Chronic Myocardial Infarction Model Research Articles

Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.

Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI). A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot. The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression. Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

Spatial and temporal tracking of multi-layered cells sheet using reporter gene imaging with human sodium iodide symporter: a preclinical study using a rat model of myocardial infarction.

This study aimed to evaluate a novel technique for cell tracking by visualising the activity of the human sodium/iodide symporter (hNIS) after transplantation of hNIS-expressing multilayered cell sheets in a rat model of chronic myocardial infarction. Triple-layered cell sheets were generated from mouse embryonic fibroblasts (MEFs) derived from mice overexpressing hNIS (hNIS-Tg). Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery in F344 athymic rats, and a triple-layered MEFs sheets were transplanted to the infarcted area two weeks after surgery. To validate the temporal tracking and kinetic analysis of the transplanted MEFs sheets, sequential cardiac single-photon emission computed tomography (SPECT) examinations with a 99mTcO4- injection were performed. The cell sheets generated using MEFs of wild-type mice (WT) served as controls. A significantly higher amount of 99mTcO4- was taken into the hNIS-Tg MEFs than into WT MEFs (146.1 ± 30.9-fold). The obvious accumulation of 99mTcO4- was observed in agreement with the region where hNIS-Tg MEFs were transplanted, and these radioactivities peaked 40-60min after 99mTcO4- administration. The volume of distribution of the hNIS-Tg MEF sheets declined gradually after transplantation, implying cellular malfunction and a loss in the number of transplanted cells. The reporter gene imaging with hNIS enables the serial tracking and quantitative kinetic analysis of cell sheets transplanted to infarcted hearts.

Enabling Reliable Visual Detection of Chronic Myocardial Infarction with Native T1 Cardiac MRI Using Data-Driven Native Contrast Mapping.

Purpose To investigate whether infarct-to-remote myocardial contrast can be optimized by replacing generic fitting algorithms used to obtain native T1 maps with a data-driven machine learning pixel-wise approach in chronic reperfused infarct in a canine model. Materials and Methods A controlled large animal model (24 canines, equal male and female animals) of chronic myocardial infarction with histologic evidence of heterogeneous infarct tissue composition was studied. Unsupervised clustering techniques using self-organizing maps and t-distributed stochastic neighbor embedding were used to analyze and visualize native T1-weighted pixel-intensity patterns. Deep neural network models were trained to map pixel-intensity patterns from native T1-weighted image series to corresponding pixels on late gadolinium enhancement (LGE) images, yielding visually enhanced noncontrast maps, a process referred to as data-driven native mapping (DNM). Pearson correlation coefficients and Bland-Altman analyses were used to compare findings from the DNM approach against standard T1 maps. Results Native T1-weighted images exhibited distinct pixel-intensity patterns between infarcted and remote territories. Granular pattern visualization revealed higher infarct-to-remote cluster separability with LGE labeling as compared with native T1 maps. Apparent contrast-to-noise ratio from DNM (mean, 15.01 ± 2.88 [SD]) was significantly different from native T1 maps (5.64 ± 1.58; P < .001) but similar to LGE contrast-to-noise ratio (15.51 ± 2.43; P = .40). Infarcted areas based on LGE were more strongly correlated with DNM compared with native T1 maps (R2 = 0.71 for native T1 maps vs LGE; R2 = 0.85 for DNM vs LGE; P < .001). Conclusion Native T1-weighted pixels carry information that can be extracted with the proposed DNM approach to maximize image contrast between infarct and remote territories for enhanced visualization of chronic infarct territories. Keywords: Chronic Myocardial Infarction, Cardiac MRI, Data-Driven Native Contrast Mapping Supplemental material is available for this article. © RSNA, 2024.

Long-Term Stimulation of the Left Dorsal Branch of the Thoracic Nerve Improves Ventricular Electrical Remodeling in a Canine Model of Chronic Myocardial Infarction.

