Chronic MI Research Articles

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 miRNAs: differential expression in coronary artery disease and associations with course of left ventricular systolic function

BackgroundMicroRNAs are paramount in post transcriptional gene regulation. We investigated platelet miRNAs in patients with CAD and examined potential associations with course of left ventricular ejection fraction (LVEF%).Materials and methodsIn a first cohort, 62 MiRNAs were measured in platelets of 100 patients suffering from CAD. Expression profiles of individuals with chronic coronary syndrome (CCS) and MI were compared (CCS n = 67, MI n = 33). Also, associations between miRNA profiles and change in left ventricular ejection fraction (LVEF%) were investigated. In a second cohort of patients suffering from CCS (n = 10), MI (n = 11) or no CAD (n = 13), we measured miRNA expression in platelets, platelet supernatant and serum. This was carried out before and after in vitro platelet activation with CRP.ResultsPlatelet miRNAs 103a-3p and 155-5p demonstrated higher expression in patients with CCS then in individuals with MI. Furthermore, multiple miRNAs were significantly higher expressed in matched controls compared to MI patients. 8 miRNAs showed higher expression in patients with improving LVEF% after a 1-year follow-up. In our second cohort, we found higher concentrations of 6 miRNAs in the platelet supernatant of patients with CCS, MI and no CAD after in vitro platelet activation. Most of these miRNAs showed a higher abundance in serum of MI patients as compared to CCS.ConclusionSeveral miRNAs show higher expression in platelets of CCS compared to MI. After in vitro platelet activation, a release of multiple miRNAs out of the thrombocyte was observed. Furthermore, upregulation of serum miRNAs was found in MI patients when compared to CCS patients and individuals without CAD. Hence, platelets could present a source of upregulated circulating miRNAs in MI and additionally affect course of LVEF%.

Anatomy of the isthmus: unraveling tissue composition of ventricular tachycardia diastolic pathway

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation Background Unequal tissue composition of post-myocardial infarction (MI) scar (viable myocardium, fibrosis, fatty infiltration) leads to heterogeneous conduction properties and excitability. The presence of a protected diastolic, slow-conducting pathway (isthmus) is the electrophysiological landmark of post-MI reentrant ventricular tachycardia (VT). Contemporary histological studies evaluating the tissue features needed for slow, protected conduction during VT are lacking. Purpose To characterize tissue composition singularities of confirmed VT isthmuses (VTI) in a chronic MI swine model, and to compare it to non-isthmus scar (NIS). Methods One-month after a non-reperfused anterior MI, 9 Landrace X Large White pigs (4 female; 33.6±2.2 Kg) with inducible VT underwent high-density activation mapping to define the diastolic corridor. VTI was defined as part of the diastolic pathway exhibiting mid-diastolic potentials. Discrete radiofrequency applications were delivered in the vicinity of the VTI and used as tissue landmarks to guide the ex vivo isthmus localization. Tissue transverse samples (5 mm) from the labelled VTI and NIS were obtained for further histological and immunohistochemical analysis. Dense scar and border zones were analyzed. Results Compared to NIS, border zone of VTI showed significantly higher fatty infiltration (p=0.016) and dense scar displayed less Collagen I (p=0.053), Collagen III (p=0.043), and Collagen Volume Fraction (p=0.027), without differences in the overall fibrotic deposition (P=0.119). Immunohistochemical studies revealed greater vascular density (Isolectin B4-positive vessels) at VTI, compared to NIS (p=0.018). Arteries and veins at the VTI were mostly surrounded by preserved cardiomyocytes (figure 1). Viable cardiomyocytes and fibroblasts at VTI displayed higher density of Cx43 and Cx40, respectively, compared to those at NIS (p=0.022 and p=0.004, respectively), despite no differences in cTnI, SERCA2 and Vimentin expression (figure 2). Conclusion The VTI exhibits distinctive tissue features compared to NIS. Unique electrophysiological properties of the VTI may be driven by increased adipocytic deposition, vascular density and Cx43/Cx40 expression, as well as lower presence of Collagen III and Collagen Volume Fraction.

