and without contrast agent compared to standard CMR to predict adverse LV remodeling following acute myocardial infarction (AMI).Materials and methodsA post hoc analysis was performed on sixty-four consecutively enrolled patients (57 ± 12 years, 54 men) with first-time reperfused AMI. Baseline CMR was obtained at 8 ± 5 days post-AMI, and follow-up CMR at 6 ± 1.4 months. T1/T2 mapping, T2-weighted, and late gadolinium enhancement (LGE) acquisitions were performed at baseline and cine imaging was used to determine adverse LV remodeling, defined as end-diastolic volume increase by 20% at 6 months.ResultsA total of 11 (17%) patients developed adverse LV remodeling. At baseline, patients with LV remodeling showed larger edema (30 ± 11 vs. 22 ± 10%LV; p < 0.05), infarct size (24 ± 11 vs. 14 ± 8%LV; p < 0.001), extracellular volume (ECVinfarct; 63 ± 12 vs. 47 ± 11%; p < 0.001), and native T2infarct (95 ± 16 vs. 78 ± 17 ms; p < 0.01). ECVinfarct and infarct size by LGE were the best predictors of LV remodeling with areas under the curve (AUCs) of 0.843 and 0.789, respectively (all p < 0.01). Native T1infarct had the lowest AUC of 0.549 (p = 0.668) and was inferior to edema size by T2-weighted imaging (AUC = 0.720; p < 0.05) and native T2infarct (AUC = 0.766; p < 0.01).ConclusionIn this study, ECVinfarct and infarct size by LGE were the best predictors for the development of LV remodeling within 6 months after AMI, with a better discriminative performance than non-contrast mapping CMR.Clinical relevance statementThis study demonstrates the predictive value of contrast-enhanced and non-contrast as well as conventional and novel CMR techniques for the development of LV remodeling following AMI, which might help define precise CMR endpoints in experimental and clinical myocardial infarction trials.Key Points• Multiparametric CMR provides insights into left ventricular remodeling at 6 months following an acute myocardial infarction.• Extracellular volume fraction and infarct size are the best predictors for adverse left ventricular remodeling.• Contrast-enhanced T1 mapping has a better predictive performance than non-contrast standard CMR and T1/T2 mapping.

In an experimental myocardial infarction model, L-arginine pre-intervention may exert cardioprotective effects by regulating OTULIN levels and mitochondrial dynamics.

The experimental myocardial infarction (MI) model originating from isoproterenol (ISO) is frequently preferred in research due to its similarity to MI-induced damage in humans. Beneficial effects of L-arginine (L-Arg), a semi-essential amino acid, in cardiovascular diseases have been shown in many studies. This study was carried out to determine whether L-Arg pre-intervention has protective effects on heart tissue in the experimental MI model. The 28 rats used in the study were randomly divided into 4 equal groups: control, L-Arg, ISO, and L-Arg+ISO. Upon completion of all applications, cardiac markers in serum and biochemical, histopathological, and immunohistochemical examinations in cardiac tissues were performed. Cardiac markers, histopathological changes, oxidative stress, inflammation, and apoptosis were increased in the experimental MI model. In addition, administration of ISO deregulated OTULIN levels and mitochondrial dynamics in heart tissue. However, L-Arg pre-intervention showed a significant protective effect against changes in ISO-induced MI. L-Arg supplementation with cardioprotective effect may reduce the risks of possible pathophysiological processes in MI.

Mitigation of Fibrosis after Myocardial Infarction in Rats by Using a Porcine Cholecyst Extracellular Matrix.

Fibrosis that occurs after nonfatal myocardial infarction (MI) is an irreversible reparative cardiac tissue remodeling process characterized by progressive deposition of highly cross-linked type I collagen. No currently available therapeutic strategy prevents or reverses MI-associated fibrotic scarring of myocardium. In this study, we used an epicardial graft prepared of porcine cholecystic extracellular matrix to treat experimental nonfatal MI in rats. Graft-assisted healing was characterized by reduced fibrosis, with scanty deposition of type I collagen. Histologically, the tissue response was associated with a favorable regenerative reaction predominated by CD4-positive helper T lymphocytes, enhanced angiogenesis, and infiltration of proliferating cells. These observations indicate that porcine cholecystic extracellular matrix delayed the fibrotic reaction and support its use as a potential biomaterial for mitigating fibrosis after MI. Delaying the progression of cardiac tissue remodeling may widen the therapeutic window for management of scarring after MI.

