Post-myocardial Infarction Heart Failure Research Articles

Abstract 4138662: Mineralocorticoid receptor antagonist in patients with acute myocardial infarction: An updated systematic review and meta-analysis of randomized trials

Background: While mineralocorticoid antagonists (MRA) reduce mortality in patients developing heart failure post myocardial infarction (MI), it is unclear whether they are beneficial in an unselected post-MI population. Aims: Using a systematic review and meta-analysis, we aim to determine the effect of MRA treatment versus no MRA treatment on all-cause mortality in unselected post-MI patients from randomized data, simultaneously with the presentation of the largest randomized controlled trial on the topic, the CLEAR SYNERGY trial. Methods/Approach: We completed a systematic review of all randomized controlled trials comparing MRA treatment to no MRA treatment in post-MI patients. We will perform our primary analysis using fixed effects with the Peto odds ratio method and use random effects as a sensitivity analysis. The primary outcome will be all-cause mortality, and secondary outcomes will include cardiovascular mortality, new or worsening heart failure, recurrent myocardial infarction and stroke. Results/Data: Our systematic review of Pubmed, Embase, and CENTRAL from inception until April 30, 2024, yielded 456 records. A total of 11,199 participants from 11 randomized clinical trials will be included in addition to the late-breaking CLEAR SYNERGY trial. The CLEAR SYNERGY trial is a 2 x 2 factorial randomized controlled trial of low-dose colchicine 0.5mg daily versus placebo and spironolactone 25mg daily versus placebo in 7,062 post-MI patients who were within 72h of the index percutaneous coronary intervention. The results of the spironolactone factorial will be presented in the fall of 2024 with an expected median follow-up of 3.5 years. As the investigators of the CLEAR SYNERGY trial, we will combine our data with the other 11 trials for a total of 12 trials and 18,261 participants. Conclusions: CLEAR SYNERGY is the largest randomized controlled trial with the longest follow-up of spironolactone in the post-MI population. Our meta-analysis will provide updated effect estimates of post-MI MRA treatment, leveraging the late-breaking CLEAR SYNERGY data to reflect the totality of the evidence.

Shenmai injection improves lipid metabolism in post-myocardial infarction heart failure based on network pharmacology and experimental validation

BackgroundShenmai injection (SMI), a traditional Chinese medicine formulation derived from the herbal decoction Shenmai Yin, is widely used in treating cardiovascular disorders. This study extensively investigated the effects and mechanisms of action of SMI on lipid metabolism in post-myocardial infarction heart failure (pMIHF). MethodsNetwork pharmacology was employed to predict the key targets and associated pathways involved in lipid metabolism for potential SMI treatments in post-myocardial infarction heart failure (pMIHF). Subsequently, a pMIHF mouse model and an ischemia/reperfusion (I/R) cell model were established to delve deeper into and validate the underlying mechanism of action. ResultsWe performed network pharmacology analysis, which identified 48 active components in SMI and 201 common gene targets. Subsequent screening using the protein–protein interaction network identified 26 core targets, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, peroxisome proliferator-activated receptor alpha (PPARα), and sirtuin 1 (SIRT1). Based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, we predicted that SMI might act on lipid metabolism in pMIHF through the PPARα pathway, a hypothesis supported by the strong binding affinity between this receptor and the active components of SMI, as confirmed via molecular docking. In a left anterior descending artery-ligation mouse model, SMI significantly improved cardiac function, reduced serum free fatty acid levels, decreased inflammatory cell infiltration and myocardial fibrosis, and maintained myocardial mitochondrial morphology. In ischemia-reperfusion (I/R) cells, SMI reduced cell apoptosis, improved mitochondrial membrane potential, and decreased mRNA expression levels of IL-6 and TNF-α, while increasing protein levels of PPARα, SIRT1, and PPARα co-activator-1 alpha (PGC1α). ConclusionCollectively, our findings suggest that SMI enhances myocardial lipid metabolism and ameliorates pMIHF by upregulating the PPARα/SIRT1/PGC1α pathway.