CE-452773-4 ANATOMY OF THE ISTHMUS: UNRAVELING TISSUE COMPOSITION OF VENTRICULAR TACHYCARDIA DIASTOLIC PATHWAY

Unequal tissue composition of post-myocardial infarction (MI) scar (viable myocardium, fibrosis, fatty infiltration) leads to heterogeneous conduction properties and excitability. The presence of a protected diastolic, slow-conducting pathway (isthmus) is the electrophysiological landmark of post-MI reentrant ventricular tachycardia (VT). Contemporary histological studies evaluating the tissue features needed for slow, protected conduction during VT are lacking. To characterize tissue composition singularities of confirmed VT isthmuses (VTI) in a chronic MI swine model, and to compare it to non-isthmus scar (NIS). One-month after a non-reperfused anterior MI, 9 Landrace X Large White pigs (4 female; 33.6±2.2 Kg) with inducible VT underwent high-density activation mapping to define the diastolic corridor. VTI was defined as part of the diastolic pathway exhibiting mid-diastolic potentials. Discrete radiofrequency applications were delivered in the vicinity of the VTI and used as tissue landmarks to guide the ex vivo isthmus localization. Tissue transverse samples (5 mm) from the labelled VTI and NIS were obtained for further histological and immunohistochemical analysis. Dense scar and border zones were analyzed. Compared to NIS, border zone of VTI showed significantly higher fatty infiltration (p=0.016) and dense scar displayed less Collagen I (p=0.053), Collagen III (p=0.043), and Collagen Volume Fraction (p=0.027), without differences in the overall fibrotic deposition (P=0.119). Immunohistochemical studies revealed greater vascular density (Isolectin B4-positive vessels) at VTI, compared to NIS (p=0.018). Arteries and veins at the VTI were mostly surrounded by preserved cardiomyocytes (figure). Viable cardiomyocytes and fibroblasts at VTI displayed higher density of Cx43 and Cx40, respectively, compared to those at NIS (p=0.022 and p=0.004, respectively), despite no differences in cTnI, SERCA2 and Vimentin expression. The VTI exhibits distinctive tissue features compared to NIS. Unique electrophysiological properties of the VTI may be driven by increased adipocytic deposition, vascular density and Cx43/Cx40 expression, as well as lower presence of Collagen III and Collagen Volume Fraction.

Temporal lipid profiling in the progression from acute to chronic heart failure in mice and ischemic human hearts

Background and aimsMyocardial infarction (MI) is a leading cause of heart failure (HF). After MI, lipids undergo several phasic changes implicated in cardiac repair if inflammation resolves on time. However, if inflammation continues, that leads to end stage HF progression and development. Numerous studies have analyzed the traditional risk factors; however, temporal lipidomics data for human and animal models are limited. Thus, we aimed to obtain sequential lipid profiling from acute to chronic HF. MethodsHere, we report the comprehensive lipidome of the hearts from diseased and healthy subjects. To induce heart failure in mice, we used a non-reperfused model of coronary ligation, and MI was confirmed by echocardiography and histology, then temporal kinetics of lipids in different tissues (heart, spleen, kidney), and plasma was quantitated from heart failure mice and compared with naïve controls. For lipid analysis in mouse and human samples, untargeted liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (LC-LTQ-Orbitrap MS) was performed. ResultsIn humans, multivariate analysis revealed distinct cardiac lipid profiles between healthy and ischemic subjects, with 16 lipid species significantly downregulated by 5-fold, mainly phosphatidylethanolamines (PE), in the ischemic heart. In contrast, PE levels were markedly increased in mouse tissues and plasma in chronic MI, indicating possible cardiac remodeling. Further, fold change analysis revealed site-specific lipid biomarkers for acute and chronic HF. A significant decrease in sulfatides (SHexCer (34:1; 2O)) and sphingomyelins (SM (d18:1/16:0)) was observed in mouse tissues and plasma in chronic HF. ConclusionsOverall, a significant decreased lipidome in human ischemic LV and differential lipid metabolites in the transition of acute to chronic HF with inter-organ communication could provide novel insights into targeting integrative pathways for the early diagnosis or development of novel therapeutics to delay/prevent HF.

Abstract 9835: Multi-Modality Imaging Assessment of Microbubbles and Cerebral Emboli in Left Ventricular Pulsed Field Ablation

