Cardiomyocyte Necrosis Research Articles

Engineered biomaterial delivery strategies are used to reduce cardiotoxicity in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Chemotherapy drugs play an integral role in OS treatment. Preoperative neoadjuvant chemotherapy and postoperative conventional adjuvant chemotherapy improve survival in patients with OS. However, the toxic side effects of chemotherapy drugs are unavoidable. Cardiotoxicity is one of the common side effects of chemotherapy drugs that cannot be ignored. Chemotherapy drugs affect the destruction of mitochondrial autophagy and mitochondria-associated proteins to cause a decrease in cardiac ejection fraction and cardiomyocyte necrosis, which in turn causes heart failure and irreversible cardiomyopathy. Biomaterials play an important role in nanomedicine. Biomaterials act as carriers to deliver chemotherapy drugs precisely around tumor cells and continuously release carriers around the tumor. It not only promotes anti-tumor effects but also reduces the cardiotoxicity of chemotherapy drugs. In this paper, we first introduce the mechanism by which chemotherapy drugs commonly used in OS cause cardiotoxicity. Subsequently, we introduce biomaterials for reducing cardiotoxicity in OS chemotherapy. Finally, we prospect biomaterial delivery strategies to reduce cardiotoxicity in OS.

The Canadian Cardiovascular Society Classification of Acute Atherothrombotic Myocardial Infarction Based on Stages of Tissue Injury Severity: An Expert Consensus Statement

Myocardial infarction (MI) remains a leading cause of morbidity and mortality. In atherothrombotic MI (ST-elevation MI and type 1 non-ST-elevation MI), coronary artery occlusion leads to ischemia. Subsequent cardiomyocyte necrosis evolves over time as a wavefront within the territory at risk. The spectrum of ischemia and reperfusion injury is wide: it can be minimal in aborted MI or myocardial necrosis can be large and complicated by microvascular obstruction and reperfusion hemorrhage. Established risk scores and infarct classifications help with patient management but do not consider tissue injury characteristics. This document outlines the Canadian Cardiovascular Society classification of acute MI. It is an expert consensus formed on the basis of decades of data on atherothrombotic MI with reperfusion therapy. Four stages of progressively worsening myocardial tissue injury are identified: (1) aborted MI (no/minimal myocardial necrosis); (2) MI with significant cardiomyocyte necrosis, but without microvascular injury; (3) cardiomyocyte necrosis and microvascular dysfunction leading to microvascular obstruction (ie, “no-reflow”); and (4) cardiomyocyte and microvascular necrosis leading to reperfusion hemorrhage. Each stage reflects progression of tissue pathology of myocardial ischemia and reperfusion injury from the previous stage. Clinical studies have shown worse remodeling and increase in adverse clinical outcomes with progressive injury. Notably, microvascular injury is of particular importance, with the most severe form (hemorrhagic MI) leading to infarct expansion and risk of mechanical complications. This classification has the potential to stratify risk in MI patients and lay the groundwork for development of new, injury stage-specific and tissue pathology-based therapies for MI.

BAK contributes critically to necrosis and infarct generation during reperfused myocardial infarction

At least seven cell death programs are activated during myocardial infarction (MI), but which are most important in causing heart damage is not understood. Two of these programs are mitochondrial-dependent necrosis and apoptosis. The canonical function of the pro-cell death BCL-2 family proteins BAX and BAK is to mediate permeabilization of the outer mitochondrial membrane during apoptosis allowing apoptogen release. BAX has also been shown to sensitize cells to mitochondrial-dependent necrosis, although the underlying mechanisms remain ill-defined. Genetic deletion of Bax or both Bax and Bak in mice reduces infarct size following reperfused myocardial infarction (MI/R), but the contribution of BAK itself to cardiomyocyte apoptosis and necrosis and infarction has not been investigated. In this study, we use Bak-deficient mice and isolated adult cardiomyocytes to delineate the role of BAK in the pathogenesis of infarct generation and post-infarct remodeling during MI/R and non-reperfused MI. Generalized homozygous deletion of Bak reduced infarct size ∼50% in MI/R in vivo, which was attributable primarily to decreases in necrosis. Protection from necrosis was also observed in BAK-deficient isolated cardiomyocytes suggesting that the cardioprotection from BAK loss in vivo is at least partially cardiomyocyte-autonomous. Interestingly, heterozygous Bak deletion, in which the heart still retains ∼28% of wild type BAK levels, reduced infarct size to a similar extent as complete BAK absence. In contrast to MI/R, homozygous Bak deletion did not attenuate acute infarct size or long-term scar size, post-infarct remodeling, cardiac dysfunction, or mortality in non-reperfused MI. We conclude that BAK contributes significantly to cardiomyocyte necrosis and infarct generation during MI/R, while its absence does not appear to impact the pathogenesis of non-reperfused MI. These observations suggest BAK may be a therapeutic target for MI/R and that even partial pharmacological antagonism may provide benefit.