To evaluate the ventricular electrophysiologic effects of long-term stimulation of the left dorsal branch of thoracic nerve (LDTN) derived from the left stellate ganglion (LSG) in a canine model of chronic myocardial infarction (MI). Seventeen adult male beagles were randomly divided into three groups: the sham group (sham operated, n = 6), the MI group (n = 6), and the MI + LDTN group (MI plus LDTN stimulation, n = 5). The canine model of chronic MI was induced by the occlusion of the left anterior descending artery (LADO). The LDTN was separated and intermittently stimulated immediately after LADO for 2months. The heart rate variability (HRV) analysis, in vivo electrophysiology, the evaluation of LSG function and neural activity, histological staining, and western blotting (WB) assay were performed to evaluate the effect of LDTN stimulation on the heart. The canine MI model was successfully established by LADO, and the LDTN was separated and stimulated immediately after LADO. The HRV analysis showed that LDTN stimulation reversed the increased LF value and LF/HF ratio of the MI group. LDTN stimulation prolonged the shortening ERP and APD90, decreased the dispersion of ERP and APD90, and increased the VFT. Additionally, LDTN stimulation inhibits the LSG function and neural activity. Furthermore, LDTN stimulation suppressed the activation of Wnt/β-catenin signaling, which contributed to the LSG neuronal apoptosis by upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic Bcl-2. LDTN stimulation could attenuate cardiac sympathetic remodeling and improve ventricular electrical remodeling, which may be mediated by suppressing the activated Wnt/β-catenin signaling pathway and then promoting the LSG neuronal apoptosis.

Piezo1-Mediated Neurogenic Inflammatory Cascade Exacerbates Ventricular Remodeling After Myocardial Infarction.

Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel-mediated neurogenic inflammatory cascade underlies ventricular remodeling-related mechanotransduction. By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)-specific Piezo1 knockdown rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling. Subsequently, neutralizing antibody-mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron-specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron-specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.

Abstract 18810: Mitochondria-Rich Extracellular Vesicles From Stem Cell-Derived Cardiomyocytes Restore Bioenergetic Metabolism of Ischemic Myocardium in a Porcine Chronic Heart Failure Model

Introduction: The disruption of mitochondrial energy metabolism underlies the pathophysiology of ischemic heart failure. We previously demonstrated that intramyocardial injection of mitochondria-rich extracellular vesicles (M-EVs) derived from iPSC-derived cardiomyocytes (iCMs) transfers mitochondria and non-mitochondrial biologics into recipient cardiomyocytes. This process stimulates mitochondrial biogenesis and enhances functional capacities in murine and porcine acute myocardial infarction (MI) models. However, the therapeutic potential and underlying mechanism in chronic heart failure models remain to be assessed. Method: M-EVs were isolated from the conditioned medium of human iCMs using differential centrifugation. A total of 11 Yorkshire pigs underwent myocardial ischemia for one hour via balloon occlusion of the left anterior descending artery (Week-0). At week-4, 1.0 x 10 11 M-EVs or PBS control were administered transendocardially to the peri-infarct region (PIR) using a percutaneous catheter delivery system (Biocardia, Inc, CA). Cardiac functions and scar size were analyzed by cardiac MRI with gadolinium contrast at week-4 (pre-injection) and -8 (post-injection). Myocardial tissue samples were collected from the PIR and remote non-ischemic areas at week-8. Proteomic analysis and single-nucleus RNA sequencing were performed to investigate comprehensive protein and gene expression profiles of the myocardium. Results: Left ventricular (LV) ejection fractions were significantly decreased at Week-4 (32.7±5.4%). M-EV treatment significantly improved absolute LVEF from week-4 to -8 in the treatment vs. non-treatment groups, +3.15% vs. -4.99%, respectively, (p&lt;0.0001). No significant difference was observed in the scar size. Multiomic analysis of proteomes and single-nucleus transcriptomes suggested restoration of dysregulated cardiometabolic protein profile and mitochondrial energy metabolism in the myocardium. Conclusion: M-EV-mediated transfer of mitochondria and enriched proteins augmented LV dysfunction in the pig chronic MI model. M-EV therapy may represent a novel biologic approach that directly targets cardiac metabolism by restoring mitochondrial function and cellular bioenergetics.