Introduction: Pulsed field ablation (PFA) may have a superior safety profile compared to other ablation technologies, but the high-voltage electrical fields have the potential to cause gaseous microbubbles (MB), which may be associated with cerebral emboli. In this study, we evaluate the MB burden of a monopolar, biphasic PFA system (CENTAURI, Galaxy Medical), that delivers a waveform designed to limit MB generation. Methods: After anticoagulation with heparin, healthy and chronic MI swine (30 day survival after 90 minute coronary balloon occlusion) underwent PFA in the LV using an open-irrigated focal catheter under intra-cardiac echocardiography (ICE) guidance and monitoring of MBs. Two additional healthy control swine received 0.5 and 1 ml of air MBs through the lumen of the ablation catheter. Swine underwent brain MRI before and after PFA (or control air MB injection) with T1, T2, FLAIR, ADC and susceptibility- and diffusion-weighted imaging (DWI) interpreted by a neuroradiologist blinded to treatment group. Gross pathology and histology of brains with any MRI findings was performed by a neuropathologist. Results: Four healthy swine underwent 50 PFA applications and 5 chronic MI swine underwent 74 applications. No PFA-related MB formation was noted on ICE. Both control swine developed multiple acute emboli in the left thalamus and caudate on DWI, ADC and FLAIR brain MRI sequences in response to air MB injection (Figure). Of the 9 PFA swine, there were no ADC nor FLAIR sequence abnormalities. There was one instance of a hyperintense focus in the left putamen on the DWI trace image, but absence of ADC or FLAIR affirmation suggested it was artifact. Gross pathology and histopathology of this region did not detect any abnormalities (Figure). Conclusion: Catheter air MB injection caused MR-detectable cerebral emboli in swine. Focal monopolar biphasic PFA with CENTAURI does not generate MBs observable on ICE, and did not cause cerebral emboli in healthy or post-infarct LVs.

Chronic mitochondrial fusion promotor as a novel pharmacological intervention to alleviate left ventricular dysfunction in rats with chronic myocardial infarction

Abstract Background Decreased cardiac mitochondrial fusion associated with increased mitochondrial dysfunction has been demonstrated in acute myocardial infarction pathology. However, whether this pathophysiologic process is associated with myocardial injury in chronic myocardial infarction (CMI) is still unclear. Recently, a novel pharmacological intervention to promote mitochondrial fusion using mitochondrial fusion promotor-M1 (M1) has been shown to exert cardioprotection against myocardial ischemia and reperfusion injury. However, the roles of M1 in CMI has never been investigated. Purpose We investigated the potential cardioprotective benefits of chronic treatment with mitochondrial fusion promotor-M1 in rats with chronic MI model. Methods Adult male Wistar rats were assigned to the sham group (n=5) and the CMI group (n=15), which was induced by a permanent left anterior descending coronary occlusion. After 1 week of operation, rats in the CMI group were randomly divided into 3 subgroups which was treated with one of the followings: 1) vehicle (3% DMSO/day, ip, CON, n=5), 2) enalapril (10 mg/kg/day, po, ENA, n=5), or 3) mitochondrial fusion promotor-M1 (2 mg/kg/day, ip, M1, n=5) once daily for 4 weeks. In the end, echocardiography for the left ventricular (LV) function was performed, and the heart was removed to determine the mitochondrial function and malondialdehyde (MDA) level for oxidative stress. Results CMI rats that received vehicle showed significantly impaired LV function and cardiac mitochondrial function as evidenced by a 60% reduction in LV ejection fraction (LVEF) along with increased mitochondrial reactive oxygen species (ROS) production, mitochondrial depolarization and mitochondrial swelling, respectively, when compared with the sham rats (Fig. 1A–D). The CMI rats also exhibited a higher cardiac tissue MDA level than those of sham rats, further indicating cardiac oxidative stress (Fig. 1E). Interestingly, chronic treatment with either enalapril or M1 effectively attenuated CMI-induced mitochondrial dysfunction and oxidative stress upregulation, thus increasing LVEF (27% improvement for both ENA and M1), when compared with the vehicle group (Fig. 1A). Conclusion Long-term promotion of mitochondrial fusion mitigated cardiac mitochondrial dysfunction and oxidative stress, eventually culminating in improved LV function in rats with CMI. These findings suggest that chronic modulation of mitochondrial fusion could be a promising pharmacological intervention to improve LV function in CMI. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand2. The Thailand Research Fund (RGJ)

Abstract P2012: GRK2-Induced Cardiomyocyte AdipoR1 Phosphorylation Blocks Adipocytes-Derived Exosomes Cardioprotection Against Ischemic Heart Failure