Abstract P3060: Modeling Immune Checkpoint Inhibitor Associated Myocarditis In Vitro

Introduction: Immune checkpoint inhibitor-associated myocarditis (ICI myocarditis) is a severe side effect of treating malignancies with immune checkpoint inhibitors. Patients suffering from ICI myocarditis often display an extraordinarily high mortality rate. Establishing a clinically relevant model to address the lack of identifiable risk factors, screening tests, or effective treatments is critically urgent. Hypothesis: Human ICI myocarditis can be accurately modeled in vitro. Methods and Results: We present the first cell culture-based model of ICI myocarditis. We use a novel method to co-culture human iPSC-derived cardiomyocytes (hiPSC-CM), human peripheral blood mononuclear cells, and immune checkpoint inhibitors to recapitulate critical aspects of clinical ICI myocarditis. Using this platform, we show rapid, significant cardiomyocyte necrosis after model initiation. We observe substantial disruption to hiPSC-CM cell morphology and sarcomere structure, and we use powerful multi-electrode array technology to define contractile functions and electrophysiological changes, demonstrating the critical similarities between this cell-based ICI myocarditis model and patient myocarditis. Our model also reveals an increased risk of arrhythmia, recapitulating, in vitro , the primary cause of death in patients suffering from ICI myocarditis. Finally, we demonstrate that this hiPSC-CM-based “model in a dish” can be rescued pharmacologically and identify specific leukocyte populations required for myocarditis development. In summary, we present the first in vitro model of ICI myocarditis and demonstrate its scalability, validity, patient relevance, and reproducibility. Utilizing the model can aid in accomplishing precision medicine objectives and holds significant potential for preventing and treating ICI myocarditis.

Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34

Heart failure is a leading cause of mortality in developed countries. Cell death is a key player in the development of heart failure. Calcium-independent phospholipase A2β (iPLA2β) produces lipid mediators by catalyzing lipids and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated through its receptor, G protein-coupled receptor 34 (GPR34). Cardiomyocyte-specific iPLA2β-deficient male mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA2β-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA2β-deficient hearts. Knockdown of Gpr34 attenuated 18:0 lysophosphatidylserine-induced necrosis in neonatal male rat cardiomyocytes, while the ablation of Gpr34 in male mice reduced the development of pressure overload-induced cardiac remodeling. Thus, the iPLA2β—lysophosphatidylserine—GPR34—necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.

Features of Myocarditis: Morphological Differential Diagnosis in Post-COVID-19 Children.

We analyzed publications covering the period from December 2019 to May 2023, published in publicly accessible international databases ("Medline", "PubMed", "Scopus"), with queries for the keywords "myocarditis", "children", "cardiovascular inflammation", "COVID-19", "SARS-CoV-2", "severe acute respiratory syndrome coronavirus 2", "differential diagnosis". It was found that no unambiguous morphological criteria for the diagnosis of myocarditis coupled to SARS-CoV-2 lesions were identified. However, the detected histopathological changes such as virus-associated degeneration, apoptosis, cardiomyocyte necrosis, moderate interstitial hyperemia, myocardial tissue oedema, and capillary endothelial cell dysfunction were the major markers of SARS-CoV-2 infection. It is necessary further reconsider morphological criteria to diagnose SARS-CoV-2-caused myocarditis, rather than solely relying on detecting viral RNA by PCR as the sole evidence-based criterion. Similar issues accompany diagnostics of myocardial lesions associated with other viral infections. Evidence for an etiological diagnosis of myocarditis can be provided by a comprehensive analysis of the diagnostic criteria obtained, confirming virus exposure, followed by development of distinct clinical symptoms, MRI and CT changes, and morphological criteria.

Atrial Fibrillation and Chronic Coronary Ischemia: A Challenging Vicious Circle.