BMP2 gene transfer induces pericardial effusion and inflammatory response in the ischemic porcine myocardium.

Pro-angiogenic gene therapy is being developed to treat coronary artery disease (CAD). We recently showed that bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor-A synergistically regulate endothelial cell sprouting in vitro. BMP2 was also shown to induce endocardial angiogenesis in neonatal mice post-myocardial infarction. In this study, we investigated the potential of BMP2 gene transfer to improve cardiomyocyte function and neovessel formation in a pig chronic myocardial infarction model. Ischemia was induced in domestic pigs by placing a bottleneck stent in the proximal part of the left anterior descending artery 14 days before gene transfer. Intramyocardial gene transfers with adenovirus vectors (1 × 1012 viral particles/pig) containing either human BMP2 (AdBMP2) or beta-galactosidase (AdLacZ) control gene were performed using a needle injection catheter. BMP2 transgene expression in the myocardium was detected with immunofluorescence staining in the gene transfer area 6 days after AdBMP2 administration. BMP2 gene transfer did not induce angiogenesis or cardiomyocyte proliferation in the ischemic pig myocardium as determined by the quantitations of CD31 or Ki-67 stainings, respectively. Accordingly, no changes in heart contractility were detected in left ventricular ejection fraction and strain measurements. However, BMP2 gene transfer induced pericardial effusion (AdBMP2: 9.41 ± 3.17 mm; AdLacZ: 3.07 ± 1.33 mm) that was measured by echocardiography. Furthermore, an increase in the number of immune cells and CD3+ T cells was found in the BMP2 gene transfer area. No changes were detected in the clinical chemistry analysis of pig serum or histology of the major organs, implicating that the gene transfer did not induce general toxicity, myocardial injury, or off-target effects. Finally, the levels of fibrosis and cardiomyocyte apoptosis detected by Sirius red or caspase 3 stainings, respectively, remained unaltered between the groups. Our results demonstrate that BMP2 gene transfer causes inflammatory changes and pericardial effusion in the adult ischemic myocardium, which thus does not support its therapeutic use in chronic CAD.

Acute effects of empagliflozin on open-loop baroreflex function and urinary glucose excretion in rats with chronic myocardial infarction

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction (n = 9). Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min−1 kg−1) to 1.91 ± 0.25 mg min−1 kg−1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction.

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

Abnormal Strain Directly Identifies Scar on Histopathology as Well as Scar Seen on Cardiac MRI and Intracardiac Electrophysiologic Mapping: Insights From an Ovine Model of Chronic Myocardial Infarction

Abnormal Strain Directly Identifies Scar on Histopathology as Well as Scar Seen on Cardiac MRI and Intracardiac Electrophysiologic Mapping: Insights From an Ovine Model of Chronic Myocardial Infarction

Collagen matricryptin promotes cardiac function by mediating scar formation

AimsA peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action. Materials and methodsUsing a permanent occlusion MI rodent model, animals received p1159 or vehicle solution up to 28 days. We assessed peptide treatment effects on scar composition and structure and on systolic function. To assess peptide effects on scar vascularization, a cohort of mice were injected with Griffonia simplicifolia isolectin-B4. To investigate p1159 mode-of-action, LV fibroblasts from naïve animals were treated with increasing doses of p1159. Key findingsMatricryptin p1159 significantly improved systolic function post-MI (2-fold greater EF compared to controls) by reducing left ventricular dilation and inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Specifically, infarcted scars from p1159-treated animals displayed collagen fibers aligned parallel to the epicardium, to resist circumferential stretching, with reduced levels of cross-linking, and improved tissue perfusion. In addition, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin α4. SignificanceOur data indicate p1159 treatment reduced adverse LV remodeling post-MI by modulating the deposition, arrangement, and perfusion of the fibrotic scar.

