Search Results (58)

Post-infarction left ventricular aneurysm is an uncommon but severe mechanical complication of transmural myocardial infarction, particularly in patients with delayed presentation or incomplete myocardial salvage. It may lead to profound distortion of left ventricular geometry, adverse remodelling, intraventricular thrombosis, mitral regurgitation, pulmonary hypertension, and advanced heart failure. We report the case of a 65-year-old male patient referred two months after a late-presenting anterior ST-segment elevation myocardial infarction caused by proximal occlusion of the left anterior descending coronary artery. At admission, the patient presented with severe decompensated heart failure, low-output status, multiorgan dysfunction, and a left ventricular ejection fraction of 12%. Transthoracic echocardiography and cardiac magnetic resonance imaging demonstrated a giant apical left ventricular aneurysm involving approximately 75% of the ventricular cavity, partial intraluminal thrombosis, extensive transmural scarring in the left anterior descending territory, and imaging features suggestive of a chronic contained free-wall rupture/pseudoaneurysmal component. Following multidisciplinary evaluation, the patient underwent surgical ventricular reconstruction using an endoventricular circular restoration technique guided by an intraventricular balloon sizer, combined with left internal thoracic artery bypass grafting to the left anterior descending artery. The early postoperative course required temporary inotropic, vasopressor, inhaled nitric oxide, and intra-aortic balloon pump support, followed by progressive haemodynamic recovery. The patient was discharged on postoperative day seven with functional improvement to NYHA class II. At six-month follow-up, he remained clinically stable without overt signs of heart failure, and echocardiography showed preserved ventricular geometry and improvement of left ventricular ejection fraction to 45%. This case highlights the potential role of carefully planned, balloon-guided surgical ventricular reconstruction in selected patients with giant post-infarction left ventricular aneurysms and end-stage heart failure when residual viable myocardium is present. Full article

Myocardial ischemia and reperfusion initiate spatially organized injury–repair programs that subsequently shape ventricular remodeling. Although cardiac fibroblasts are indispensable for scar formation, single-cell and spatial transcriptomic studies reveal temporally dynamic and regionally distinct fibroblast-lineage states. This critical narrative review integrates direct evidence from myocardial ischemia–reperfusion (I/R) with model-labeled evidence from permanent myocardial infarction, clinically heterogeneous human infarction, fibroblast-specific ubiquitin biology, cell-cycle regulation, and cardiac fibroblast atlases. A direct fibroblast I/R study identifies an HSP47–USP10–SMAD4 deubiquitination axis, whereas most other fibroblast ubiquitin–proteasome system (UPS) mechanisms derive from permanent infarction, non-ischemic cardiac stress, or in vitro systems. We propose that CCNB1-associated, G2/M-enriched cycling fibroblast-lineage states may impose heightened proteostatic demands within defined post-ischemic niches. The conceptual novelty is not that CCNB1 turnover or UPS activity is cardiac-specific; both are general features of proliferating cells. Rather, the framework asks whether fibroblast lineage, injury-model provenance, anatomical niche, temporal window, cell state, and substrate-specific UPS nodes jointly define proteostatic dependencies during post-ischemic remodeling. RNA-based ubiquitin-related signatures remain transcriptional proxies and do not directly quantify ubiquitinated substrates, ubiquitin-chain topology, enzyme activity, or proteasome flux. Resolving the proposed relationships will require spatial colocalization, protein-level and ubiquitin-remnant profiling, proteasome and ribosome assays, fibroblast-specific perturbation, and validation in human infarct tissue. Full article