Atrial fibrillation, the most frequent arrhythmia in clinical practice and chronic coronary syndrome, is one of the forms of coronary ischemia to have a strong dual relationship. Atrial fibrillation may accelerate atherosclerosis and may increase oxygen consumption in the myocardium, creating a mismatch between supply and demand, thus promoting the development or worsening of coronary ischemia. Chronic coronary syndrome alters the structure and function of gap junction proteins, affecting the conduction of action potential and leading to ischemic necrosis of cardiomyocytes and their replacement with fibrous tissue, in this way sustaining the focal ectopic activity in atrial myocardium. They have many risk factors in common, such as hypertension, obesity, type 2 diabetes mellitus, and dyslipidemia. It is vital for the prognosis of patients to break this vicious circle by controlling risk factors, drug therapies, of which antithrombotic therapy may sometimes be challenging in terms of prothrombotic and bleeding risk, and interventional therapies (revascularization and catheter ablation).

Importance of cardio markers in the diagnosis of myocardial infarction

In recent times, the death rate due to myocardial infarction is increasing. Early diagnosis of the disease is of great importance in preventing the death rate of this disease. Cardiomarkers are important in the diagnosis of myocardial infarction. Current myocardial infarction cardiomarkers can be divided into several groups: cardio markers of cardiomyocyte necrosis and ischemia, neuroendocrine cardio markers, inflammatory cardiomarkers , as well as a number of new cardiomarkers whose diagnostic value is still not well studied . Cardiac Fatty Acid Binding Protein, Myoglobulin, Troponin T, Creatine Kinase – MB, etc.

Punica granatum L. Extract Shows Cardioprotective Effects Measured by Oxidative Stress Markers and Biomarkers of Heart Failure in an Animal Model of Metabolic Syndrome.

Metabolic syndrome (MetS) significantly increases the risk of cardiovascular diseases (CVD), a leading cause of death globally. The presented study investigated the cardioprotective role of dietary polyphenols found in pomegranate peels in an animal model of metabolic syndrome. Zucker diabetic fatty rats (ZDF, MetS rats, fa/fa) were supplemented with polyphenol-rich pomegranate peel extract (EPP) at two dosages: 100 mg/kg BW and 200 mg/kg BW. The extract was administered for 8 weeks. The effect of ethanolic peel extract on the concentration of oxidative stress markers (CAT, SOD, MnSOD, GR, GST, GPx, TOS, SH, and MDA), biomarkers of heart failure (cTnI, GAL-3), and alternations in tissue architecture was assessed. The results showed a significant increase in SH concentration mediated via EPP supplementation (p < 0.001). Treatment with a 100 mg/kg BW dosage reduced the TOS level more efficiently than the higher dose. Interestingly, the CAT and GST activities were relevantly higher in the MetS 100 group (p < 0.001) compared to the MetS control. The rats administered EPP at a dose of 200 mg/kg BW did not follow a similar trend. No differences in the GR (p = 0.063), SOD (p = 0.455), MnSOD (p = 0.155), and MDA (p = 0.790) concentration were observed after exposure to the pomegranate peel extract. The administration of EPP did not influence the cTnI and GAL-3 levels. Histology analysis of the heart and aorta sections revealed no toxic changes in phenolic-treated rats. The findings of this study prove that the extract from pomegranate peels possesses free radical scavenging properties in the myocardium. The effect on alleviating ventricular remodeling and cardiomyocyte necrosis was not confirmed and requires further investigation.

Cell-Specific Mechanisms in the Heart of COVID-19 Patients.

From the onset of the pandemic, evidence of cardiac involvement in acute COVID-19 abounded. Cardiac presentations ranged from arrhythmias to ischemia, myopericarditis/myocarditis, ventricular dysfunction to acute heart failure, and even cardiogenic shock. Elevated serum cardiac troponin levels were prevalent among hospitalized patients with COVID-19; the higher the magnitude of troponin elevation, the greater the COVID-19 illness severity and in-hospital death risk. Whether these consequences were due to direct SARS-CoV-2 infection of cardiac cells or secondary to inflammatory responses steered early cardiac autopsy studies. SARS-CoV-2 was reportedly detected in endothelial cells, cardiac myocytes, and within the extracellular space. However, findings were inconsistent and different methodologies had their limitations. Initial autopsy reports suggested that SARS-CoV-2 myocarditis was common, setting off studies to find and phenotype inflammatory infiltrates in the heart. Nonetheless, subsequent studies rarely detected myocarditis. Microthrombi, cardiomyocyte necrosis, and inflammatory infiltrates without cardiomyocyte damage were much more common. In vitro and ex vivo experimental platforms have assessed the cellular tropism of SARS-CoV-2 and elucidated mechanisms of viral entry into and replication within cardiac cells. Data point to pericytes as the primary target of SARS-CoV-2 in the heart. Infection of pericytes can account for the observed pericyte and endothelial cell death, innate immune response, and immunothrombosis commonly observed in COVID-19 hearts. These processes are bidirectional and synergistic, rendering a definitive order of events elusive. Single-cell/nucleus analyses of COVID-19 myocardial tissue and isolated cardiac cells have provided granular data about the cellular composition and cell type-specific transcriptomic signatures of COVID-19 and microthrombi-positive COVID-19 hearts. Still, much remains unknown and more in vivo studies are needed. This review seeks to provide an overview of the current understanding of COVID-19 cardiac pathophysiology. Cell type-specific mechanisms and the studies that provided such insights will be highlighted. Given the unprecedented pace of COVID-19 research, more mechanistic details are sure to emerge since the writing of this review. Importantly, our current knowledge offers significant clues about the cardiac pathophysiology of long COVID-19, the increased postrecovery risk of cardiac events, and thus, the future landscape of cardiovascular disease.