Post-myocardial infarction heart failure and long-term high-fat diet: Cardiac endoplasmic reticulum stress and unfolded protein response in Sprague Dawley rat model.

Myocardial infarction (MI) significantly contributes to the global mortality rate, often leading to heart failure (HF) due to left ventricular remodeling. Key factors in the pathomechanism of HF include nitrosative/oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. Furthermore, while a high-fat diet (HFD) is known to exacerbate post-MI cardiac remodeling, its impact on these critical factors in the context of HF is not as well understood. This study aimed to assess the impact of post-MI HF and HFD on inflammation, nitro-oxidative stress, ER stress, and unfolded protein response (UPR). The study was performed on fragments of the left ventricle harvested from 30 male adult Sprague Dawley rats, which were divided into four groups based on diet (normal-fat vs. high-fat) and surgical procedure (sham operation vs. coronary artery ligation to induce MI). We assessed body weight, NT-proBNP levels, protein levels related to nitrosative/oxidative stress, ER stress, UPR, apoptosis, and nitric oxide synthases, through Western Blot and ELISA. HFD and MI significantly influenced body weight and NT-proBNP concentrations. HFD elevated 3-nitrotyrosine and myeloperoxidase levels and altered nitric oxide synthase levels. HFD and MI significantly affected ER stress markers and activated or inhibited UPR pathways. The study demonstrates significant impacts of post-MI HF and dietary fat content on cardiac function and stress markers in a rat model. The interaction between HFD and MI on UPR activation suggests the importance of dietary management in post-MI recovery and HF prevention.

Caveolar Compartmentalization of Pacemaker Signaling is Required for Stable Rhythmicity of Sinus Nodal Cells and is Disrupted in Heart Failure.

Heart rhythm relies on complex interactions between electrogenic membrane proteins and intracellular Ca2+ signaling in sinoatrial node (SAN) myocytes; however, mechanisms underlying the functional organization of proteins involved in SAN pacemaking and its structural foundation remain elusive. Caveolae are nanoscale, plasma membrane pits that compartmentalize various ion channels and transporters, including those involved in SAN pacemaking, via binding with the caveolin-3 scaffolding protein, but the precise role of caveolae in cardiac pacemaker function is unknown. Our objective was to determine the role of caveolae in SAN pacemaking and dysfunction (SND). Biochemical co-purification, in vivo electrocardiogram monitoring, ex vivo optical mapping, in vitro confocal Ca2+ imaging, and immunofluorescent and electron microscopy analyses were performed in wild type, cardiac-specific caveolin-3 knockout, and 8-weeks post-myocardial infarction heart failure (HF) mice. SAN tissue samples from donor human hearts were used for biochemical studies. We utilized a novel 3-dimensional single SAN cell mathematical model to determine the functional outcomes of protein nanodomain-specific localization and redistribution in SAN pacemaking. In both mouse and human SANs, caveolae compartmentalized HCN4, Cav1.2, Cav1.3, Cav3.1 and NCX1 proteins within discrete pacemaker signalosomes via direct association with caveolin-3. This compartmentalization positioned electrogenic sarcolemmal proteins near the subsarcolemmal sarcoplasmic reticulum (SR) membrane and ensured fast and robust activation of NCX1 by subsarcolemmal local SR Ca2+ release events (LCRs), which diffuse across ~15-nm subsarcolemmal cleft. Disruption of caveolae led to the development of SND via suppression of pacemaker automaticity through a 50% decrease of the L-type Ca2+ current, a negative shift of the HCN current (I f) activation curve, and a 40% reduction of Na+/Ca2+-exchanger function, along with ~2.3-times widening of the sarcolemma-SR distance. These changes significantly decreased the SAN depolarizing force, both during diastolic depolarization and upstroke phase, leading to bradycardia, sinus pauses, recurrent development of SAN quiescence, and significant increase in heart rate lability. Computational modeling, supported by biochemical studies, identified NCX1 redistribution to extra-caveolar membrane as the primary mechanism of SAN pauses and quiescence due to the impaired ability of NCX1 to be effectively activated by LCRs and trigger action potentials. HF remodeling mirrored caveolae disruption leading to NCX1-LCR uncoupling and SND. SAN pacemaking is driven by complex protein interactions within a nanoscale caveolar pacemaker signalosome. Disruption of caveolae leads to SND, potentially demonstrating a new dimension of SAN remodeling and providing a newly recognized target for therapy.