Background: Myocardial infarction triggers a complex remodeling process involving inflammation, hypertrophy, fibrosis, and electrical adaptation, ultimately predisposing the heart to failure. Krüppel-like factors (KLFs) are transcriptional regulators implicated in cardiovascular development and disease; however, a comprehensive temporal characterization of their coordinated activity during post-injury remodeling remains lacking. Objective: To define the temporal orchestration of the KLF family during myocardial injury and hypertrophy, and to integrate these dynamics within regulatory networks associated with cardiac remodeling. Methods: Myocardial injury was induced in rats using intraperitoneal isoproterenol. Left ventricular tissue was collected over a 21-day period. Cardiac morphometry, histology, immunohistochemistry, and quantitative gene expression analyses were performed to evaluate structural and transcriptional changes. Publicly available human cardiac and fibroblast datasets were analyzed for translational comparison, and protein–protein interaction networks were constructed to identify functional associations. Results: Isoproterenol treatment induced progressive hypertrophy, structural disorganization, and sustained fibrotic remodeling. KLFs displayed coordinated, phase-specific regulation, characterized by early activation of inflammation-associated members, intermediate engagement of factors linked to transforming growth factor signaling and hypertrophy modulation, and late induction of regulators associated with apoptosis and scar formation. These temporal patterns paralleled changes in inflammatory mediators, cardiac transcription factors, and genes involved in electrical and calcium handling pathways. Human expression analyses supported tissue-specific specialization of key KLFs. Conclusions: KLFs exhibit a coordinated and temporally structured regulatory program during myocardial remodeling, functioning as a transcriptional network that integrates inflammation, fibrosis, hypertrophy, and electrical adaptation. These findings position KLFs as key regulatory nodes in cardiac remodeling and potential targets for therapeutic intervention. Full article

Epicardial mesothelium plays a pivotal role in postinfarction cardiac repair by generating fibroblasts, producing extracellular matrix, and releasing paracrine mechanisms. However, interspecies differences have not been sufficiently studied, particularly in in vivo models of scar-free healing such as the African spiny mouse (Acomys cahirinus). This study aimed to compare the profibrotic response of epicardial mesothelial cells (MCs) from Acomys and C57BL/6 mice to hypoxic stress, a key factor in postinfarction recovery. We isolated epicardial MCs from the African spiny mouse (Acomys cahirinus), a species with documented cardiac regenerative capabilities, and from C57BL/6 laboratory mice. Using a CoCl₂-induced hypoxia model in vitro, we assessed cell viability, morphological changes, and expression of epithelial and fibroblast markers. In vivo, following experimental myocardial infarction (MI), we evaluated tissue hypoxia (pimonidazole adducts), epicardial activation (layer thickness, Wt1⁺ and TBX18⁺ progenitor cells), and collagen accumulation. The study was conducted using real-time PCR, Western blotting, immunohistochemical analysis and microscopic examination. In vitro, MCs from both species exhibited an epithelial-like phenotype under normoxic conditions, expressing E-cadherin and cytokeratin 18. Hypoxia (200 µM CoCl₂) induced a comparable response in both Acomys and C57BL/6 cells, characterized by a shift to a spindle-shaped, fibroblast-like morphology, decreased E-cadherin expression, and increased pro-collagen 1 and α-SMA expression. Following MI, both species exhibited similarly extensive hypoxic areas affecting the epicardial zone. Epicardial activation dynamics were comparable: from day 3 post-MI, epicardial thickness increased significantly, and Wt1⁺ and TBX18⁺ progenitor cells accumulated, peaking during the first week. Collagen accumulation in the epicardial region was similar between species, although the number of Wt1⁺ cells was higher in C57BL/6 on day 7. Despite the well-known superior regenerative capacity of spiny mice, epicardial MCs from Acomys and C57BL/6 demonstrated similar signs of profibrotic responses to hypoxic stimulation both in vitro and following MI. These findings suggest that species-specific regenerative outcomes may not be attributable to differential acute epicardial sensitivity to hypoxia, but rather to downstream mechanisms or additional factors influencing the cardiac repair process. This study provides the first characterization of Acomys epicardial MCs and establishes a foundation for further investigation of evolutionarily conserved and species-specific mechanisms of cardiac regeneration. Full article