Background: Despite significant reduction in acute MI death, ischemic heart failure (IHF) and resultant death continually escalate with incompletely understood mechanism. We recently reported that adipocyte-derived exosomes (ADp-Exo) protect heart from acute MI/R injury. However, it remains unknown whether and how cardiomyocytes (CM) response to ADp-Exo is altered during the chronic phase of MI, negatively impacting IHF development. Methods and Results: Intramyocardial injection of ADp-Exo (isolated from epididymal fat pad) immediately after MI (90 min MI/4 weeks reperfusion) significantly attenuated post-MI remodeling. However, the protective effects were completely lost when ADp-Exo were administered 1 week after MI. To identify the molecular mechanisms responsible for ADp-Exo cardioprotection and its alteration during chronic MI, a series of in vitro experiments were performed. Adiponectin (APN), a potent cardioprotective adipokine, was detected on the surface of ADp-Exo (Exo-flow kit). Treatment of CM with ADp-Exo activated multiple cell salvage kinases (e.g., ACC, ERK and AMPK). These effects were lost in APN neutralization antibody pre-incubated ADp-Exo or ADp-Exo from APNKO mice, suggesting Exo surface APN may mediate ADp-Exo cardioprotection. Moreover, ADp-Exo cell salvage kinase activation effect was absent in CM from AdipoR1KO mice or GRK2 transfected CM, suggesting GRK2-induced AdipoR1 phosphorylation at Ser 205 (as we demonstrated in Circulation, 2015 and Circ Res, 2022) is likely responsible for incapability of ADp-Exo protection during post-MI remodeling. To obtain direct evidence supporting this novel hypothesis, AdipoR1 S205A or AdipoR1 S205E (pseudo-phosphorylation) mice were generated. ADp-Exo cardioprotection was restored in AdipoR1 S205A mice, even when they were administered 1 week after MI. In contrast, ADp-Exo cardioprotection was lost in AdipoR1 S205E mice, even when they were administered immediately after MI. Conclusions: We demonstrate for the first time that, APN located on the surface of ADp-Exo acts as the critical executor of ADp-CM communication, mediating ADp-Exo cardioprotection. GRK2-induced CM AdipoR1 phosphorylation blocks ADp-Exo protective action, contributing to IHF progression.

Amniotic Membrane-Derived Mesenchymal Stem Cells for Heart Failure: A Systematic Review and Meta-Analysis of the Published Preclinical Studies.

Background: Ischemic cardiomyopathies are the leading causes of mortality and morbidity. Stem cell therapy using amniotic membrane mesenchymal stem cells have emerged as a promising cardiac regeneration modality. They have shown great immunological advantage when used in allogeneic or xenogeneic transplantation. The aim of the current study is to accumulate evidence from published preclinical studies on the application of amniotic membrane derived mesenchymal stem cells (AMSCs) in the treatment of ischemic cardiomyopathies including myocardial ischemia and heart failure. The aim is to define if there is enough high-quality current evidence to support starting the use of these cells in clinical trials. Methods: PubMed, SCOPUS, EMBASE, and ISI Web of Science databases were searched without temporal and language restrictions. Data were extracted from selected studies. The primary outcomes were left ventricular ejection fraction (LVEF) and LV fibrosis. The risk of bias (ROB) assessment was performed using SYRCLE's ROB tool. After qualitative synthesis, provided that data meets the criteria for quantitative analysis, a meta-analysis was performed using Stata software V12 to investigate the heterogeneity of the data and to get an overall estimate of the effect size of the treatment on each outcome. Results: On primary search, 438 citations were retrieved. After screening, three studies were selected for quantitative analysis of each of the outcomes LVEF and LV fibrosis. Their administration in acute and chronic MI alleviates heart failure and improves LVEF (SMD=3.56, 95% CI: 2.24-4.87, I-squared=83.1%, p=0.003) and reduces infarct size (SMD= -4.41, 95% CI: (-5.68)-(-3.14), I-squared=79.0%, p=0.009). These observations were achieved in the acute MI model, HF following ischemia due to coronary artery stenosis and coronary artery occlusion with the early restoration of the perfusion. Conclusion: Present low and medium quality evidence from preclinical studies confirm the efficacy of the AMSCs in the preclinical models of acute MI and HF following ischemia due to coronary artery stenosis and permanent/temporary coronary artery occlusion. High-quality preclinical studies are indicated to bridge the gaps in translation of the current findings of AMSCs research for the treatment of patients with acute and chronic myocardial ischemia and heart failure.

RNA-sequencing reveals transcriptional signature of pathological remodeling in the diaphragm of rats after myocardial infarction.

The diaphragm is the main inspiratory muscle, and the chronic phase post-myocardial infarction (MI) is characterized by diaphragm morphological, contractile, and metabolic abnormalities. However, the mechanisms of diaphragm weakness are not fully understood. In the current study, we aimed to identify the transcriptome changes associated with diaphragm abnormalities in the chronic stage MI. We ligated the left coronary artery to cause MI in rats and performed RNA-sequencing (RNA-Seq) in diaphragm samples 16weeks post-surgery. The sham group underwent thoracotomy and pericardiotomy but no artery ligation. We identified 112 differentially expressed genes (DEGs) out of a total of 9664 genes. Myocardial infarction upregulated and downregulated 42 and 70 genes, respectively. Analysis of DEGs in the framework of skeletal muscle-specific biological networks suggest remodeling in the neuromuscular junction, extracellular matrix, sarcomere, cytoskeleton, and changes in metabolism and iron homeostasis. Overall, the data are consistent with pathological remodeling of the diaphragm and reveal potential biological targets to prevent diaphragm weakness in the chronic stage MI.