The significance of plasma biomarkers in predicting heart failure among patients with acute myocardial infarction

Background: Acute myocardial infarction (AMI) is characterized by high mortality and disability rates. Timely and effective revascularization has saved the lives of many patients. However, some patients develop complications such as heart failure (HF) following myocardial infarction, which significantly affects their quality of life and may even be life-threatening. Therefore, the search for effective biomarkers to predict the occurrence of HF after AMI, along with early prevention and treatment strategies, will greatly improve clinical outcomes for patients with post-myocardial infarction HF Methods: A total of 170 patients with acute myocardial infarction (AMI) were enrolled in this study, including 44 patients with post-AMI heart failure (HF) and 126 patients with post-AMI non-HF. We measured the serum biomarkers NT-proBNP, cTNT, PLR, NLR, and GDF-15 in all patients using enzyme-linked immunosorbent assay (ELISA). Subsequently, we performed t-tests to assess the predictive value of these biomarkers for post-AMI heart failure (HF). Results: In the group of HF patients, cTNT, NT-proBNP, GDF-15 and NLR was significantly higher than in the group without HF, but PLR was not .The AUC of NLR to predict HF after AMI was 0.632 (95%CI:0.542-0.723), P=0.010, with a cut-off value of (3.86×109)/L , GDF-15 was 0.661 (95%CI0.560-0.763), P=0.002, with a cut-off value of 1.35 ng/mL, and NT-proBNP was 0.82 (95%CI0.723-0.876), P<0.001, with a cut-off value of 1444 pg/mL. Conclusions: In five biomarkers, there is predictive value in NT-proBNP , NLR, GDF-15 for patients with HF after AMI .

The benefits and protective effects of copper nanoparticles green-formulated by Foeniculum vulgare extract on rats with heart failure following myocardial infarction

This study explores the potential of green-synthesized copper nanoparticles (Cu@Fv NPs) derived from fennel (Foeniculum vulgare) seeds for treating heart failure after a myocardial infarction. Fennel boasts a rich history in traditional medicine, and this research leverages its properties for a novel approach to nanomedicine. We successfully synthesized Cu@Fv NPs with well-defined spherical morphology and an average size of 48.46 nm, as confirmed by advanced characterization techniques. In vivo studies on rats with induced heart failure demonstrated the protective effects of Cu@Fv NPs. Notably, oral administration of Cu@Fv NPs at specific doses significantly reduced the lung/body weight ratio, inhibited neurohormonal activation, and led to a remarkable decrease in infarct size. Additionally, Cu@Fv NPs treatment resulted in improved cardiac function, evidenced by increased +/−dp/dt(max) and decreased LVEDP. These findings unveil the promising potential of Cu@Fv NPs as a biocompatible and potentially superior therapeutic strategy for managing heart failure post-myocardial infarction. This green synthesis method offers a sustainable and eco-friendly alternative to conventional nanoparticle production, paving the way for further exploration in nanomedicine.

Potential Role of Gene Therapy Targeting Hippo Signaling with Adeno-Associated Virus Based Vectors in Heart Failure Post-Myocardial Infarction

Heart failure is a condition that occurs when the heart cannot pump enough blood for the body's needs. This disease is caused by loss of cardiomyocytes and fibrosis, and is a leading cause of death worldwide. Current therapeutic treatments cannot generally directly replace lost cardiomyocytes in the myocardium, so the prognosis for patients with post-myocardial infarction heart failure remains poor. Based on the results of recent research, deactivating the Salvador (Sav) function in the Hippo pathway can regenerate cardiomyocyte cells. Gene therapy using Sav knockdown with adeno-associated virus (AAV) vector-based short hairpin RNA (shRNA), and restricted to cardiomyocytes by using the cTnT promoter, can specifically target cardiomyocyte cells in the infarction area so that it can become a new therapy for heart failure after myocardial infarction. Keywords: AAV, gene therapy, hippo pathway, post-myocardial infarction heart failure