The protective effects of humanin in rats with experimental myocardial infarction: The role of asprosin and spexin

ObjectiveIn this study, by applying humanin (HN) before myocardial infarction (MI) in rats, its protection in MI and the possible roles in asprosin and spexin were investigated. Materials and methodsThe rats were divided into 7 groups each with 6 rats (group I (control), group II (HN 48th hour), group III (HN 7th day), group IV (MI 48th hour), group V (MI 7th day), group VI (MI + HN 48th hour), group VII (MI + HN 7th day). To create MI, 200 mg/kg isoproterenol (ISO) was administered subcutaneously to the rats. 2 mg/kg HN was given intraperitoneally (ip) to rats alone and before MI. Molecular parameters asprosin and spexin were examined by immunohistochemical in heart tissue. Biochemical parameters (aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), Troponin I) were studied in serum by enzyme-linked immunosorbent assay (ELISA) method. ResultsIt was found in the study that the levels of spexin elevated especially towards the 7th day after MI and decreased more significantly towards the 7th day, after HN application before MI. Asprosin elevated significantly towards the 7th day after MI and decreased especially on the 7th day after HN application before MI. Also, serum AST, LDH, CK-MB, and Troponin I levels tended to decrease and a significant decrease was detected in congested veins in the heart tissue at the 48th hour of MI and erythrocyte extravasation, congested veins and necrotic muscle fibers at the 7th day of MI in rats given HN before MI. ConclusionIt was concluded that HN has a cardioprotective effect in MI and asprosin and spexin might mediate this effect.

Comparative Cardioprotective Effect of Herbs of Hridya dashemani (Karamarda- Carissa carandas L., Badara- Ziziphus jujuba Lam.) versus Arjuna-Terminalia arjuna (Roxb.ex.DC.) Wight&amp;Arn. against Isoprenaline induced Myocardial Infarction in Rats

Hridya dashemani (ten cardioprotective herbs) includes fruits of Amra, Amrataka, Lakucha, Karamarda, Vrukshamla, Amlavetasa, Kuvala, Badara, Dadima and Matulunga. In Ayurveda, these herbs have been known to be conducive to heart. The present study was designed to evaluate the cardioprotective action of two herbs of Hridya dashemani fruits of Karamarda (Carissa carandas L.) and fruits of Badara (Ziziphus jujuba Lam.)] on the basis of biochemical&amp;histopathological parameters in isoprenaline (ISO) induced myocardial infarction (MI) in experimental rats and to compare with stem bark of Arjuna (Terminalia arjuna (Roxb.ex.DC.) Wight&amp;Arn.), a well-known cardioprotective herb. Total 36 male wistar albino rats were randomly divided into six groups. Group I- normal control (NC), group II- ISO induced MI, group IIIpositive control with hesperidin (100 mg/kg b.w), group IV- Badara (Z. jujuba – 450 mg/kg b.w), group V- Karamarda (C. carandus – 450 mg/kg b.w), group VI- Arjuna (T. arjuna – 450 mg/kg b.w). After 21 days of pre-treatment, experimental MI was induced in all groups except NC by injecting ISO subcutaneously (85 mg/kg) on 19th&amp;20th day at an interval of 24 hours. Serum biochemical parameters, including cardiac biomarkers and histopathological examination of heart tissues were evaluated. ISO treated rats had a significant (p &lt; 0.05) elevation in serum levels of diagnostic marker enzymes (AST, ALT, CK-MB, LDH, ALP) when compared to NC. All the pre-treated groups had significantly (p &lt; 0.05) reduced marker enzyme serum levels compared to the ISO treated control. The protective role of these herbs was further confirmed by histopathological examination. The comparison revealed that Karamarda (C. carandus) pre-treated had similar protective effect as Arjuna (T. arjuna) in various biochemical parameters (AST, ALT, ALP, LDH, CK-MB, HDL, cholesterol, creatinine). It may be concluded from the present study that 450 mg/kg b.w of water extract of the above herbs have cardioprotective action against isoprenaline induced MI, with Karamarda (C. carandus), Arjuna (T. arjuna) having almost similar effects. The study paves way to further evaluate these herbs as preventive and curative in cardiovascular disease (CVD) clinical management.

Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion.

Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine. In a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing. As compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = -2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC. Intracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.