Diffusion tensor cardiovascular magnetic resonance predicts adverse remodelling after myocardial infarction

Abstract Background Changes in myocardial microstructure that underlie post-myocardial infarction (MI) left ventricular (LV) remodelling may contribute to progressive deterioration in cardiac function and increased risk of adverse clinical events. Diffusion Tensor Cardiovascular Magnetic Resonance (DT-CMR) derived parameters provide in vivo measures of helix angle (HA) and sheetlet angle (SA), which allow non-invasive characterization of microstructural dynamics associated with cardiac contraction. Purpose To evaluate the relationship between DT-CMR metrics of myocardial microstructure with the development of adverse LV remodelling and to determine the relationship between DT-CMR and strain post- MI. Methods We performed a longitudinal pre-clinical CMR study whereby DT-CMR, cine imaging and strain were acquired pre-MI and 3 days and 16 weeks post- MI in a pig model. HA (E1A), SA (E2A), and sheetlet angle mobility (ΔE2A = E2Asystole– E2Adiastole), as well as circumferential (Ecc) and radial (Err) strain were calculated at each timepoint and related to change in left ventricular end-diastolic volume (ΔLVEDV) and change in left ventricular end-systolic volume (ΔLVESV) between 3 days post-MI and 16 weeks post-MI. The translational value of this preclinical study was further assessed in six patients with chronic MI. Results ΔE2A over the whole LV (global ΔE2A) at 3 days post-MI correlated significantly with ΔLVEDV (R2=0.89, p=0.0013, Fig.1A;) and ΔLVESV (R2=0.81, p=0.0055, Fig.1B). Global Ecc at 3 days post-MI also correlated with both ΔLVEDV (R2=0.75, p=0.012, Fig.1C) and ΔLVESV (R2=0.71, p=0.018, Fig.1D). Global Err at 3 days post-MI did not show significant correlation with either ΔLVEDV (R2=0.32, p=0.19, Fig.1E) or ΔLVESV (R2=0.35, p=0.17, Fig.1F). Global ΔE2A correlated strongly with global Ecc 3 days post-MI (R2=0.9, p=0.00099, Fig.1G) but less strongly with global Err 3 days post-MI (R2=0.57, p=0.049, Fig.1H). Global ΔE2A at the chronic stage correlated significantly with ejection Fraction (EF), in both clinical (R2=0.87, p=0.007) and preclinical data (R2=0.87, p=0.0024). Global ΔE2A correlated well with LVEDV (clinical: R2=0.72, p=0.033; preclinical: R2=0.8, p=0.0066) and LVESV (clinical: R2=0.78, p=0.020; preclinical: R2=0.89, p=0.0013). In vivo E1A maps at 16 weeks post-MI and ex vivo DT-CMR demonstrated reduced right-handed helix angles in the endocardium of the infarct region. Conclusion ΔE2A measured at 3 day post-reperfused MI is strongly correlated with the development of increased end-systolic and end-diastolic volumes, and may therefore serve as a novel CMR early predictor of adverse LV remodelling after reperfused MI. Strong correlations between ΔE2A, LV volumes and EF in a small cohort of stable patients with remodelled hearts after chronic MI confirm the feasibility of performing these measurements in patients and the plausibility of further evaluation of ΔE2A as a predictor of adverse remodelling after reperfused MI. Sheetlet mobility predicts volume change Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Institutes of Health by the Division of Intramural Research (NHLBI, NIH, DHHS); British Heart Foundation

Role of Cardiac Magnetic Resonance Imaging in Diagnosis of Myocardial Infarction

Introduction: Cardiac Magnetic Resonance Imaging provides an accurate and reproducible modality for the assessment of global ventricular volumes and function, and valuable in establishing a diagnosis of chronic and acute MI and distinguishing this condition from non-ischemic cardiomyopathies. Aim: To evaluate the role of cardiac Magnetic Resonance Imaging technique in diagnosis of myocardial infarction, assessment of myocardial viability. Subject and Method: The study was conducted over a period of 3 years at Assiut University Hospital. Fifty-six patients were recruited. All patients were subjected to full history taking and radiological evaluation using a 1.5-T MR system and echocardiography. Agreement regarding segmental wall motion was assessed by using Cohen’s Kappa statistics. Also ejection fraction measurement by both modalities was compared using bland-Altman plots. Agreement between Magnetic Resonance Imaging and conventional coronary angiography in detection of diseased coronary arteries was examined using Cohen’s kappa coefficient (κ). Results: It was found that ejection fraction detected by Echo were overestimated relative to Magnetic Resonance Imaging with statistically significant difference (p=0.004). While LV diameters detected by echocardiography were underestimated relative to Magnetic Resonance Imaging. Good agreement between Magnetic Resonance Imaging and Echo regarding segmental wall motion. There was positive very high correlation between the two modalities in evaluation of LV Functionality indices. Conclusion: CMR is superior to echo in evaluating left ventricular functionality indices with echo underestimating these indices except the ejection fraction which is overestimated by Echo. Moreover, CMR is better in evaluating post MI complications and associated cardiac abnormalities.

