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1.
Basic Res Cardiol ; 116(1): 52, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515837

RESUMO

Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies ('IMPACT'), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.

3.
Adv Sci (Weinh) ; 8(11): e2003987, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34105284

RESUMO

Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn2+ dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping-manganese-enhanced MRI (MEMRI) reveals elevated and increasing Mn2+ uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold-standard technique, late-gadolinium-enhanced MRI. These data, coupled with the re-emergence of clinical Mn2+ -based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34169381

RESUMO

PURPOSE: Coronavirus disease 19 (COVID-19) has, to date, been diagnosed in over 130 million persons worldwide and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several variants of concern have emerged including those in the United Kingdom, South Africa, and Brazil. SARS-CoV-2 can cause a dysregulated inflammatory response known as a cytokine storm, which can progress rapidly to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Suppressing these cytokine elevations may be key to improving outcomes. Remote ischemic conditioning (RIC) is a simple, non-invasive procedure whereby a blood pressure cuff is inflated and deflated on the upper arm for several cycles. "RIC in COVID-19" is a pilot, multi-center, randomized clinical trial, designed to ascertain whether RIC suppresses inflammatory cytokine production. METHODS: A minimum of 55 adult patients with diagnosed COVID-19, but not of critical status, will be enrolled from centers in the United Kingdom, Brazil, and South Africa. RIC will be administered daily for up to 15 days. The primary outcome is the level of inflammatory cytokines that are involved in the cytokine storm that can occur following SARS-CoV-2 infection. The secondary endpoint is the time between admission and until intensive care admission or death. The in vitro cytotoxicity of patient blood will also be assessed using primary human cardiac endothelial cells. CONCLUSIONS: The results of this pilot study will provide initial evidence on the ability of RIC to suppress the production of inflammatory cytokines in the setting of COVID-19. TRIAL REGISTRATION: NCT04699227, registered January 7th, 2021.

5.
Cardiovasc Res ; 117(10): 2161-2174, 2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34114614

RESUMO

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.


Assuntos
Pesquisa Biomédica , Cardiologia , Proliferação de Células , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Regeneração , Animais , COVID-19/patologia , COVID-19/virologia , Comunicação Celular , Microambiente Celular , Exossomos/metabolismo , Exossomos/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Fenótipo , RNA não Traduzido/metabolismo , SARS-CoV-2/patogenicidade
6.
Cardiovasc Res ; 117(10): 2148-2160, 2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34117887

RESUMO

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.


Assuntos
COVID-19/virologia , Cardiopatias/virologia , Coração/virologia , Miócitos Cardíacos/virologia , SARS-CoV-2/patogenicidade , Animais , Biomarcadores/metabolismo , Coagulação Sanguínea , COVID-19/complicações , Fibrose , Coração/fisiopatologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Remodelação Ventricular
7.
Eur Heart J ; 42(27): 2630-2642, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34059914

RESUMO

A substantial number of chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) experience periprocedural myocardial injury or infarction. Accurate diagnosis of these PCI-related complications is required to guide further management given that their occurrence may be associated with increased risk of major adverse cardiac events (MACE). Due to lack of scientific data, the cut-off thresholds of post-PCI cardiac troponin (cTn) elevation used for defining periprocedural myocardial injury and infarction, have been selected based on expert consensus opinions, and their prognostic relevance remains unclear. In this Consensus Document from the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI), we recommend, whenever possible, the measurement of baseline (pre-PCI) cTn and post-PCI cTn values in all CCS patients undergoing PCI. We confirm the prognostic relevance of the post-PCI cTn elevation >5× 99th percentile URL threshold used to define type 4a myocardial infarction (MI). In the absence of periprocedural angiographic flow-limiting complications or electrocardiogram (ECG) and imaging evidence of new myocardial ischaemia, we propose the same post-PCI cTn cut-off threshold (>5× 99th percentile URL) be used to define prognostically relevant 'major' periprocedural myocardial injury. As both type 4a MI and major periprocedural myocardial injury are strong independent predictors of all-cause mortality at 1 year post-PCI, they may be used as quality metrics and surrogate endpoints for clinical trials. Further research is needed to evaluate treatment strategies for reducing the risk of major periprocedural myocardial injury, type 4a MI, and MACE in CCS patients undergoing PCI.


