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Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review).International Journal of Molecular... Feb 2022Stroke is the leading cause of disabilities and cognitive deficits, accounting for 5.2% of all mortalities worldwide. Transient or permanent occlusion of cerebral... (Review)
Review
Stroke is the leading cause of disabilities and cognitive deficits, accounting for 5.2% of all mortalities worldwide. Transient or permanent occlusion of cerebral vessels leads to ischemic strokes, which constitutes the majority of strokes. Ischemic strokes induce brain infarcts, along with cerebral tissue death and focal neuronal damage. The infarct size and neurological severity after ischemic stroke episodes depends on the time period since occurrence, the severity of ischemia, systemic blood pressure, vein systems and location of infarcts, amongst others. Ischemic stroke is a complex disease, and neuronal injuries after ischemic strokes have been the focus of current studies. The present review will provide a basic pathological background of ischemic stroke and cerebral infarcts. Moreover, the major mechanisms underlying ischemic stroke and neuronal injuries are summarized. This review will also briefly summarize some representative clinical trials and up‑to‑date treatments that have been applied to stroke and brain infarcts.
Topics: Animals; Brain Ischemia; Cerebral Infarction; Humans; Ischemic Stroke; Neurons; Neuroprotection; Oxidative Stress
PubMed: 34878154
DOI: 10.3892/ijmm.2021.5070 -
JAMA Nov 2021Cardiogenic shock affects between 40 000 and 50 000 people in the US per year and is the leading cause of in-hospital mortality following acute myocardial infarction. (Review)
Review
IMPORTANCE
Cardiogenic shock affects between 40 000 and 50 000 people in the US per year and is the leading cause of in-hospital mortality following acute myocardial infarction.
OBSERVATIONS
Thirty-day mortality for patients with cardiogenic shock due to myocardial infarction is approximately 40%, and 1-year mortality approaches 50%. Immediate revascularization of the infarct-related coronary artery remains the only treatment for cardiogenic shock associated with acute myocardial infarction supported by randomized clinical trials. The Percutaneous Coronary Intervention Strategies with Acute Myocardial Infarction and Cardiogenic Shock (CULPRIT-SHOCK) clinical trial demonstrated a reduction in the primary outcome of 30-day death or kidney replacement therapy; 158 of 344 patients (45.9%) in the culprit lesion revascularization-only group compared with 189 of 341 patients (55.4%) in the multivessel percutaneous coronary intervention group (relative risk, 0.83 [95% CI, 0.71-0.96]; P = .01). Despite a lack of randomized trials demonstrating benefit, percutaneous mechanical circulatory support devices are frequently used to manage cardiogenic shock following acute myocardial infarction.
CONCLUSIONS AND RELEVANCE
Cardiogenic shock occurs in up to 10% of patients immediately following acute myocardial infarction and is associated with mortality rates of nearly 40% at 30 days and 50% at 1 year. Current evidence and clinical practice guidelines support immediate revascularization of the infarct-related coronary artery as the primary therapy for cardiogenic shock following acute myocardial infarction.
Topics: Cardiotonic Agents; Extracorporeal Membrane Oxygenation; Heart-Assist Devices; Humans; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Shock, Cardiogenic; Time-to-Treatment
PubMed: 34751704
DOI: 10.1001/jama.2021.18323 -
Circulation Jul 2021Over the past few decades, advances in pharmacological, catheter-based, and surgical reperfusion have improved outcomes for patients with acute myocardial infarctions.... (Review)
Review
Over the past few decades, advances in pharmacological, catheter-based, and surgical reperfusion have improved outcomes for patients with acute myocardial infarctions. However, patients with large infarcts or those who do not receive timely revascularization remain at risk for mechanical complications of acute myocardial infarction. The most commonly encountered mechanical complications are acute mitral regurgitation secondary to papillary muscle rupture, ventricular septal defect, pseudoaneurysm, and free wall rupture; each complication is associated with a significant risk of morbidity, mortality, and hospital resource utilization. The care for patients with mechanical complications is complex and requires a multidisciplinary collaboration for prompt recognition, diagnosis, hemodynamic stabilization, and decision support to assist patients and families in the selection of definitive therapies or palliation. However, because of the relatively small number of high-quality studies that exist to guide clinical practice, there is significant variability in care that mainly depends on local expertise and available resources.