Lipidomic analyses reveal potential biomarkers for predicting death and heart failure after acute myocardial infarction

BackgroundAcute myocardial infarction (AMI) and postmyocardial infarction heart failure (pMIHF) have high mortality rates worldwide. This study aimed to explore lipidomic profiles and identify potential biomarkers for the prediction of death and heart failure (HF) after AMI.MethodsAll serum samples were collected at Xuanwu Hospital, Capital Medical University, and their clinical characteristics and lipidomic profiles were analyzed in different groups. LC-MS/MS was used for lipidomic analyses, and underlying biomarkers were screened by receiver operating characteristic (ROC) curve analysis.ResultsLipidomic analyses of the survival and nonsurvival groups revealed that the decrease of the content of SM (d18:1/22:0), PE (P-20:1/18:0), PC (18:2), LPE (18:2), PE (P-20:0/18:0), LPC (18:0) and PC (20:0/20:3) while increase of the content of PG (18:1/18:1) could increase the risk of death after AMI. In parallel, the lipidomic analysis of the HF and non-HF groups revealed that the decrease of the content of PC (20:3/20:4), LPC (20:3), LPC (18:0), LPC (18:2), LPC (20:0), LPC (18:3), LPE (16:1) and PC (18:2/20:3) could increase the risk of HF after AMI.ConclusionSeveral lipids could be potential biomarkers for the prediction of death and HF after AMI.

Macrophage-mediated heart repair and remodeling: A promising therapeutic target for post-myocardial infarction heart failure.

Heart failure (HF) remains prevalent in patients who survived myocardial infarction (MI). Despite the accessibility of the primary percutaneous coronary intervention and medications that alleviate ventricular remodeling with functional improvement, there is an urgent need for clinicians and basic scientists to further reveal the mechanisms behind post-MI HF as well as investigate earlier and more efficient treatment after MI. Growing numbers of studies have highlighted the crucial role of macrophages in cardiac repair and remodeling following MI, and timely intervention targeting the immune response via macrophages may represent a promising therapeutic avenue. Recently, technology such as single-cell sequencing has provided us with an updated and in-depth understanding of the role of macrophages in MI. Meanwhile, the development of biomaterials has made it possible for macrophage-targeted therapy. Thus, an overall and thorough understanding of the role of macrophages in post-MI HF and the current development status of macrophage-based therapy will assist in the further study and development of macrophage-targeted treatment for post-infarction cardiac remodeling. This review synthesizes the spatiotemporal dynamics, function, mechanism and signaling of macrophages in the process of HF after MI, as well as discusses the emerging bio-materials and possible therapeutic agents targeting macrophages for post-MI HF.

Excessive autophagy of myocardial cells promotes ferroptosis and exacerbates heart failure in the state of myocardial infarction