Videos of in vivo cine cMRI display mid-ventricular slices at baseline without MI, at 48 hrs of acute MI phase and at 7 weeks of chronic MI phase on the rabbits of moderate (first line) and severe (second line) LVSD

Videos of in vivo cine cMRI display mid-ventricular slices at baseline without MI, at 48 hrs of acute MI phase and at 7 weeks of chronic MI phase on the rabbits of moderate (first line) and severe (second line) LVSD

Sustained release of basic fibroblast growth factor using gelatin hydrogel improved left ventricular function through the alteration of collagen subtype in a rat chronic myocardial infarction model.

Chronic myocardial infarction (CMI) tends to be resistant to treatments possibly due to extensive solid fibrotic scar, hypoxia mediated by poorly vascularized environment, and/or inflammation and apoptosis. Here we aimed to testify the therapeutic effects of sustained release of basic fibroblast growth factor (bFGF) using gelatin hydrogel (GH) in a rat chronic MI model and to elucidate the therapeutic mechanism including the alteration of extracellular matrix component. CMI model rats are prepared by the permanent ligation of proximal left anterior descending coronary artery. After 4weeks, GH sheets (GHSs) with bFGF (100µg) (bFGF group)or with phosphate-buffered saline (Vehicle group) were implanted to the CMI models to evaluate the effect of bFGF-GHS on chronic scar tissue. Sham operation group was also prepared (n = 5 for each). 4weeks after implantation, bFGF-GHS significantly improved cardiac contractile function (fractional shortening: 21.8 ± 1.1 vs 21.5 ± 1.3 vs 29.7 ± 1.8%; P < 0.001/fractional area change: 33.0 ± 1.4 vs 34.1 ± 2.3 vs 40.6 ± 1.8%; P < 0.001) (Sham vs Vehicle vs bFGF) accompanied with neovascularization. Immunohistochemical studies revealed that bFGF-GHS increased collagen III/I ratio indicating the alteration of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I mRNA expression within border MI zone. The implantation of bFGF-GHS altered the collagen subtype of the fibrotic scar more suitable for tissue repair. The treatment of sustained-release bFGF may be promising for ischemic heart disease through chronic pathology.

Long‐Term Survival of Adult Cardiac Myocytes in Large Transmural Post‐Myocardial Infarction Scars Is Supported by a Functional, Local Microvascular Network

The presence of surviving cardiac myocytes in post‐myocardial infarction (MI) scars has been repeatedly documented in humans as well as in various laboratory animals, particularly in rats. In the majority of cases, the long‐term survival of cardiac myocytes in post‐MI scars has been attributed either to continuing arterial blood supply from the bordering noninfarcted myocardium or to a rapid reestablishment of blood perfusion through the original coronary artery after a transient period of ischemia. On the other hand, in a rat model of chronic MI produced by permanent ligation of the left coronary artery, the persistent survival of adult cardiac myocytes in remote areas of the large transmural scar remains yet poorly understood. Considering the fact that in such model the left coronary artery remained permanently occluded for the duration of an entire experimental period, the presence of viable cardiac myocytes in mature scars has been often explained by simple diffusion of oxygen and nutrients from either the left ventricular (LV) cavity or large subepicardial veins. In order to test this hypothesis, in our current study, a special emphasis has been made on investigation of the regional microenvironment, particularly the source of nourishing blood supply, which could facilitate long‐term survival of adult cardiac myocytes in scars. A large transmural MI was induced in 12‐month‐old male Sprague‐Dawley rats by permanent ligation of the left coronary artery. The patency of residual blood vessels was assessed in vivo in 4‐, 8‐ and 12‐week‐old scars by infusion of 15‐micron microspheres into the LV cavity shortly before euthanasia. The hearts were collected 3 days, 1, 2, 4, 8 and 12 weeks after MI and evaluated with histology, immunohistochemistry and quantitative morphometry. We found that, at all time points, the large, transmurally infarcted/ scarred area had a sparse population of viable cardiac myocytes primarily localized in subendocardial and subepicardial regions. We also confirmed the finding that in the subepicardial region, the groups of surviving cardiac myocytes were often seen around large residual veins. However, further examination has revealed that all clusters of surviving cardiac myocytes were always associated with a network of patent microvessels, including capillaries, venules and arteriolar‐like vessels. Most importantly, the presence of microspheres in the venules of such microvascular networks has substantiated the concept that blood perfused through these microvessels was originated from the LV cavity. This hypothesis was further strengthen by the fact that the endocardial surface of some transmural scars revealed the presence of patent orifices from the Thebesian veins, suggesting that the remnants of the venous vascular system within the scars, including subendocardial and subepicardial venous plexuses as well as intramural venous sinusoids, could to some extent undergo retrograde perfusion with arterial blood. Taken together, our current findings suggest that long‐term survival of adult cardiac myocytes in large, transmural post‐MI scars is sustained by the local microcirculatory networks which are structurally and functionally coupled with the residual venous system that maintains direct connections with the cavity of the left ventricle.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Native T1 mapping for characterization of acute and chronic myocardial infarction in swine: Comparison with contrast-enhanced MRI.