Topics: Acute Disease; American Heart Association; Humans; Myocardial Infarction; United States
PubMed: 34126755
DOI: 10.1161/CIR.0000000000000985 -
American Journal of Physiology. Cell... Oct 2022The heart contains a population of resident macrophages that markedly expands following injury through recruitment of monocytes and through proliferation of macrophages.... (Review)
Review
The heart contains a population of resident macrophages that markedly expands following injury through recruitment of monocytes and through proliferation of macrophages. In myocardial infarction, macrophages have been implicated in both injurious and reparative responses. In coronary atherosclerotic lesions, macrophages have been implicated in disease progression and in the pathogenesis of plaque rupture. Following myocardial infarction, resident macrophages contribute to initiation and regulation of the inflammatory response. Phagocytosis and efferocytosis are major functions of macrophages during the inflammatory phase of infarct healing, and mediate phenotypic changes, leading to acquisition of an anti-inflammatory macrophage phenotype. Infarct macrophages respond to changes in the cytokine content and extracellular matrix composition of their environment and secrete fibrogenic and angiogenic mediators, playing a central role in repair of the infarcted heart. Macrophages may also play a role in scar maturation and may contribute to chronic adverse remodeling of noninfarcted segments. Single cell studies have revealed a remarkable heterogeneity of macrophage populations in infarcted hearts; however, the relations between transcriptomic profiles and functional properties remain poorly defined. This review manuscript discusses the fate, mechanisms of expansion and activation, and role of macrophages in the infarcted heart. Considering their critical role in injury, repair, and remodeling, macrophages are important, but challenging, targets for therapeutic interventions in myocardial infarction.
Topics: Cytokines; Humans; Macrophages; Monocytes; Myocardial Infarction; Phagocytosis
PubMed: 36094436
DOI: 10.1152/ajpcell.00230.2022 -
Archivos de Cardiologia de Mexico Nov 2021Cardiovascular disease is the leading cause of death in adults around the world. Young adult population has suffered changes in lifestyle over the decades, favoring the... (Review)
Review
Cardiovascular disease is the leading cause of death in adults around the world. Young adult population has suffered changes in lifestyle over the decades, favoring the appearance of atherosclerosis at early ages, and as a consequence, the incidence of cardiovascular events emerges prematurely. It has been identified that most common risk factors are potentially modifiable. There is a greater prevalence of non-atherosclerotic etiologies of myocardial infarction such as spontaneous coronary dissection, congenital malformations, coronary embolism, and coronary spasm. Different angiographic findings and outcomes according to age and gender have been recognized. For this reason, we searched PubMed for published research and registries for the study of acute myocardial infarction in young patients. With this data, we carried out the present review to better understand the common findings in this group, and to compare them with older age groups.
Topics: Adult; Age Factors; Coronary Angiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Sex Factors
PubMed: 33471784
DOI: 10.24875/ACM.20000386 -
Cells Apr 2022The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury and play a reparative role but also contribute to... (Review)
Review
The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury and play a reparative role but also contribute to maladaptive fibrotic remodeling. Following myocardial infarction, cardiac fibroblasts undergo dynamic phenotypic transitions, contributing to the regulation of inflammatory, reparative, and angiogenic responses. This review manuscript discusses the mechanisms of regulation, roles and fate of fibroblasts in the infarcted heart. During the inflammatory phase of infarct healing, the release of alarmins by necrotic cells promotes a pro-inflammatory and matrix-degrading fibroblast phenotype that may contribute to leukocyte recruitment. The clearance of dead cells and matrix debris from the infarct stimulates anti-inflammatory pathways and activates transforming growth factor (TGF)-β cascades, resulting in the conversion of fibroblasts to α-smooth muscle actin (α-SMA)-expressing myofibroblasts. Activated myofibroblasts secrete large amounts of matrix proteins and form a collagen-based scar that protects the infarcted ventricle from catastrophic complications, such as cardiac rupture. Moreover, infarct fibroblasts may also contribute to cardiac repair by stimulating angiogenesis. During scar maturation, fibroblasts disassemble α-SMA+ stress fibers and convert to specialized cells that may serve in scar maintenance. The prolonged activation of fibroblasts and myofibroblasts in the infarct border zone and in the remote remodeling myocardium may contribute to adverse remodeling and to the pathogenesis of heart failure. In addition to their phenotypic plasticity, fibroblasts exhibit remarkable heterogeneity. Subsets with distinct phenotypic profiles may be responsible for the wide range of functions of fibroblast populations in infarcted and remodeling hearts.
Topics: Animals; Cicatrix; Fibroblasts; Mammals; Myocardial Infarction; Myocardium; Myofibroblasts; Transforming Growth Factor beta
PubMed: 35563692
DOI: 10.3390/cells11091386 -
Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair.Circulation Research Sep 2020Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled...
RATIONALE
Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled receptor) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear.
OBJECTIVE
To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms.
METHODS AND RESULTS
During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in macrophage-specific Lgr4 knockout mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, macrophage-specific Lgr4 knockout infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with proinflammatory responses in macrophage-specific Lgr4 knockout infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of AP (activator protein)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing CREB (cAMP response element-binding protein)-mediated , , and transactivation.