Myocardial infarction (MI) triggers a robust inflammatory response that is essential for tissue repair but, when excessive or prolonged, drives pathological cardiac remodelling and heart failure. Colony-stimulating factor 2 (CSF2) signalling has been implicated in driving pro-inflammatory macrophage activation post-MI. Here, we investigated the role of macrophage-specific CSF2 receptor alpha (CSF2RA) signalling in post-MI remodelling using a tamoxifen-inducible genetic mouse model and permanent coronary artery ligation. Macrophage-specific Csf2ra deficiency significantly improved left ventricular systolic function post-MI without altering cardiac fibrosis burden. Functional improvement was associated with enhanced collagen scar maturation, characterised by an increased proportion of mature collagen fibres, and with accumulation of anti-inflammatory, pro-reparative macrophages within the infarct. These macrophage changes were accompanied by increased fibroblast density, consistent with altered macrophage–fibroblast crosstalk. Collectively, these findings identify macrophage-intrinsic CSF2RA signalling as a critical regulator of inflammatory resolution and scar maturation after MI and provide mechanistic support for the rationale of selective CSF2RA inhibition as a therapeutic strategy to limit adverse cardiac remodelling and improve post-infarction recovery. Full article

Acute myocardial infarction (AMI) results from a lack of oxygen supply to the myocardium, leading to the loss of cardiomyocytes and their replacement with fibrotic scar tissue. This process is closely associated with the development of heart failure. Regenerative medicine has emerged as a promising strategy to enhance treatment outcomes in severe cases of heart failure. This study aimed to evaluate myocardial regeneration after AMI using a biomaterial composed of mononuclear stem cells and human amniotic membrane. A total of 120 Wistar rats were subjected to experimentally induced AMI. On the 7th day post-infarction, rats with an ejection fraction of <50% on echocardiography were randomized into four groups: (1) control; (2) stem cells; (3) amniotic membrane; and (4) amniotic membrane combined with stem cells. On the 30th day, the surviving animals underwent a second echocardiographic evaluation and were subsequently euthanized. The group treated with the combination of amniotic membrane and stem cells showed reduced systolic and diastolic ventricular volumes. Histological analysis revealed that these animals exhibited less fibrosis and a lower percentage of type I collagen. Based on the results of the study, it was concluded that the combination of human amniotic membrane and mononuclear stem cells decreased ventricular volumes and myocardial fibrosis, suggesting more favorable ventricular remodeling in this experimental model. Full article

Background/Objective: GHRP-6 is a GH secretagogue hexapeptide with expanding and promising cardioprotective effects. Having determined 0.4 mg/kg as the minimum effective dose for enhancing inotropy based on echocardiographic parameters in healthy rats, we implemented a non-reperfusion myocardial infarct model, with its consequent left ventricle wall thinning and ballooning, via permanent left descending coronary artery ligation. Methods: Rats were assigned to three groups: sham-operated/normal rats, infarcted + saline-treated control rats, and infarcted + GHRP-6-administration rats. Treatments were initiated post-surgery and continued for 7 days. On day 7, the animals were echocardiographically and histologically evaluated. For mitochondrial proteomic analysis, an additional 12 healthy rats were used. Six animals received GHRP-6 or normal saline and were observed for 6 h after the inoculation. Results: Here, we show that GHRP-6 attenuated myocardial tissue demise, reduced myocardial interstitial fibrosis/scarring, and integrally improved left ventricle physiology. The proteomic analysis indicated that the GHRP-6 cardioprotective effects may be theoretically mediated by the concerted upregulation of proteins/pathways involved in fatty acid beta-oxidation, apoptosis prevention pathways, antioxidant defenses, and mitochondrial metabolic reprogramming. Conclusions: GHRP-6 is a potent cardioprotective candidate attenuating morphological and functional outcomes caused by late ischemia. Full article