Blocking RIPK2 Function Alleviates Myocardial Ischemia/Reperfusion Injury by Regulating the AKT and NF-κB Pathways

ABSTRACT Objective Inflammation and oxidation brought on by myocardial ischemia-reperfusion (MI/R) injury lead to cardiomyocyte apoptosis and necrosis. The receptor interacting serine/threonine kinase 2 (RIPK2) plays significant roles in oxidative stress and excessive inflammation. The purpose of this research is to examine the roles of RIPK2 in MI/R injury. Methods The in vivo animal model was constructed by acute coronary I/R, and the in vitro cell model was established by oxygen and glucose deprivation/reperfusion (OGD/R)-stimulated cardiomyocyte injury. RIPK2 expression was examined using qRT-PCR and Western blot. CCK-8 was proposed as a method for detecting cell proliferation. ELISA was utilized to measure inflammatory cytokines (TNF-α, IL-6, and IL-1β) and myocardial injury indicators (CK-MB, Mb, cTnI, and LDH). The levels of MDA and ROS were determined by the kit and fluorescent probe. H&E was conducted to assess MI/R injury after silencing of RIPK2. Results In MI/R rats and OGD/R-treated H9C2 cardiomyocytes, RIPK2 was overexpressed at both the mRNA and protein levels. RIPK2 inhibition promoted cell proliferation while inhibiting apoptosis, as evidenced by decreased TUNEL-positive cells and cleaved caspase-3. RIPK2 inhibition reduced MDA and ROS levels, as well as the contents of inflammatory factors. RIPK2 silencing reduced CK-MB, Mb, cTnI, and LDH levels in rat serum and alleviated MI/R injury. Furthermore, RIPK2 inhibition increased p-AKT while decreasing NF-B p-p65 expression. Conclusion Silencing of RIPK2 reduced apoptosis, proinflammatory factors, and oxidative stress in MI/R by activating AKT and suppressing NF-κB signals, suggesting a potential therapeutic strategy for MI/R injury.

Histologia do miocárdio normal e infartado

Introduction: Myocardial infarction is a pathology that presents high morbidity and mortality. It is the result of cardiomyocyte necrosis caused by oxygenation difficulties. Objective: The aim of this study was to review the histology of the myocardium and its histological changes when infarcted. Method: This is a narrative review of technical books and scientific articles published in SciELO and PubMed. Results: The myocardium is formed by cardiomyocytes, which contract due to the sarcomeres arranged in their myofibrils and present efficient electrical communication with each other through gap junctions. Myocardial infarction promotes the death of cardiomyocytes, alterations in cytoplasmic elements and electrical conduction, in addition to the formation of fibrous scar tissue. Conclusion: In conclusion, the myocardium is highly vascularized and formed by elongated contractile cardiomyocytes with a sarcometric composition. In ischemic conditions, such as myocardial infarction, there is histological remodeling in cardiac muscle tissue that leads to fibrosis and loss of contractile functions.

Preclinical Large Animal Porcine Models for Cardiac Regeneration and Its Clinical Translation: Role of hiPSC-Derived Cardiomyocytes.