Assuntos
Doença da Artéria Coronariana , Traumatismos Cardíacos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Biomarcadores , Consenso , Humanos , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco , Resultado do Tratamento
8.
Cytotherapy ; 23(5): 373-380, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33934807

RESUMO

Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50-200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex "work-in-progress" MoA and to develop assays likely to be compliant with regulatory guidance for assay validation.

9.
Basic Res Cardiol ; 116(1): 32, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33942194

RESUMO

Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9-39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.

10.
J Cell Mol Med ; 25(9): 4455-4465, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33797200

RESUMO

Myocardial infarction requires urgent reperfusion to salvage viable heart tissue. However, reperfusion increases infarct size further by promoting mitochondrial damage in cardiomyocytes. Exosomes from a wide range of different cell sources have been shown to activate cardioprotective pathways in cardiomyocytes, thereby reducing infarct size. Yet, it is currently challenging to obtain highly pure exosomes in quantities enough for clinical studies. To overcome this problem, we used exosomes isolated from CTX0E03 neuronal stem cells, which are genetically stable, conditionally inducible and can be produced on an industrial scale. However, it is unknown whether exosomes from neuronal stem cells may reduce cardiac ischaemia/reperfusion injury. In this study, we demonstrate that exosomes from differentiating CTX0E03 cells can reduce infarct size in mice. In an in vitro assay, these exosomes delayed cardiomyocyte mitochondrial permeability transition pore opening, which is responsible for cardiomyocyte death after reperfusion. The mechanism of MPTP inhibition was via gp130 signalling and the downstream JAK/STAT pathway. Our results support previous findings that exosomes from non-cardiomyocyte-related cells produce exosomes capable of protecting cardiomyocytes from myocardial infarction. We anticipate our findings may encourage scientists to use exosomes obtained from reproducible clinical-grade stocks of cells for their ischaemia/reperfusion studies.


Assuntos
Receptor gp130 de Citocina/metabolismo , Exossomos/fisiologia , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/complicações , Células-Tronco Neurais/fisiologia , Substâncias Protetoras/administração & dosagem , Animais , Receptor gp130 de Citocina/genética , Regulação da Expressão Gênica , Janus Quinase 1/genética , Janus Quinase 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Células-Tronco Neurais/citologia
11.
Cardiovasc Res ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33878183

RESUMO

Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. Aims The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. Methods and results Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone H4 release was detected early during reperfusion. Sodium-ß-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralising compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS, or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. Conclusion Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Translational perspective Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). New approaches are needed to prevent cardiomyocyte injury and limit final infarct size. We show that histones released from damaged cells, and histone-H4 in particular, causes rapid cardiomyocyte death during I/R. mCBS, a compounds targeting histones non-specifically, was cardioprotective in ex vivo rat hearts, while HIPe, a targeting histone H4 specifically, was cardioprotective in an in vivo rat model. HIPe may have potential as a therapeutic agent in the setting of acute myocardial infarction.