Both acute and chronic myocardial infarction (AMI and CMI, respectively) exhibit delayed enhancement; however, clinical decision-making processes frequently require the differentiation of these two types of myocardial injury. To investigate the reliability of AMI and CMI characterization using native T1 mapping and its feasibility for discriminating AMI from CMI. Case-control. The study cohort comprised 12 AMI (mean post-MI, 3.75 ± 1.29 days) and 15 CMI (mean post-MI, 39.53 ± 6.10 days) Bama mini-pigs. Balanced steady-state free precession (bSSFP), segmented-turbo-FLASH-PSIR, and modified Look-Locker inversion recovery (MOLLI) sequences at 3.0T. The infarct sizes were compared on matching short-axis slices of late-gadolinium-enhanced (LGE) images and T1 maps by two experienced radiologists. The infarct sizes were compared on matching short-axis slices of LGE images and T1 maps, and agreement was determined using linear regression and Bland-Altman analyses. The native T1 values were compared between AMI and CMI models (independent sample t-test). The intraclass correlation coefficient was used to assess inter- and intraobserver variability. Measured infarct sizes did not differ between native T1 mapping and LGE images (AMI: P = 0.913; CMI: P = 0.233), and good agreement was observed between the two techniques (AMI: bias, -3.38 ± 19.38%; R2 = 0.96; CMI: bias, -10.55 ± 10.90%; R2 = 0.90). However, the native infarction myocardium T1 values and the T1 signal intensity ratio of infarct and remote myocardium (T1 SI ratio) did not differ significantly between AMI and CMI (P = 0.173). Noncontrast native T1 mapping can accurately determine acute and chronic infarct areas as well as conventional LGE imaging; however, it cannot distinguish acute from chronic MI. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1406-1414.

The relationship between acute myocardial infarction and mood disorders

Acute myocardial infarction (AMI) acts as an important risk factor for occurrence of depression, which affectS long term morbidity and mortality considering baseline health state in patients with AMI.To estimate frequency of depression among patients within first 3 weeks after occurrence of AMI and to evaluate the effect of different demographic factors, biochemical changes, type and site of M.I on its frequency. This is a cross sectional study that enrolled 116 patients with AMI who had been admitted to coronary care unite (CCU) at Al-Diwaniya Teaching Hospital during the period between 1st of July 2007-31st of October 2008. Only 80 patients were followed up the Diagnosis of depression was done according to criteria of structural clinical interview for diagnostic and statistical manual of mental disorder-4- revision (SCID-DSM-4-R).This study revealed that 22.5% of patients had post-AMI depression. The females constitute 88.89% of depressed group, ≥ 65year old age were 44.44%, patients with hypertension and hyperlipidemia were 66.67%, diabetic patients were 27.78% and patients had positive history of MI were 33.33%. Patients with ejection fraction (E.F) &lt; 35%, renal failure or insufficiency, chronic obstructive pulmonary disease (COPD) and anterior MI were 22.22%. Patients with non ST elevation myocardial infarction (NSTEMI), peak creatine phosphokinase (CPK) ≥500 u/l and current smoker constitute 66.67%, 55.56% and 16.67% respectively. This study proves that depression after AMI was more common in females and less common in diabetic patients, current smokers and patients with COPD.

Effects of local cardiac denervation on cardiac innervation and ventricular arrhythmia after chronic myocardial infarction.