IntroductionThis study investigates the molecular mechanisms by which excessive autophagy exacerbates post-myocardial infarction heart failure(post-MI HF) through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis.Material and methodsWe developed a post-MI heart failure model in Sprague-Dawley rats via coronary artery ligation, alongside an in vitro heart failure model using hypoxia/reoxygenation-stimulated H9C2 cells. Intervention with rapamycin (autophagy activator), 3-methyladenine (autophagy inhibitor), desferrioxamine, and ferredoxin-1(ferroptosis inhibitors). Various techniques, including echocardiography, immunofluorescence colocalization, C11 BODIPY 581/591 staining, flow cytometry, transmission electron microscopy, western blotting, and RT-qPCR, were employed.ResultsIn vivo analyses revealed that NCOA4-mediated ferritinophagy and ferroptosis are significant in post-MI HF. Manipulating autophagy through rapamycin and 3-methyladenine influenced the expression of NCOA4 and glutathione peroxidase 4 (GPX4), subsequently affecting ferroptosis and modulating heart failure severity. Our in vitro experiments corroborated these findings, demonstrating that heightened autophagy amplifies NCOA4 expression, which in turn fosters ferroptosis and exacerbates myocardial injury. Interestingly, silencing of NCOA4 partially mitigated autophagy-induced iron deficiency, indicating a crucial intersection between autophagy and iron metabolism. Moreover, the cardioprotective effects observed following NCOA4 silencing were negated by concurrent GPX4 silencing.ConclusionsOur findings elucidate that autophagy precedes NCOA4 in its regulatory pathway and directly influences ferritinophagy. Enhanced autophagy augments intracellular free iron and unstable iron pools, triggering lipid peroxidation through ferritinophagy, which promotes ferroptosis and impairs cardiac function. These insights offer a novel scientific basis for developing therapeutic strategies for heart failure post-MI HF.

Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury

The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.

Subclinical congestion in patients presenting with acute coronary syndrome

Abstract Funding Acknowledgements None. Introduction Patients admitted due to acute coronary syndrome (ACS) are stratified using Killip class for the severity of the post myocardial infarction (MI) heart failure (HF). Killip class classification is mainly based on clinical examination and overt signs and symptoms are usually needed to be present. Purpose To evaluate subclinical congestion with lung ultrasound (LUS) in patients presenting with acute coronary syndrome. Methods For a period of 4 years, we recorded the patients presented to the emergency department of our hospital due to acute coronary syndrome (HF) and no symptoms or signs of heart failure (Killip class I). LUS was performed on admission and patients were classified as having either "wet lung" (&amp;gt;3 b-lines in at least 3 lung fields) or "dry lung". Baseline characteristcs, laboratory findings as well as the result of the coronary angiogram were alse recorded. Results 286 patients were recorded, with mean age 71,2 years, 43,35% were female and 56,6% male. 36.01% of the patients presented with ST elevation MI (STEMI) and 63.98% with non ST elevation MI (NSTEMI). 34.2% of patients were classified as having "wet lung". Of them, 63.98% were STEMI patients and 36.1% NSTEMI. 27.2% were males and 72.8% females and 64.6% older than 60 years old. 10.7% had on admission left ventricular ejection fraction (LVEF) &amp;gt;50% whereas 89.3 % had LVEF &amp;lt;50%.Finally, 12,7% were found to have 1 vessel disease, 23.4% 2 vessel disease and 63.9% 3 vessel disease. Compared to patients classified as having "dry lung", patients with "wet lung" stayed in the hospital 74 days (vs 3.2, p&amp;lt;0.01), and their mean troponin levels were 10721 pg/ml (vs 3254 pg/ml, p&amp;lt;0.01). "Wet lung" patients were found to have mean GFR 56,2 mL/min/1.73 m² (vs 86.7 mL/min/1.73 m² , p&amp;lt;0.05). Conclusion 34.2% of the patients admitted due to ACS Killip 1, were classified as having "wet lung" when examined with LUS, suggesting a status of subclinical congestion. These patients were most often STEMI patients, female and of older age and were found to have reduced LVEF. Compared to the "dry lung" patients had higher troponin levels and most oftenly impaired renal function. LUS could help identify these patients, that although they seem to be asymptomatic in terms of HF, they probably need closer monitoring.

FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation

Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFβ and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFβ-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin–proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFβ. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function.

A division-of-labor mode contributes to the cardioprotective potential of mesenchymal stem/stromal cells in heart failure post myocardial infarction.