Adult Bone Marrow-Derived Mesenchymal Stem Cells Seeded on Tissue-Engineered Cardiac Patch Contribute to Myocardial Scar Remodeling and Enhance Revascularization in a Rabbit Model of Chronic Myocardial Infarction.

Although the transplantation of tissue-engineered cardiac patches with adult bone marrow-derived mesenchymal stem cells (MSCs) can enhance cardiac function after acute or chronic myocardial infarction (MI), the recovery mechanism remains controversial. This experiment aimed to investigate the outcome measurements of MSCs within a tissue-engineered cardiac patch in a rabbit chronic MI model. This experiment was divided into four groups: left anterior descending artery (LAD) sham-operation group (N = 7), sham-transplantation (control, N = 7), non-seeded patch group (N = 7), and MSCs-seeded patch group (N = 6). PKH26 and 5-Bromo-2'-deoxyuridine (BrdU) labeled MSCs-seeded or non-seeded patches were transplanted onto chronically infarct rabbit hearts. Cardiac function was evaluated by cardiac hemodynamics. H&E staining was performed to count the number of vessels in the infarcted area. Masson staining was used to observe cardiac fiber formation and to measure scar thickness. Four weeks after transplantation, a remarkable improvement in cardiac functionality could be distinctly observed, which was most significant in the MSCs-seeded patch group. Moreover, labeled cells were detected in the myocardial scar, with most of them differentiated into myofibroblasts, some into smooth muscle cells, and only a few into cardiomyocytes in the MSCs-seeded patch group. We also observed significant revascularization in the infarct area implanted in either MSCs-seeded or non-seeded patches. In addition, there were significantly greater numbers of microvessels in the MSCs-seeded patch group than in the non-seeded patch group.

The administration of valproic acid exerts a protective effect by reducing the infarct size and the triggering of ventricular fibrillation in an experimental model of chronic myocardial infarction

Abstract Introduction In myocardial infarction there are complications associated with adverse cardiac remodeling that occurs during the fibrotic process, producing an arrhythmogenic substrate that favors the triggering of ventricular arrhythmias such as ventricular fibrillation (VF). These complications also contribute to infarct expansion and mortality. Purpose To analyze, in a model of chronic infarction (5 weeks) in rabbits, the effects of valproic acid (VA), an inhibitor of histone deacetylase enzymes, on the inducibility of ventricular fibrillation and infarct size. Methods 47 New Zealand rabbits were assigned to sham (n=15), control (n=22) and VA-treated (n=10) groups. After midsternal thoracotomy and pericardiotomy, the circumflex coronary artery was occluded (1 hour), followed by reperfusion (control and treated groups). 500 mg/kg of VA were administered every 24 hours for 5 weeks. Then, the animals were sacrificed, their hearts excised and placed in a Langendorff perfusion system. We used a multielectrode recording plate (256 electrodes) and ventricular stimulation electrodes in the left ventricular epicardium. The inducibility of VF was analyzed using ventricular extrastimulus tests (VEST) with two basic stimulation cycle lengths (250 and 150 ms) and up to the three extrastimuli in each cycle. VEST was applied in four peri-infarct stimulation zones. After the electrophysiological study, the circumflex coronary artery was occluded, and the aorta was perfused with thioflavin-S to determine the area at risk (AR). We made sections of the left ventricle (LV) which were incubated in a triphenyltetrazolium chloride solution to determine the infarct size. The images obtained were digitized and manually quantified. The quantification was performed in 3 sections, located below the ligature of the coronary occlusion. Unpaired Student's t-test or chi-square test were used when appropriate (p&amp;lt;0.05). Results Infarct size decreased in the VA-treated group compared to the control group, when expressed as a percentage of AR (40.3±5.3% vs. 69.8±20.4%, respectively) and when expressed as percentage of LV (19.3±7.8% vs. 38.6±16.4% respectively). The myocardium of the sham group did not exhibit areas of necrosis. Regarding VF inducibility, the treated group presented lower arrhythmia inducibility, regardless of the number of extrastimuli and pacing cycle length, triggering the arrhythmia in 40% of cases compared to 59% in the control group (p=0.011). Likewise, more extrastimuli were needed in VA-treated animals to trigger VF than controls (2 (50%) and 3 (50%) extrastimuli vs. 1 (15%), 2 (46%) and 3 (38%) extrastimuli needed, respectively; χ2=16.526; p&amp;lt;0.005). Conclusion VA did exhibit a protective effect, as shown by its ability to limit the extension of the infarct size and to reduce the inducibility of ventricular fibrillation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Carlos III Health Institute and Institute of Health Research (INCLIVA)