Kynurenic acid (KynA), a tryptophan metabolite that regulates immune homeostasis via G protein-coupled receptor 35 (GPR35), has an undefined role in post-myocardial infarction (MI) immune responses. To clarify this role, we established a murine MI model and administered KynA intraperitoneally to evaluate cardiac function and ventricular remodeling. Macrophage infiltration was assessed, and macrophages were depleted via clodronate liposomes to confirm their contribution to KynA-mediated cardioprotection. In bone marrow-derived macrophages (BMDMs), GPR35-targeted siRNA verified the receptor-dependent action of KynA. KynA improved cardiac function, reduced infarct scarring and fibrosis, and suppressed pro-inflammatory macrophage infiltration in MI mice, with these cardioprotective effects abrogated by macrophage depletion. Mechanistically, KynA inhibited voltage-dependent anion channel 1 oligomerization, prevented mitochondrial DNA leakage, and downregulated the cGAS/STING/TBK1/IκBα/P65 pathway in macrophages, while exogenous mitochondrial DNA counteracted this inhibition. Collectively, the KynA/GPR35 axis exerts cardioprotective effects against MI by attenuating macrophage pro-inflammatory responses, highlighting its potential as a novel therapeutic target. Full article

An ancient evolutionary regenerative mechanism of injured myocardium in vertebrates has been conserved in zebrafish, urodeles (salamander, newt, and axolotl) and neonatal mice. This innate regenerative mechanism is characterized by extensive migration of pro-regenerative macrophages into the injured myocardium and non-immune activation of parts of the complement system. Loss of regenerative activity in neonatal mice within a few days after birth implies that it is suppressed and replaced by fibrotic repair and scar formation. Fibrosis prevents ventricular wall rupture following myocardial infarction (MI), but it compromises contractility and can lead to heart failure and premature death. Reactivation of the suppressed regenerative mechanism in post-MI adult mice may be feasible by localized immune activation of the complement system, resulting in extensive recruitment of pro-regenerative macrophages into the injured myocardium, recapitulating neonatal mechanisms. Localized complement activation can be achieved by a new method of harnessing the natural anti-Gal antibody, which constitutes ~1% of human immunoglobulins and binds the carbohydrate antigen “α-gal epitope”. α-Gal nanoparticles (small liposomes presenting multiple α-gal epitopes) bind anti-Gal when administered into reperfused myocardium post-MI in anti-Gal-producing mice, thereby inducing localized complement activation. In this novel approach, macrophages recruited into the ischemic myocardium by complement cleavage chemotactic peptides, and binding anti-Gal-coated α-gal nanoparticles, polarize to become pro-regenerative macrophages that produce pro-regenerative cytokines and recruit stem cells. This process results in near-complete regeneration of the injured myocardium within 14 days. Future evaluation of this novel approach in larger animal models will help in determining whether trans-endocardial delivery by catheter of α-gal nanoparticles into ischemic myocardium warrants clinical application in acute MI. Full article

Ischemic heart disease remains the leading cause of cardiovascular mortality worldwide. In myocardial infarction (MI), extracellular vesicles (EVs)—particularly small EVs (sEVs)—transport therapeutic cargo such as miR-21-5p, which suppresses apoptosis, and other proteins, lipids, and RNAs that can modulate cell death, inflammation, angiogenesis, and remodeling. This review synthesizes recent mechanistic and preclinical evidence on native and engineered EVs for post-MI repair, mapping therapeutic entry points across the MI timeline (acute injury, inflammation, and healing) and comparing EV sources (stem-cell and non-stem-cell), administration routes, and dosing strategies. We highlight engineering approaches—including surface ligands for cardiac homing, rational cargo loading to enhance potency, and biomaterial depots to prolong myocardial residence—that aim to improve tropism, durability, and efficacy. Manufacturing and analytical considerations are discussed in the context of contemporary guidance, with emphasis on identity, purity, and potency assays, as well as safety, immunogenicity, and pharmacology relevant to cardiac populations. Across small- and large-animal models, EV-based interventions have been associated with reduced infarct/scar burden, enhanced vascularization, and improved ventricular function, with representative preclinical studies reporting approximately 25–45% relative reductions in infarct size in rodent and porcine MI models, despite substantial heterogeneity in EV sources, formulations, and outcome reporting that limits cross-study comparability. We conclude that achieving clinical translation will require standardized cardiac-targeting strategies, validated good manufacturing practice (GMP)-compatible manufacturing platforms, and harmonized potency assays, alongside rigorous, head-to-head preclinical designs, to advance EV-based cardiorepair toward clinical testing. Full article