Treatment of heart failure post myocardial infarction (post-MI HF) with mesenchymal stem/stromal cells (MSCs) holds great promise. Nevertheless, 2-dimensional (2D) GMP-grade MSCs from different labs and donor sources have different therapeutic efficacy and still in a low yield. Therefore, it is crucial to increase the production and find novel ways to assess the therapeutic efficacy of MSCs. hUC-MSCs were cultured in 3-dimensional (3D) expansion system for obtaining enough cells for clinical use, named as 3D MSCs. A post-MI HF mouse model was employed to conduct in vivo and in vitro experiments. Single-cell and bulk RNA-seq analyses were performed on 3D MSCs. A total of 125 combination algorithms were leveraged to screen for core ligand genes. Shinyapp and shinycell workflows were used for deploying web-server. 3D GMP-grade MSCs can significantly and stably reduce the extent of post-MI HF. To understand the stable potential cardioprotective mechanism, scRNA-seq revealed the heterogeneity and division-of-labor mode of 3D MSCs at the cellular level. Specifically, scissor phenotypic analysis identified a reported wound-healing CD142+ MSCs subpopulation that is also associated with cardiac protection ability and CD142- MSCs that is in proliferative state, contributing to the cardioprotective function and self-renewal, respectively. Differential expression analysis was conducted on CD142+ MSCs and CD142- MSCs and the differentially expressed ligand-related model was achieved by employing 125 combination algorithms. The present study developed a machine learning predictive model based on 13 ligands. Further analysis using CellChat demonstrated that CD142+ MSCs have a stronger secretion capacity compared to CD142- MSCs and Flow cytometry sorting of the CD142+ MSCs and qRT-PCR validation confirmed the significant upregulation of these 13 ligand factors in CD142+ MSCs. Clinical GMP-grade 3D MSCs could serve as a stable cardioprotective cell product. Using scissor analysis on scRNA-seq data, we have clarified the potential functional and proliferative subpopulation, which cooperatively contributed to self-renewal and functional maintenance for 3D MSCs, named as "division of labor" mode of MSCs. Moreover, a ligand model was robustly developed for predicting the secretory efficacy of MSCs. A user-friendly web-server and a predictive model were constructed and available (https://wangxc.shinyapps.io/3D_MSCs/).

Reticulon 3 deficiency ameliorates post-myocardial infarction heart failure by alleviating mitochondrial dysfunction and inflammation.

Multiple molecular mechanisms are involved in the development of heart failure (HF) after myocardial infarction (MI). However, interventions targeting these pathological processes alone remain clinically ineffective. Therefore, it is essential to identify new therapeutic targets for alleviating cardiac dysfunction after MI. Here, gain- and loss-of-function approaches were used to investigate the role of reticulon 3 (RTN3) in HF after MI. We found that RTN3 was elevated in the myocardium of patients with HF and mice with MI. Cardiomyocyte-specific RTN3 overexpression decreased systolic function in mice under physiological conditions and exacerbated the development of HF induced by MI. Conversely, RTN3 knockout alleviated cardiac dysfunction after MI. Mechanistically, RTN3 bound and mediated heat shock protein beta-1 (HSPB1) translocation from the cytosol to the endoplasmic reticulum. The reduction of cytosolic HSPB1 was responsible for the elevation of TLR4, which impaired mitochondrial function and promoted inflammation through toll-like receptor 4 (TLR4)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1α) and TLR4/Nuclear factor-kappa B(NFκB) pathways, respectively. Furthermore, the HSPB1 inhibitor reversed the protective effect of RTN3 knockout on MI. Additionally, elevated plasma RTN3 level is associated with decreased cardiac function in patients with acute MI. This study identified RTN3 as a critical driver of HF after MI and suggests targeting RTN3 as a promising therapeutic strategy for MI and related cardiovascular diseases.

A Personalized Cell-Based Therapy for Ischemic Heart Failure With Reduced Ejection Fraction: Safety and Feasibility Outcomes of the Roll-In Cohort of the CardiAMP Cell Therapy Trial and Review of Similar Trials.

