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BACKGROUND AND PURPOSE: Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect. EXPERIMENTAL APPROACH: ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis. KEY RESULTS: Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways. CONCLUSION AND IMPLICATIONS: This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways.
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PURPOSE: Remote ischemic conditioning (RIC) has been shown to be a powerful cardioprotective therapy in animal models. However, a protective effect in patients presenting with acute myocardial infarction has failed to be confirmed. A recent pre-clinical study reported that aspirin which is routinely given to patients undergoing reperfusion therapy blocked the infarct-limiting effect of ischemic postconditioning. The present study was designed to test whether aspirin could also be blocking the infarct-limiting effect of RIC. METHODS: This was investigated in vivo using male Sprague Dawley rats (n = 5 to 6 per group) subjected to either 30 min of regional myocardial ischemia, followed by 120-min reperfusion, or additionally to a RIC protocol initiated after 20-min myocardial ischemia. The RIC protocol included four cycles of 5-min hind limb ischemia interspersed with 5-min reperfusion. Intravenous aspirin (30 mg/kg) or vehicle (saline) was administered after 15-min myocardial ischemia. RESULTS: RIC significantly reduced infarct size (IS) normalized to the area at risk, by 47%. Aspirin administration did not affect IS nor did it attenuate the infarct-limiting effect of RIC. CONCLUSION: Aspirin administration in the setting of myocardial infarction is not likely to interfere with the cardioprotective effect of RIC.
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Nitric oxide (NO) and carbon monoxide (CO) represent a pair of biologically active gases with an increasingly well-defined range of effects on circulating platelets. These gases interact with platelets and cells in the vessels and heart and exert fundamentally similar biological effects, albeit through different mechanisms and with some peculiarity. Within the cardiovascular system, for example, the gases are predominantly vasodilators and exert antiaggregatory effects, and are protective against damage in myocardial ischemia-reperfusion injury. Indeed, NO is an important vasodilator acting on vascular smooth muscle and is able to inhibit platelet activation. NO reacts with superoxide anion (O2(-â¢)) to form peroxynitrite (ONOO(-)), a nitrosating agent capable of inducing oxidative/nitrative signaling and stress both at cardiovascular, platelet, and plasma levels. CO reduces platelet reactivity, therefore it is an anticoagulant, but it also has some cardioprotective and procoagulant properties. This review article summarizes current knowledge on the platelets and roles of gas mediators (NO, and CO) in cardioprotection. In particular, we aim to examine the link and interactions between platelets, NO, and CO and cardioprotective pathways.
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Gasotransmisores , Daño por Reperfusión Miocárdica , Humanos , Óxido Nítrico/metabolismo , Óxidos , Gasotransmisores/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Gases , VasodilatadoresRESUMEN
Despite the development of cutting-edge treatments, coronary artery disease (CAD) morbidity and mortality rates remain present at high levels. Therefore, new cardioprotective approaches are crucial to improve the health of patients. To date, experimental investigations of acute ischemia-reperfusion injury (IRI) have generally demonstrated the efficacy of local ischemic preconditioning and postconditioning cardioprotection techniques as well as of remote conditioning. However, application in clinical settings is still highly controversial and debated. Currently, remote ischemic conditioning (RIC) seems to be the most promising method for heart repair. Protective factors are released into the bloodstream, and protection can be transferred within and across species. For a long time, the cross-function and cross-transmission mechanisms of cardioprotection were largely unknown. Recently, it has been shown that small, anuclear, bilayered lipid membrane particles, known as extracellular vesicles (EVs), are the drivers of signal transduction in cardiac IRI and RIC. EVs are related to the pathophysiological processes of cardiovascular diseases (CVDs), according to compelling evidence. In this review, we will first review the current state of knowledge on myocardial IRI and cardioprotective strategies explored over the past 37 years. Second, we will briefly discuss the role of EVs in CVD and the most recent improvements on EVs as prognostic biomarkers, diagnostic, and therapeutic agents. We will discuss how EVs can be used as a new drug delivery mechanism and how they can be employed in cardiac treatment, also from a perspective of overcoming the impasse that results from neglecting confounding factors.
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Since coronary reperfusion was introduced into clinical practice in the late 1970s, the further translation of several successful animal experiments on cardioprotection into clinical practice has been disappointing to date. Animal experiments are often performed on young, healthy animals lacking the risk factors, co-morbidities and co-medications characteristic of acute myocardial infarction patients. Many hopes were kindled in 1986 when ischemic preconditioning was discovered. However, it is not yet known how long ischemia can last and what is the best modality for additional cardioprotection through conditioning to obtain benefits. There is a lack of experimental studies on the long-term effects of additional cardioprotection, in addition to the reduction in infarct size; in particular, there is a lack of studies on vessel protection, repair, inflammation, remodeling, and mortality. The reproducibility and robustness of experimental studies are often limited by species differences, the role of co-morbidities, vascular damage, inflammatory processes, and co-medications, which are not adequately considered. In particular, inflammatory processes, including NLRP3 inflammasome, play an important role in the long-term effects. Future studies should focus on interventions/agents with robust preclinical data and should recruit patients who truly have the potential to benefit from further cardioprotection. Here we focus on the main mechanisms and targets of cardioprotection during remote conditioning and their alteration by one of the most common co-morbidities, namely diabetes, in which microvascular lesions and inflammatory processes play extremely important roles.