Myocardial Infarction (MI) occurs due to a blockage in the coronary artery resulting in ischemia and necrosis of cardiomyocytes in the left ventricular heart muscle. The dying cardiac tissue is replaced with fibrous scar tissue, causing a decrease in myocardial contractility and thus affecting the functional capacity of the myocardium. Treatments, such as stent placements, cardiac bypasses, or transplants are beneficial but with many limitations, and may decrease the overall life expectancy due to related complications. In recent years, with the advent of human induced pluripotent stem cells (hiPSCs), newer avenues using cell-based approaches for the treatment of MI have emerged as a potential for cardiac regeneration. While hiPSCs and their derived differentiated cells are promising candidates, their translatability for clinical applications has been hindered due to poor preclinical reproducibility. Various preclinical animal models for MI, ranging from mice to non-human primates, have been adopted in cardiovascular research to mimic MI in humans. Therefore, a comprehensive literature review was essential to elucidate the factors affecting the reproducibility and translatability of large animal models. In this review article, we have discussed different animal models available for studying stem-cell transplantation in cardiovascular applications, mainly focusing on the highly translatable porcine MI model.

Polystyrene microplastics induce myocardial inflammation and cell death via the TLR4/NF-κB pathway in carp

Microplastics (MPs) have attracted widespread attention as an emerging environmental pollutant. Especially in aquatic ecosystems, the harm of MPs to aquatic animals has increasingly become a severe environmental problem. In this study, we constructed a carp polystyrene microplastics (PS-MPs) exposure model to explore the damage and mechanism of PS-MPs exposure to carp myocardial tissue. The results of H&E, TUNEL, and AO/EB staining showed that PS-MPs exposure could induce inflammation, apoptosis, and necrosis in carp myocardial tissue and cardiomyocytes. In addition, our study explored the targeting relationship between PS-MPs and TLR4 and found that PS-MPs exposure could significantly increase the expression of TLR4 pathway-related factors. As the concentration of PS-MPs increased, the NF-κB pathway and inflammation-related factors increased dose-dependent. In addition, myocardial injury induced by exposure to PS-MPs was predominantly apoptotic, accompanied by necrosis. In short, our data suggest that PS-MPs cause damage to myocardial tissue via the TLR4\\NF-κB pathway. The above findings enrich the theory of toxicological studies on PS-MPs and provide an essential reference for aquaculture.

Sema3A alleviates viral myocarditis by modulating SIRT1 to regulate cardiomyocyte mitophagy.

Viral myocarditis (VMC) is a common myocardial inflammatory disease characterized by inflammatory cell infiltration and cardiomyocyte necrosis. Sema3A was reported to reduce cardiac inflammation and improve cardiac function after myocardial infarction, but its role in VMC remains to be explored. Here, a VMC mouse model was established by infection with CVB3, and Sema3A was overexpressed in vivo by intraventricular injection of an adenovirus-mediated Sema3A expression vector (Ad-Sema3A). We found that Sema3A overexpression attenuated CVB3-induced cardiac dysfunction and tissue inflammation. And Sema3A also reduced macrophage accumulation and NLRP3 inflammasome activation in the myocardium of VMC mice. In vitro, LPS was used to stimulate primary splenic macrophages to mimic the macrophage activation state in vivo. Activated macrophages were co-cultured with primary mouse cardiomyocytes to evaluate macrophage infiltration-induced cardiomyocyte damage. Ectopic expression of Sema3A in cardiomyocytes effectively protected cardiomyocytes from activated macrophage-induced inflammation, apoptosis, and ROS accumulation. Mechanistically, cardiomyocyte-expressed Sema3A mitigated macrophage infiltration-caused cardiomyocyte dysfunction by promoting cardiomyocyte mitophagy and hindering NLRP3 inflammasome activation. Furthermore, NAM (a SIRT1 inhibitor) reversed the protective effect of Sema3A against activated macrophage-induced cardiomyocyte dysfunction by suppressing cardiomyocyte mitophagy. In conclusion, Sema3A promoted cardiomyocyte mitophagy and suppressed inflammasome activation by regulating SIRT1, thereby attenuating macrophage infiltration-induced cardiomyocyte injury in VMC.

How Does COVID-19 Affect the Heart?

Cardiac consequences occur in bothacute COVID-19and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, andmolecular studies. COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies ofCOVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfillinghistologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation. The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.

Effects of sevoflurane and its metabolite hexafluoroisopropanol on hypoxia/reoxygenation-induced injury and mitochondrial bioenergetics in murine cardiomyocytes.