CardiAMP Cell Therapy for Heart Failure trial is a prospective, multicenter, randomized, controlled, double-blinded trial that has been granted breakthrough designation by the United States Food and Drug Administration. This trial evaluates clinical outcomes of intramyocardial delivery of a high dose of autologous bone marrow mononuclear cells in chronic postmyocardial infarction heart failure patients. This trial represents the first attempt to personalize marrow-derived cell-based therapy for the treatment of ischemic heart failure with reduced ejection fraction. The roll-in cohort of 10 patients demonstrated improvements in 6-minute walk distance at 6 months (+47.8 m, P = 0.01), 12 months (+46.4 m, P = 0.06), and 24 months (+31 m), and improvements in New York Heart Association class at 3 months (P = 0.015) and 6 months (P = 0.037). Four patients were reduced to New York Heart Association class I at 24 months and Minnesota Living with Heart Failure Questionnaire score was improved in 6 of 10 patients at 24 months. The improved clinical outcomes demonstrated in CardiAMP are consistent with previous clinical trials including the Transendocardial Autologous Cells in Ischemic Heart Failure (TAC-HFT) trial, Prospective Randomized Trial of Direct Endomyocardial Implantation of Bone Marrow Cells for Treatment of Severe Coronary Artery Diseases (PROTECT-CAD), and REGENERATE-Ischemic Heart Disease trial.

Fuyu Decoction ameliorates myocardial fibrosis in rat model of heart failure by regulating Nrf2/GPX4-mediated ferroptosis

This study aims to investigate the effect and mechanism of Fuyu Decoction(FYD) in the treatment of myocardial fibrosis in the rat model of heart failure(HF). Sixty Wistar rats were randomized into a modeling group(n=50) and a sham group(n=10). A post-myocardial infarction HF model was established by ligating the left anterior descending coronary artery in rats. The successfully modeled rats were assigned into model, low-dose(2.5 g·kg~(-1)) FYD(FYD-L), high-dose(5.0 g·kg~(-1)) FYD(FYD-H), and FYD+Nrf2 inhibitor(ML385, 30 mg·kg~(-1)) groups(n=10). FYD was administrated by gavage and ML385 by intraperitoneal injection. The rats in the sham and model groups were administrated with equal amounts of normal saline by gavage. After 8 weeks of intervention, the cardiac function indicators were measured, and the myocardial tissue morphology and collagen deposition were observed. The positive expression of collagens Ⅰ and Ⅲ, apoptosis, and oxidative stress were examined, and the levels of Fe~(2+) and reactive oxygen species(ROS) were determined. The protein levels of nuclear factor erythroid 2-related factor 2(Nrf2), solute carrier family 7 member 11(SLC7A11), glutathione peroxidase 4(GPX4), and acyl-coenzyme A synthase long chain family member 4(ACSL4) in the myocardial tissue were determined. Compared with sham group, the model group showed decreased left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), increased left ventricular end internal dimension in systole(LVIDs), left ventricular internal diameter in diastole(LVIDd), and myocardial collagen deposition, positive expression of collagens Ⅰ and Ⅲ, elevated apoptosis rate and malondialdehyde(MDA), Fe~(2+), and ROS levels, lowered superoxide dismutase(SOD) and glutathione peroxidase(GSH) levels, down-regulated protein levels of Nrf2, SLC7A11, and GPX4, and up-regulated protein level of ACSL4. Compared with the model group, the above indicators were restored by FYD. Moreover, ML385 reversed the protective effect of FYD on myocardial fibrosis in HF rats. In conclusion, FYD can inhibit ferroptosis by activating the Nrf2/GPX4 pathway, thereby ameliorating myocardial fibrosis in HF rats.

Carbonic Anhydrase 3 is required for cardiac repair post myocardial infarction via Smad7-Smad2/3 signaling pathway.