12.
Basic Res Cardiol ; 116(1): 12, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33629195

RESUMO

The benefits of remote ischaemic conditioning (RIC) have been difficult to translate to humans, when considering traditional outcome measures, such as mortality and heart failure. This paper reviews the recent literature of the anti-inflammatory effects of RIC, with a particular focus on the innate immune response and cytokine inhibition. Given the current COVID-19 pandemic, the inflammatory hypothesis of cardiac protection is an attractive target on which to re-purpose such novel therapies. A PubMed/MEDLINE™ search was performed on July 13th 2020, for the key terms RIC, cytokines, the innate immune system and inflammation. Data suggest that RIC attenuates inflammation in animals by immune conditioning, cytokine inhibition, cell survival and the release of anti-inflammatory exosomes. It is proposed that RIC inhibits cytokine release via a reduction in nuclear factor kappa beta (NF-κB)-mediated NLRP3 inflammasome production. In vivo, RIC attenuates pro-inflammatory cytokine release in myocardial/cerebral infarction and LPS models of endotoxaemia. In the latter group, cytokine inhibition is associated with a profound survival benefit. Further clinical trials should establish whether the benefits of RIC in inflammation can be observed in humans. Moreover, we must consider whether uncomplicated MI and elective surgery are the most suitable clinical conditions in which to test this hypothesis.


Assuntos
Citocinas/fisiologia , Imunidade Inata , Inflamação/terapia , Precondicionamento Isquêmico Miocárdico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , COVID-19/complicações , Sobrevivência Celular , Vesículas Extracelulares/fisiologia , Humanos , Imunidade Humoral , Inflamação/sangue , Traumatismo por Reperfusão Miocárdica/imunologia
14.
Cardiovasc Res ; 117(2): 367-385, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32484892

RESUMO

Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

15.
Free Radic Biol Med ; 163: 325-343, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33359685

RESUMO

Global epidemiological studies reported a shift from maternal/infectious communicable diseases to chronic non-communicable diseases and a major part is attributable to atherosclerosis and metabolic disorders. Accordingly, ischemic heart disease was identified as a leading risk factor for global mortality and morbidity with a prevalence of 128 million people. Almost 9 million premature deaths can be attributed to ischemic heart disease and subsequent acute myocardial infarction and heart failure, also representing a substantial socioeconomic burden. As evidenced by typical oxidative stress markers such as lipid peroxidation products or oxidized DNA/RNA bases, the formation of reactive oxygen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial resperatory chain) plays a central role for the severity of ischemia/reperfusion damage. The underlying mechanisms comprise direct oxidative damage but also adverse redox-regulation of kinase and calcium signaling, inflammation and cardiac remodeling among others. These processes and the role of reactive oxygen species are discussed in the present review. We also present and discuss potential targets for redox-based therapies that are either already established in the clinics (e.g. guanylyl cyclase activators and stimulators) or at least successfully tested in preclinical models of myocardial infarction and heart failure (mitochondria-targeted antioxidants). However, reactive oxygen species have not only detrimental effects but are also involved in essential cellular signaling and may even act protective as seen by ischemic pre- and post-conditioning or eustress - which makes redox therapy quite challenging.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio
16.
Basic Res Cardiol ; 115(6): 73, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33258000

RESUMO

Atherosclerotic plaques impair vascular function and can lead to arterial obstruction and tissue ischaemia. Rupture of an atherosclerotic plaque within a coronary artery can result in an acute myocardial infarction, which is responsible for significant morbidity and mortality worldwide. Prompt reperfusion can salvage some of the ischaemic territory, but ischaemia and reperfusion (IR) still causes substantial injury and is, therefore, a therapeutic target for further infarct limitation. Numerous cardioprotective strategies have been identified that can limit IR injury in animal models, but none have yet been translated effectively to patients. This disconnect prompts an urgent re-examination of the experimental models used to study IR. Since coronary atherosclerosis is the most prevalent morbidity in this patient population, and impairs coronary vessel function, it is potentially a major confounder in cardioprotective studies. Surprisingly, most studies suggest that atherosclerosis does not have a major impact on cardioprotection in mouse models. However, a major limitation of atherosclerotic animal models is that the plaques usually manifest in the aorta and proximal great vessels, and rarely in the coronary vessels. In this review, we examine the commonly used mouse models of atherosclerosis and their effect on coronary artery function and infarct size. We conclude that none of the commonly used strains of mice are ideal for this purpose; however, more recently developed mouse models of atherosclerosis fulfil the requirement for coronary artery lesions, plaque rupture and lipoprotein patterns resembling the human profile, and may enable the identification of therapeutic interventions more applicable in the clinical setting.