Ultrasound-guided injection of botulinum toxin type A blocks cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic myocardial infarction

Strategies to improve various cardiovascular diseases by blocking cardiac sympathetic ganglion have been increasingly available currently. Botulinum toxin type A (BTA), a typical neurotoxin, has been shown to block neural transmission in a safe and long-lasting manner. The aim of the present preclinical study was to assess the efficacy of BTA microinjection to alleviate cardiac remodeling after chronic myocardial infarction (MI) by blocking cardiac sympathetic ganglion in a canine model. Beagles were randomly divided into a control group (saline microinjection with sham surgery), an MI group (saline microinjection with MI), and an MI + BTA group (BTA microinjection with MI). Ultrasound-guided percutaneous BTA or saline injection into the left stellate ganglion (LSG) was performed followed by MI induction via left anterior descending artery occlusion (LADO) or sham surgery. After 30 days, electrocardiography, Doppler echocardiography, LSG function, neural activity, and ventricular electrophysiological detection were performed in all experimental dogs. At the end, LSG and ventricular tissues were collected for further detection. BTA treatment significantly inhibited LSG function and neural activity and improved heart rate variability. Additionally, BTA application alleviated ventricular remodeling, ameliorated cardiac function, and prevented ventricular arrhythmias after 30-day chronic LADO-induced MI. Ultrasound-guided percutaneous microinjection of BTA can block cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic LADO-induced MI. Ultrasound-guided BTA microinjection has potential for clinical application as a novel cardiac sympathetic ganglion blockade strategy for MI.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5andpro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

Autologous Bone Marrow Mononuclear Cells (BMMC)-Associated Anti-Inflammatory Nanoparticles for Cardiac Repair after Myocardial Infarction.

To investigate the effect of transplantation of stem cells from the bone marrow mononuclear cells (BMMC) associated with 15d-PGJ2-loaded nanoparticles in a rat model of chronic MI. Chronic myocardial infarction (MI) was induced by the ligation of the left anterior descending artery in 40 male Wistar rats. After surgery, we transplanted bone marrow associated with 15d-PGJ2-loaded nanoparticle by intramyocardial injection (106 cells/per injection) seven days post-MI. Myocardial infarction was confirmed by echocardiography, and histological analyses of infarct morphology, gap junctions, and angiogenesis were obtained. Our results from immunohistochemical analyses demonstrated the presence of angiogenesis identified in the transplanted region and that there was significant expression of connexin-43 gap junctions, showing a more effective electrical and mechanical integration of the host myocardium. This study suggests that the application of nanoparticle technology in the prevention and treatment of MI is an emerging field and can be a strategy for cardiac repair.

PO-628-06 EFFECT OF ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITOR AND EMPAGLIFLOZINE ON ISCHEMIC VENTRICULAR TACHYCARDIA SUBSTRATE: A HIGH-DENSITY MAPPING AND MRI STUDY