Appropriate fibrosis is required to prevent subsequent adverse remodeling and heart failure post myocardial infarction (MI), and cardiac fibroblasts (CFs) play a critical role during the process. Carbonic anhydrase 3 (CAR3) is an important mediator in multiple biological processes besides its CO2 hydration activity; however, the role and underlying mechanism of CAR3 on cardiac repair post MI injury remains unknown. Here, we found that CAR3 expression was up-regulated in cardiac tissue in infarct area at the reparative phase of MI, with a peak at 7 days post MI. The upregulation was detected mainly on fibroblast instead of cardiomyocyte, and primary cardiac fibroblasts treated with TGF-β1 recaptured our observation. While CAR3 deficiency leads to weakened collagen density, enlarged infarct size and aggravated cardiac dysfunction post-MI. In fibroblast, we observed that CAR3 deficiency restrains collagen synthesis, cell migration and gel contraction of cardiac fibroblasts, whereas overexpression of CAR3 in CFs improves wound healing and cardiac fibroblast activation. Mechanistically, CAR3 stabilizes Smad7 protein via modulating its acetylation, which dampens phosphorylation of Smad2 and Smad3, thus inhibiting fibroblast transformation. In contrast, inhibition of Smad7 acetylation with C646 blunts CAR3 deficiency induced suppression of fibroblast activation and impaired cardiac healing. Our data demonstrate a protective role of CAR3 in cardiac wound repair post MI via promoting fibroblasts activation through Smad7-TGF-β/Smad2/3 signaling pathway.

Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction.

Post-myocardial infarction heart failure (HF) is a major public health concern. Previous studies have reported the critical role of immune response in HF pathogenesis. However, limited studies have reported predictive immune-associated biomarkers for HF. So we attempted to identify potential immune-related indicators for HF early diagnosis and therapy guidance. This study identified two potential immune-related hub genes (IRHGs), namely CXCR5 and FOS, using bioinformatic approaches. The expression levels of CXCR5 and FOS and their ability to predict long-term HF were analyzed. Functional enrichment analysis revealed that the hub genes were enriched in immune system processes, including the interleukin-17 and nuclear factor-kappa B signaling pathways, which are involved in the pathogenesis of HF. Quantitative real-time polymerase chain reaction revealed that the Fos mRNA levels, but not the Cxcr5 mRNA levels, were downregulated in the mice of the HF group. This study successfully identified two IRHGs that were significantly and differentially expressed in the HF group and could predict long-term HF, providing novel insights for future studies on HF and developing novel therapeutic targets for HF.

Abstract 16391: Pro-Neoplastic Properties of Small Extracellular Vesicles From Failing Hearts

Background: Heart diseases are associated with an increased incidence of cancer independently of shared risk factors. The mechanism beyond this link is complex, unclear and limits our ability to develop effective therapies. We aimed to test the hypothesis that small cardiac extracellular vesicles (sEVs) contribute to the link between HF and cancer. Methods &amp; Results: We used mouse models of heterotopic and orthotopic lung cancer and post-myocardial infarction (MI) heart failure (HF). sEVs were isolated by size exclusion chromatography. To determine the role of cardiac EVs in tumor growth, we focused on sEVs from cardiac mesenchymal stromal cells (cMSCs). cMSCs after MI secreted twice more sEVs, characterized with a unique proteome, compared with cMSCs from sham-MI ( Fig 1A ). cMSC-sEVs from post-MI HF harbored more tumor-promoting cytokines and microRNA (miR), such as periostin, osteopontin, IL-6, TNFα, galectin-3, and miR's 221 and 21. The pro-neoplastic effects of cMSC-sEVs on cancer cells were depended on cancer type, with a marked increase in proliferation and migration of lung and colon cancer cells but only a modest increase with more malignant triple-negative breast and melanoma cancer cells. Next, we inoculated lung cancer cells into mice and found that post-MI HF accelerated tumor growth. Furthermore, adoptive transfer of cMSC-sEVs from failing hearts accelerated tumor growth with and without systemic EV depletion ( Fig 1B ). Finally, we found that spironolactone mitigated the neoplastic effects of HF, attenuated tumor growth ( Fig 1C ), and reduced the number of cMSC-sEVs by 26%. Conclusions: We show, for the first time, that cardiac extracellular vesicles from post-MI failing heart harbor pro-neoplastic properties and promote tumor growth independently of other secreted factors. Spironolactone reduces the number of cardiac extracellular vesicles and the pro-neoplastic effects of post-MI heart failure.