The volatile anaesthetic sevoflurane protects cardiac tissue from reoxygenation/reperfusion. Mitochondria play an essential role in conditioning. We aimed to investigate how sevoflurane and its primary metabolite hexafluoroisopropanol (HFIP) affect necrosis, apoptosis, and reactive oxygen species formation in cardiomyocytes upon hypoxia/reoxygenation injury. Moreover, we aimed to describe the similarities in the mode of action in a mitochondrial bioenergetics analysis. Murine cardiomyocytes were exposed to hypoxia (0.2% O2 for 6 h), followed by reoxygenation (air with 5% CO2 for 2 h) in the presence or absence sevoflurane 2.2% or HFIP 4 mM. Lactate dehydrogenase (LDH) release (necrosis), caspase activation (apoptosis), reactive oxygen species, mitochondrial membrane potential, and mitochondrial function (Seahorse XF analyser) were measured. Hypoxia/reoxygenation increased cell death by 44% (+31 to+55%, P<0.001). Reoxygenation in the presence of sevoflurane 2.2% or HFIP 4 mM increased LDH release only by+18% (+6 to+30%) and 20% (+7 to+32%), respectively. Apoptosis and reactive oxygen species formation were attenuated by sevoflurane and HFIP. Mitochondrial bioenergetics analysis of the two substances was profoundly different. Sevoflurane did not influence oxygen consumption rate (OCR) or extracellular acidification rate (ECAR), whereas HFIP reduced OCR and increased ECAR, an effect similar to oligomycin, an adenosine triphosphate (ATP) synthase inhibitor. When blocking the metabolism of sevoflurane into HFIP, protective effects of sevoflurane - but not of HFIP - on LDH release and caspase were mitigated. Together, our data suggest that sevoflurane metabolism into HFIP plays an essential role in cardiomyocyte postconditioning after hypoxia/reoxygenation injury.

Pathological Aspects and Immunohistochemical Evaluation of Troponin C in the Cardiovascular System of Dogs With Pheochromocytoma

Functional pheochromocytomas secrete catecholamines and have been associated with cardiovascular lesions in dogs. This study aimed to describe the postmortem pathological findings in the cardiovascular system of dogs with pheochromocytoma and to evaluate the expression of cardiac troponin C in these dogs using immunohistochemical analysis. Twelve cases were identified, with a mean age of 10.6 years. The heart of all dogs was enlarged and with concentric hypertrophy of the left ventricular myocardium. Histological analysis showed cardiomyocyte necrosis and degeneration in the myocardium, with frequent bands of contraction, fibrosis, inflammation, and thickening of the medium-caliber arteries in the myocardium. There was a marked decrease or absence of immunolabeling in necrotic cardiomyocytes. We conclude that IHC for troponin C can be a useful tool for detecting myocardial necrosis in dogs with pheochromocytomas, including early cases of necrosis with only incipient cardiac changes where overt histologic abnormalities are not immediately apparent in the cardiomyocytes.

Modern View on the Role of Sex-Specific Levels of High-Sensitive Cardiospecific Troponins T and I in the Diagnosis of Myocardial Infarction.

It is well known that the molecules of cardiospecific troponins T and I are localized in the troponin-tropomyosin complex of the cytoplasm of cardiac myocytes and, due to the specific localization, these cardiospecific troponins are widely used as diagnostic biomarkers of myocardial infarction. Cardiospecific troponins are released from the cytoplasm of cardiac myocytes as a result of irreversible cell damage (for example, ischemic necrosis of cardiomyocytes in myocardial infarction or apoptosis of cardiac myocytes in cardiomyopathies and heart failure) or reversible damage (for example, intense physical exertion, hypertension, the influence of stress factors, etc.). Current immunochemical methods for determining cardiospecific troponins T and I have extremely high sensitivity to subclinical (minor) damage to myocardial cells and, thanks to modern high-sensitive methods, it is possible to detect damage to cardiac myocytes in the early (subclinical) stages of a number of cardiovascular pathologies, including myocardial infarction. So, recently, leading cardiological communities (the European Society of Cardiology, the American Heart Association, the American College of Cardiology, etc.) have approved algorithms for early diagnosis of myocardial infarction based on the assessment of serum levels of cardiospecific troponins in the first 1 - 3 h after the onset of pain syndrome. An important factor that may affect early diagnostic algorithms of myocardial infarction are sex-specific features of serum levels of cardiospecific troponins T and I. This manuscript presents a modern view on the role of sex-specific serum levels of cardiospecific troponins T and I in the diagnosis of myocardial infarction and the mechanisms of formation of sex-specific serum levels of troponins.

Co-administration of JQ1, a bromodomain-containing protein 4 inhibitor, enhances the antitumor effect of combretastatin A4, a microtubule inhibitor, while attenuating its cardiotoxicity

Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and cardiotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated.CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co-administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly.In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1.These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.