Angiotensin receptor neprilysin inhibitor (ARNI) and empagliflozine reduce cardiovascular death in heart failure, but mechanistic data on this effect are scarce. To assess the effect of ARNI and empagliflozine on scar remodeling and ventricular tachycardia (VT) inducibility in a swine model of chronic myocardial infarction (MI). Left anterior descending artery MI was induced in 40 Landrace Large X White pigs. Thirty-one animals (78%) survived the MI induction procedure and were randomized to receive treatment with beta-blocker (BB) only (group 1, n=7), empagliflozine+BB (group 2, n=8), ARNI + BB (group 3, n=8) or empagliflozine + ARNI + BB (group 4, n=8). Contrast-enhanced (ce)-MRI were performed at 2-day (baseline) and 1-month post-MI and were post-processed with ADAS 3D; ventricular scar subtypes and borderzone (BZ) corridors volume were measured. EP study with endo-epicardial high-density mapping was performed 1-month post-MI. VT was inducible in 21/31 subjects (68%). Treatment with ARNI (groups 3 and 4) showed a significant reduction of VT inducibility (OR 0.15 [0.026-0.91], p=0.03) compared to non-ARNI groups (100%, 75%, 50% and 50% for groups 1, 2, 3 and 4, respectively), representing a 30% relative risk reduction. Treatment with empagliflozine (group 2) did not reduce VT inducibility (p=0.704). Baseline ceMRI data showed a mean core and BZ scar mass of 5.4±3.1 and 6.1±3.1 grams, respectively, without significant differences in the percentage of core scar. The mean number of corridors was 2.1±1.2 with a mean mass of 1.3±1.0, without significant differences across groups. Treatment with ARNI and empagliflozine significantly reduced the number (+1.0, -1.1, -1.2 and -1.7 corridors for groups 1, 2, 3 and 4, respectively; p=0.021) and mass of corridors (+0.3, -1.6, -0.8 and -0.4 grams for groups 1, 2, 3 and 4, respectively; p=0.012) at the follow-up ceMRI. ARNI and empagliflozine groups tended to reduce overall BZ mass compared to the control group (reduction of the BZ percentage -1.2±4, -4.9±2, -5.6±2, -3.8±4; p=0.102). Treatment with ARNI reduced VT inducibility by 30% after MI, likely driven by a significant reduction of the number and mass of BZ corridors. Empagliflozine reduced the number and mass of BZ corridors, without impact on VT inducibility.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

NP202 treatment improves left ventricular systolic function and attenuates pathological remodelling following chronic myocardial infarction

AimsMyocardial injury is a major contributor to left ventricular (LV) remodelling activating neurohormonal and inflammatory processes that create an environment of enhanced oxidative stress. This results in geometric and structural alterations leading to reduced LV systolic function. In this study we evaluated the efficacy of NP202, a synthetic flavonol, on cardiac remodelling in a chronic model of myocardial infarction (MI). Main methodsA rat model of chronic MI was induced by permanent surgical ligation of the coronary artery. NP202 treatment was commenced 2 days post-MI for 6 weeks at different doses (1, 10 and 20 mg/kg/day) to determine efficacy. Cardiac function was assessed by echocardiography prior to treatment and at week 6, and pressure-volume measurements were performed prior to tissue collection. Tissues were analysed for changes in fibrotic and inflammatory markers using immunohistochemistry and gene expression analysis. Key findingsRats treated with NP202 demonstrated improved LV systolic function and LV geometry compared to vehicle treated animals. Furthermore, measures of hypertrophy and interstitial fibrosis were attenuated in the non-infarct region of the myocardium with NP202 at the higher dose of 20 mg/kg (P < 0.05). At the tissue level, NP202 reduced monocyte chemoattractant protein-1 expression (P < 0.05) and tended to attenuate active caspase-3 expression to similar levels observed in sham animals (P = 0.075). SignificanceImproved LV function and structural changes observed with NP202 may be mediated through inhibition of inflammatory and apoptotic processes in the MI setting. NP202 could therefore prove a useful addition to standard therapy in patients with post-MI LV dysfunction.