17.
Basic Res Cardiol ; 115(6): 69, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188438

RESUMO

Treatment of acute myocardial infarct patients (AMI) includes rapid restoration of coronary blood flow and pharmacological therapy aimed to prevent pain and maintain vessel patency. Many interventions have been investigated to offer additional protection. One such intervention is remote ischaemic conditioning (RIC) involving short-episodes of ischaemia of the arm with a blood pressure cuff, followed by reperfusion to protect the heart organs from subsequent severe ischaemia. However, the recent CONDI2-ERIC-PPCI multicentre study of RIC in STEMI showed no benefit in clinical outcome in low risk patients. It could also be argued that these patients were already in a partially protected state, highlighting the disconnect between animal- and clinical-based outcome studies. To improve potential translatability, we developed an animal model using pharmacological agents similar to those given to patients presenting with an AMI, prior to PPCI. Rats underwent MI on a combined background of an opioid agonist, heparin and a platelet-inhibitor thereby allowing us to assess whether additional cardioprotective strategies had any effect over and above this "cocktail". We demonstrated that the "background drugs" were protective in their own right, reducing MI from 57.5 ± 3.7% to 37.3 ± 2.9% (n = 11, p < 0.001). On this background of drugs, RIC did not add any further protection (38.0 ± 3.4%). However, using a caspase inhibitor, which acts via a different mechanistic pathway to RIC, we were able to demonstrate additional protection (20.6 ± 3.3%). This concept provides initial evidence to develop models which can be used to evaluate future animal-to-clinical translation in cardioprotective studies.

18.
Sci Rep ; 10(1): 16874, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037284

RESUMO

Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.


Assuntos
Pós-Condicionamento Isquêmico/métodos , Precondicionamento Isquêmico/métodos , AVC Isquêmico/terapia , Neuroproteção , Animais , Modelos Animais de Doenças , Masculino , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Segurança , Resultado do Tratamento
19.
Expert Opin Ther Targets ; 24(8): 723-730, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32594778

RESUMO

INTRODUCTION: The cytokine release syndrome (CRS) of COVID-19 is associated with the development of critical illness requiring multi-organ support. Further research is required to halt progression of multi-organ injury induced by hyper-inflammation. AREAS COVERED: PubMed/MEDLINETM databases were accessed between May 9th-June 9th, 2020, to review the latest perspectives on the treatment and pathogenesis of CRS. EXPERT OPINION: Over-activity of chemotaxis triggers a macrophage activation syndrome (MAS) resulting in the release of pro-inflammatory cytokines. IL-6 and TNF- α are at the forefront of hyper-inflammation. The inflammatory cascade induces endothelial activation and capillary leak, leading to circulatory collapse and shock. As endothelial dysfunction persists, there is activation of the clotting cascade and microvascular obstruction. Continued endothelial activation results in multi-organ failure, regardless of pulmonary tissue damage. We propose that targeting the endothelium may interrupt this cycle. Immuno-modulating therapies have been suggested, however, further data is necessary to confirm that they do not jeopardize adaptive immunity. Inhibition of IL-6 and the Janus Kinase, signal transducer and activator of transcription proteins pathway (JAK/STAT), are favorable targets. Remote ischemic conditioning (RIC) reduces the inflammation of sepsis in animal models and should be considered as a low risk intervention, in combination with cardiovascular protection.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Síndrome da Liberação de Citocina , Insuficiência de Múltiplos Órgãos , Pandemias , Administração dos Cuidados ao Paciente/métodos , Pneumonia Viral , Animais , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Insuficiência de Múltiplos Órgãos/prevenção & controle , Insuficiência de Múltiplos Órgãos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia , SARS-CoV-2 , Transdução de Sinais/imunologia
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