Despite the advances in medical therapies for treating myocardial infarction (MI), morbidity and mortality rates remain high. Following MI, increased methylglyoxal (MG) production leads to the accumulation of advanced glycation end-products (AGEs), which contribute to adverse remodeling and to the deterioration of cardiac function. We previously reported that an injectable collagen type I hydrogel improves the repair and function of mouse hearts post-MI. Notably, we observed that the injected hydrogel was a target for MG-AGE glycation, and that there were less MG-modified proteins in the myocardium. In this study, we further evaluated this protective mechanism by pre-glycating the hydrogels and assessing their therapeutic efficacy for treating MI. In vitro experiments showed that the viability of macrophages was reduced when cultured with the glycated hydrogel in the presence of MG. In vivo, female C57BL/6 mice were randomly assigned to receive intramyocardial injections of one of three treatments: phosphate-buffered saline, normal collagen hydrogel, or MG-glycated hydrogel. After 28 days, echocardiography was performed to evaluate cardiac function, and hearts were harvested for immunohistochemistry. Our results showed that the MG-glycated hydrogel had a reduced treatment effect (greater scar size, fewer wound-healing macrophages, less viable myocardium and decreased cardiac function) compared to mice that received the normal collagen hydrogel. In summary, this study demonstrates that the ability of the collagen hydrogel to act as a target for glycation and remove MG from the environment contributes to its therapeutic effect in treating the post-MI heart. Full article

Background: Following myocardial infarction (MI), cardiac fibroblasts (CFs) adopt distinct phenotypes to ensure scar formation and healing. Although leukocytes are a critical driver of post-MI healing, the role of neutrophils in modulating CF phenotype remains insufficiently explored. We therefore investigated the impact of soluble mediators released by neutrophil subtypes found post-MI—pro-inflammatory (N1) and anti-inflammatory (N2)—on shaping CFs phenotype. Methods: In vitro, human 3D grown CFs were indirectly co-cultured with N1 or N2 neutrophil-like cells using a two-chamber Transwell system. After 24 h, expression of inflammatory, remodeling, and pro-fibrotic markers was evaluated in fibroblasts and conditioned media. In vivo, soluble mediators derived from polarized mouse neutrophils (SN1 or SN2) were injected into the infarcted myocardium of C57BL/6J after MI surgery. The effects on the healing process were investigated at 1 and 7 days post-MI. Results: In vitro, CFs were found to exhibit a pro-inflammatory and matrix-degrading phenotype following indirect co-culture with N1 cells, characterized by overexpression of IL-1β, IL-6, MCP-1, and metalloproteases MMP-3/MMP-9. In vivo, both SN1 and SN2 treatments significantly reduced pro-inflammatory markers IL-1β and IL-6 gene expression at day 1 post-MI (inflammatory phase). At day 7 post-MI (resolution phase), SN1/SN2 treatments continued to limit local inflammation, while mitigating fibrotic remodeling by reducing CCN2, α-SMA, and key extracellular matrix proteins. Conclusions: Together, these findings suggest that while N1-derived mediators promote a pro-inflammatory fibroblast phenotype in vitro, factors secreted by both N1 and N2 support a more balanced reparative response in vivo, by limiting local inflammation and potentially mitigating adverse remodeling post-MI. Full article