Abstract 10597: Epidural Sympathetic Afferent Blockade by Resiniferatoxin Reverses Vagal Dysfunction Following Myocardial Infarction

Introduction: Myocardial infarction (MI) induces sympathovagal imbalance, predisposing for ventricular tachyarrhythmias (VT). Thoracic epidural anesthesia reduces VT burden through sympathetic blockade. However, it is unknown if sympathetic afferent activation may cause vagal dysfunction, and if blockade of these spinal afferents can improve vagal function and reduce VT burden. Methods: Chronic MI was percutaneously created in Yorkshire pigs (n=8). In terminal experiments 6 to 8 weeks post MI, an epidural catheter was placed at the C7-T1 epidural space. After sternotomy, a 56 electrode sock was placed over the ventricles to record activation recovery intervals (ARI, surrogate of action potential duration). Effective refractory periods (ERP) were assessed via extra-stimulus pacing and left ventricular (LV) pressure monitored via a pressure catheter. Vagal function was assessed by baroreflex sensitivity (BRS) after phenylephrine (3 μg/kg, IV). ARIs, ERP, LV function, and BRS were checked before and after epidural RTX (0.6 μg/kg/ml). VT inducibility was assessed by endocardial extra-stimulus pacing from the right ventricular apex. Results: Epidural RTX led to a modest hemodynamic response peaking at 10.2 ± 4.2 min post-RTX with stabilization by 118 ± 15 min, characterized by increased LV systolic pressure (121±5.6 to 133±9.7 mmHg; p =ns) and contractility (1411±74 to 1514±163 mmHg/s; p =ns). While ARI and atrial/ventricular ERP did not change significantly, BRS was significantly augmented by 2 hrs (2.1±0.6 to 4.3±0.8 ms/mmHg, p &lt;0.01). 9/9 animals in our chronic MI model were inducible for VT by extra-stimulus pacing whereas only 1/6 were inducible for VT after epidural RTX ( p &lt;0.001). Conclusion: Blockade of nociceptive spinal sympathetic afferents by RTX augments reflexive vagal function without altering basal cardiac function. Blockade of nociceptive afferents and restoration of parasympathetic function alone may be sufficient to suppress VT.

Abstract 14327: Intramyocardial Delivery of an Imageable Theranostic Hydrogel Post Myocardial Infarction Alters Regional Strain and Reduces Remodeling in Chronic Porcine Model

Introduction: Myocardial infarction (MI) causes acute regional changes in stiffness and strain, resulting in pathological remodeling in the left ventricle (LV). Intramyocardial injection of hydrogel (HG) into the MI region may alter deformation and improve LV remodeling. Using high resolution cineCT (CCT) we evaluated changes in regional strain, global function, and geometry in chronic porcine MI model. Methods: Yorkshire pigs (n=12) subjected to 90 min balloon occlusion and reperfusion were randomized 5 days post MI to intramyocardial delivery of MI+HG (n=6) or MI only (n=6). Imageable HG was delivered in a 3x3 grid after assessing MI region with hybrid 201 Tl SPECT/CT. Contrast CCT was performed at baseline, day 5 (post MI before HG delivery), and day 12 (7 days post HG delivery) to assess end diastolic volume (EDV) and ejection fraction (EF). Custom software was used to calculate 3D myocardial Lagrangian strains on 6 HG animals and 3 MI only animals in remote, border (&gt;50% normal) and MI regions (&lt;50% normal). Results: At day 5 in both groups, EDV increased by 13.2% (p=0.016), LVEF decreased by 15.7% (p=0.008), and radial strain (E rr ) decreased in MI region by -0.11 (p=0.007). On day 12, EDV decreased by 8.3% in the MI+HG group but increased by 10.4% in the MI only group (p=0.003). LVEF increased significantly in the MI+HG group by 8.96% and was significantly greater than in MI only group (p=0.027) which had no significant changes. Average change in E rr between baseline and day 12 was not different between groups within the MI (p=0.13) or border region (p=0.67). However, average E rr did not decline in the MI+HG group (+0.029) but significantly declined in MI only group (-0.14, p=0.017) (MI+HG vs MI only; p=0.003), mirroring EDV changes. Conclusions: Intramyocardial delivery of HG 5 days post-MI resulted in greater improvement in E rr in remote region and global LVEF and a decrease in EDV suggesting reduced LV remodeling compared to MI only controls.