BackgroundModulation of the autonomic nervous system (ANS) has already been demonstrated to display antiarrhythmic effects in patients and animals with MI. In this study, we investigated whether local cardiac denervation has any beneficial effects on ventricular electrical stability and cardiac function in the chronic phase of MI.MethodsTwenty-one anesthetized dogs were randomly assigned into the sham-operated, MI and MI-ablation groups, respectively. Four weeks after local cardiac denervation, LSG stimulation was used to induce VPCs and VAs. The ventricular fibrillation threshold (VFT) and the incidence of inducible VPCs were measured with electrophysiological protocol. Cardiac innervation was determined with immunohistochemical staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). The global cardiac and regional ventricular function was evaluated with doppler echocardiography in this study.ResultsFour weeks after operation, the incidence of inducible VPC and VF in MI-ablation group were significantly reduced compared to the MI dogs (p<0.05). Moreover, local cardiac denervation significantly improved VFT in the infarcted border zone (p<0.05). The densities of GAP43 and TH-positive nerve fibers in the infarcted border zone in the MI-ablation group were lower than those in the MI group (p<0.05). However, the local cardiac denervation did not significantly improve cardiac function in the chronic phase of MI, determined by the left ventricle diameter (LV), left atrial diameter (LA), ejection fraction (EF).ConclusionsSummarily, in the chronic phase of MI, local cardiac denervation reduces the ventricular electrical instability, and attenuates spatial heterogeneity of sympathetic nerve reconstruction. Our study suggests that this methodology might decrease malignant ventricular arrhythmia in chronic MI, and has a great potential for clinical application.

Sexual dimorphisms of mRNA and miRNA in human/murine heart disease.

BackgroundSexual dimorphisms are well recognized in various cardiac diseases such as ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Thorough understanding of the underlying genetic programs is crucial to optimize treatment strategies specified for each gender. By performing meta-analysis and microarray analysis, we sought to comprehensively characterize the sexual dimorphisms in the healthy and diseased heart at the level of both mRNA and miRNA transcriptome.ResultsExisting mRNA microarray data of both mouse and human heart were integrated, identifying dozens/ hundreds of sexually dimorphic genes in healthy heart, ICM, HCM, and DCM. These sexually dimorphic genes overrepresented gene ontologies (GOs) important for cardiac homeostasis. Further, microarray of miRNA, isolated from mouse sham left ventricle (LV) (n = 6 & n = 5 for male & female) and chronic MI LV (n = 19 & n = 19) and from human normal LV (n = 6 & n = 6) and ICM LV (n = 4 & n = 5), was conducted. This revealed that 13 mouse miRNAs are sexually dimorphic in MI and 6 in normal heart. In human, 3 miRNAs were sexually dimorphic in ICM and 15 in normal heart. These data revealed miRNA-mRNA networks that operate in a sexually-biased fashion.ConclusionsmRNA and miRNA transcriptome of normal and disease heart show significant sex differences, which might impact the cardiac homeostasis. Together this study provides the first comprehensive picture of the genome-wide program underlying the heart sexual dimorphisms, laying the foundation for gender specific treatment strategies.

Bioelectronic block of paravertebral sympathetic nerves mitigates post–myocardial infarction ventricular arrhythmias

Autonomic dysfunction contributes to induction of ventricular tachyarrhythmia (VT). To determine the efficacy of charge-balanced direct current (CBDC), applied to the T1-T2 segment of the paravertebral sympathetic chain, on VT inducibility post-myocardial infarction (MI). In a porcine model, CBDC was applied in acute animals (n = 7) to optimize stimulation parameters for sympathetic blockade and in chronic MI animals (n = 7) to evaluate the potential for VTs. Chronic MI was induced by microsphere embolization of the left anterior descending coronary artery. At termination, in anesthetized animals and following thoracotomy, an epicardial sock array was placed over both ventricles and a quadripolar carousel electrode positioned underlying the right T1-T2 paravertebral chain. In acute animals, the efficacy of CBDC carousel (CBDCC) block was assessed by evaluating cardiac function during T2 paravertebral ganglion stimulation with and without CBDCC. In chronic MI animals, VT inducibility was assessed by extrasystolic (S1-S2) stimulations at baseline and under >66% CBDCC blockade of T2-evoked sympathoexcitation. CBDCC demonstrated a current-dependent and reversible block without impacting basal cardiac function. VT was induced at baseline in all chronic MI animals. One animal died after baseline induction. Of the 6 remaining animals, only 1 was reinducible with simultaneous CBDCC application (P < .002 from baseline). The ventricular effective refractory period (VERP) was prolonged with CBDCC (323 ± 26 ms) compared to baseline (271 ± 32 ms) (P < .05). Axonal block of the T1-T2 paravertebral chain with CBDCC reduced VT in a chronic MI model. CBDCC prolonged VERP, without altering baseline cardiac function, resulting in improved electrical stability.