Acute myocardial infarction (MI) is a major cardiovascular event and a leading cause of mortality worldwide. Beyond the initial ischemic injury, the inflammatory and immune responses play pivotal roles in both tissue damage and subsequent healing. While the anti-inflammatory strategies targeting neutrophil-driven injury have demonstrated potential in limiting early cardiac damage, growing evidence highlights the critical role of innate immune cells beyond the acute phase. Neutrophils, traditionally associated with tissue injury, also contribute to the resolution of inflammation and initiate key repair processes. Monocytes and macrophages follow a dynamic trajectory, transitioning from pro-inflammatory to reparative states, and play essential roles in debris clearance, angiogenesis, and scar formation. In the early inflammatory phase of acute MI, immune cells such as neutrophils and monocytes are rapidly recruited and activated. While they initially amplify inflammation through the release of pro-inflammatory mediators, their subsequent transition toward anti-inflammatory and reparative phenotypes helps limit tissue damage by clearing necrotic debris from the infarcted area and contributes to the resolution of inflammation. Accumulating evidence reveals a complex crosstalk between neutrophils and macrophages post-MI, with resident macrophages being involved in neutrophil recruitment, and neutrophil-derived signals participating in monocyte recruitment and macrophage polarization, thereby coordinating the spatial and temporal phases of cardiac repair. Understanding how neutrophil-derived mediators influence macrophage responses and whether macrophage-secreted factors reciprocally modulate neutrophil behavior opens promising pathways for developing targeted therapies to limit adverse remodeling following MI. Therefore, this review aims to (i) provide an overview of the roles of neutrophils and monocytes/macrophages in the pathophysiology of myocardial infarction, (ii) explore the mechanisms of communication, particularly via neutrophil-derived secreted factors, that influence monocyte/macrophage function and impact post-MI inflammation, repair, and remodeling, and (iii) highlight the potential therapies interfering with inflammation and neutrophil/macrophage cross-talk. Full article

Differentiating peripartum cardiomyopathy (PPCM) from pregnancy-associated myocardial infarction (PAMI) is challenging due to shared risk factors. We report a case of a 35-year-old woman who suffered a seizure and cardiac arrest in the final month of her second pregnancy. Echocardiography showed a normal left ventricular ejection fraction (LVEF). Three days later, she developed heart failure symptoms and a marked reduction in LVEF. After one month of treatment, LVEF nearly normalized, but regional wall motion abnormalities subsequently appeared, prompting coronary angiography, which showed normal coronary arteries. Thus, PPCM was diagnosed. One year later, cardiac magnetic resonance imaging, performed due to her wish for another pregnancy, showed a scar consistent with a previous transmural myocardial infarction. We interpret this as a case of PAMI. Despite medical contraindications, she became pregnant one year after the infarction and delivered via C-section. Five years post-event, there are no signs of heart failure. This case lies in the gray zone of pregnancy-related cardiac complications and highlights the importance of multimodality imaging for thorough structural and functional assessment. Full article

Cardiac magnetic resonance (CMR) imaging has become a key tool in evaluating myocardial injury secondary to coronary artery disease (CAD), providing detailed assessments of cardiac morphology, function, and tissue composition. The integration of artificial intelligence (AI), including machine learning and deep learning techniques, has enhanced the diagnostic capabilities of CMR by automating segmentation, improving image interpretation, and accelerating clinical workflows. Radiomics, through the extraction of quantitative imaging features, complements AI by revealing sub-visual patterns relevant to disease characterization. This systematic review analyzed AI applications in CMR for CAD. A structured search was conducted in MEDLINE, Web of Science, and Scopus up to 17 March 2025, following PRISMA guidelines and quality-assessed with the CLAIM checklist. A total of 106 studies were included: 46 on classification, 19 using radiomics, and 41 on segmentation. AI models were used to classify CAD vs. controls, predict major adverse cardiovascular events (MACE), arrhythmias, and post-infarction remodeling. Radiomics enabled differentiation of acute vs. chronic infarction and prediction of microvascular obstruction, sometimes from non-contrast CMR. Segmentation achieved high performance for myocardium (DSC up to 0.95), but scar and edema delineation were more challenging. Reported performance was moderate-to-high across tasks (classification AUC = 0.66–1.00; segmentation DSC = 0.43–0.97; radiomics AUC = 0.57–0.99). Despite promising results, limitations included small or overlapping datasets. In conclusion, AI and radiomics offer substantial potential to support diagnosis and prognosis of CAD through advanced CMR image analysis. Full article