CONCLUSIONS
Together, our data highlight the significance of Lgr4 in governing proinflammatory phenotype of infarct macrophages and postinfarction repair.
Topics: Aged; Animals; Apoptosis; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Female; Humans; Inflammation; Inflammation Mediators; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phenotype; Proto-Oncogene Proteins c-fos; RAW 264.7 Cells; Receptors, G-Protein-Coupled; Signal Transduction; Transcription Factor AP-1; Ventricular Function, Left; Ventricular Remodeling
PubMed: 32600176
DOI: 10.1161/CIRCRESAHA.119.315807 -
EBioMedicine Apr 2022Myocardial infarction is lethal to patients because of insufficient blood perfusion to vital organs. Several attempts have been made to improve its prognosis, among... (Review)
Review
Myocardial infarction is lethal to patients because of insufficient blood perfusion to vital organs. Several attempts have been made to improve its prognosis, among which nanomaterial research offers an opportunity to address this problem at the molecular level and has the potential to improve disease prevention, diagnosis, and treatment significantly. Up to now, nanomaterial-based technology has played a crucial role in broad novel diagnostic and therapeutic strategies for cardiac repair. This review summarizes various nanomaterial applications in myocardial infarction from multiple aspects, including high precision detection, pro-angiogenesis, regulating immune homeostasis, and miRNA and stem cell delivery vehicles. We also propose promising research hotspots that have not been reported much yet, such as conjugating pro-angiogenetic elements with nanoparticles to construct drug carriers, developing nanodrugs targeting other immune cells except for macrophages in the infarcted myocardium or the remote region. Though most of those strategies are preclinical and lack clinical trials, there is tremendous potential for their further applications in the future.
Topics: Drug Carriers; Humans; Myocardial Infarction; Myocardium; Nanoparticles; Stem Cells
PubMed: 35367772
DOI: 10.1016/j.ebiom.2022.103968 -
Current Problems in Cardiology Dec 2022For almost 30 years, urgent revascularization termed primary percutaneous coronary intervention has been a cornerstone of modern care for acute myocardial infarction... (Review)
Review
For almost 30 years, urgent revascularization termed primary percutaneous coronary intervention has been a cornerstone of modern care for acute myocardial infarction (AMI). It lowers mortality and improved cardiovascular outcome compared to conservative therapy including thrombolysis. Reperfusion injury, which occurs after successful re-opening of the formerly occluded coronary artery, had been exploited as a potential therapeutic target. When revascularization became faster and primary percutaneous coronary intervention was successfully performed within 60-90 minutes of symptom onset, the interest in a potential additive effect of targeting reperfusion injury vanished. More recently, several meta-analyses indicated that limiting reperfusion injury prevents microvascular obstruction and reduces final infarct size, thereby lowering the probability of heart failure events and improving quality of life in AMI survivors. Here, we describe the current strategies to limit reperfusion injury and to improve post-AMI outcomes such as systemic or intracoronary hypothermia, left-ventricular unloading, intracoronary infusion of super-saturated oxygen, intermittent coronary sinus occlusion, and C-reactive protein apheresis.
Topics: Humans; Quality of Life; Myocardial Infarction; Percutaneous Coronary Intervention; Coronary Vessels; Reperfusion Injury
PubMed: 36108813
DOI: 10.1016/j.cpcardiol.2022.101398 -
Cell Reports Oct 2023The immune system plays a critical role during myocardial injury, contributing to repair and remodeling post myocardial infarction (MI). The myocardial infarct and...
The immune system plays a critical role during myocardial injury, contributing to repair and remodeling post myocardial infarction (MI). The myocardial infarct and border zone exhibit high heterogeneity, in turn leading to reconstructing macrophage subsets and specific functions. Here we use a combination of single-cell RNA sequencing, spatial transcriptomes, and reporter mice to characterize temporal-spatial dynamics of cardiac macrophage subtype in response to MI. We identify that transient appearance of monocyte-derived Bhlhe41 Mφs in the "developing" infarct zone peaked at day 7, while other monocyte-derived macrophages are identified in "old" infarct zone. Functional characterization by co-culture of Bhlhe41 Mφs with cardiomyocytes and fibroblasts or depletion of Bhlhe41 Mφs unveils a crucial contribution of Bhlhe41 Mφs in suppression of myofibroblast activation. This work highlights the importance of Bhlhe41 Mφ phenotype and plasticity in preventing excessive fibrosis and limiting the expansion of developing infarct area.
Topics: Mice; Animals; Myocardium; Macrophages; Myocardial Infarction; Heart; Monocytes; Mice, Inbred C57BL
PubMed: 37751357
DOI: 10.1016/j.celrep.2023.113174