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Precondicionamiento Isquémico Miocárdico , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Animales , Humanos , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
Objectives: Despite a common utilization of "Negative Pressure Wound Therapy" (NPWT) Devices in a wide range of specialties, some of the basic mechanisms of action of the techniques are still on debate. Conflicting results from prior studies demonstrate our lack of understanding how wound-bed perfusion or cutaneous microcirculation is affected by NPWT. Methods: We conducted a prospective randomized study which included 45 healthy subjects to further investigate the acute effects of NPWT on cutaneous microcirculation underneath the applied dressing. Three modes of application, namely, continuous, intermittent, cyclic, were tested. Amongst others, measurements of elicited surface pressure and a comprehensive microcirculatory analysis were carried out by utilizing an O2C-device. For the detection of (systemic) remote effects, perfusion changes of the contra-lateral thigh were evaluated. Results: All three tested modes of application led to a significant (p < 0.05) improvement in local tissue perfusion with an increased blood flow of max +151% and tissue oxygen saturation of +28.2% compared to baseline values. Surface pressure under the dressing significantly increased up to 29.29 mmHg due to the activation of the NPWT device. Continuous, intermittent, and cyclic application of negative pressure were accurately sensed by participants, resulting in reported pain values that mirrored the different levels of applied suction. Although the cyclic application mode showed the most pronounced effects regarding microcirculatory changes, no statistical significance between groups was observed. Conclusion: We could demonstrate a significant improvement of cutaneous microcirculation under an applied NPWT dressing with favorable effects due to cyclic mode of application. An increased surface pressure leads to a better venous drainage of the tissue, which was shown to increase arterial inflow with a consecutive improvement of oxygen supply. Further research is warranted to evaluate our findings regarding wound bed perfusion in the clinical field with respect to formation of granulation tissue and wound healing.
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Remote ischemic conditioning (RIC) represents an innovative and attractive neuroprotective approach in brain ischemia. The purpose of this intervention is to activate endogenous tolerance mechanisms by inflicting a subliminal ischemia injury to the limbs, or to another "remote" region, leading to a protective systemic response against ischemic brain injury. Among the multiple candidates that have been proposed as putative mediators of the protective effect generated by the subthreshold peripheral ischemic insult, it has been hypothesized that microRNAs may play a vital role in the infarct-sparing effect of RIC. The effect of miRNAs can be exploited at different levels: (1) as transducers of protective messages to the brain or (2) as effectors of brain protection. The purpose of the present review is to summarize the most recent evidence supporting the involvement of microRNAs in brain protection elicited by remote conditioning, highlighting potential and pitfalls in their exploitation as diagnostic and therapeutic tools. The understanding of these processes could help provide light on the molecular pathways involved in brain protection for the future development of miRNA-based theranostic agents in stroke.
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AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 µm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.
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Arterias/fisiopatología , Poscondicionamiento Isquémico , Daño por Reperfusión Miocárdica/prevención & control , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/terapia , Extremidad Superior/irrigación sanguínea , Función Ventricular Izquierda , Remodelación Ventricular , Adulto , Anciano , Arterias/metabolismo , MicroARN Circulante/sangre , Células Endoteliales/metabolismo , Femenino , Glicocálix/metabolismo , Grecia , Humanos , Mediadores de Inflamación/metabolismo , Poscondicionamiento Isquémico/efectos adversos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Estrés Oxidativo , Intervención Coronaria Percutánea/efectos adversos , Estudios Prospectivos , Flujo Sanguíneo Regional , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Rigidez VascularRESUMEN
AIMS: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. METHODS AND RESULTS: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. CONCLUSION: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
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Cardiopatías/prevención & control , Miembro Posterior/irrigación sanguínea , Precondicionamiento Isquémico , Mitocondrias Cardíacas/ultraestructura , Miocardio/ultraestructura , Volumen Sistólico , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Antibióticos Antineoplásicos , Autofagia , Proteínas Relacionadas con la Autofagia/metabolismo , Cardiotoxicidad , Modelos Animales de Enfermedad , Doxorrubicina , Fibrosis , Cardiopatías/inducido químicamente , Cardiopatías/patología , Cardiopatías/fisiopatología , Imagen por Resonancia Cinemagnética , Masculino , Mitocondrias Cardíacas/metabolismo , Dinámicas Mitocondriales , Miocardio/metabolismo , Flujo Sanguíneo Regional , Sus scrofa , Factores de TiempoRESUMEN
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.
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Analgésicos Opioides/farmacología , Anticoagulantes/farmacología , Inhibidores de Caspasas/farmacología , Circulación Coronaria/efectos de los fármacos , Extremidades/irrigación sanguínea , Precondicionamiento Isquémico Miocárdico , Infarto del Miocardio/prevención & control , Miocardio/patología , Inhibidores de Agregación Plaquetaria/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Supervivencia Tisular , Investigación Biomédica TraslacionalRESUMEN
Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.
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Cardiomiopatías Diabéticas/epidemiología , Ejercicio Físico , Precondicionamiento Isquémico , Isquemia Miocárdica/epidemiología , Animales , Diabetes Mellitus/epidemiología , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/terapia , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Redes y Vías Metabólicas , Isquemia Miocárdica/etiología , Isquemia Miocárdica/prevención & control , Isquemia Miocárdica/terapia , Daño por Reperfusión Miocárdica/epidemiología , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/terapiaRESUMEN
The present study aimed to investigate the effects of intestinal remote ischemic preconditioning (iRIC) on ischemia-reperfusion injury (IRI) and gut barrier integrity in a rat model of total hepatic ischemia (THI). Male Wistar rats (n = 50; 250-300 g) were randomly allocated into two experimental groups: RIC/Control. Thirty minutes of THI was induced by clamping the hepatoduodenal ligament. iRIC was applied as 4-min of ischemia followed by 11-min of reperfusion by clamping the superior mesenteric artery. Animals were sacrificed at 1, 2, 6, 24 h post-reperfusion (n = 5/group/timepoint). RIC of the gut significantly improved microcirculation of the ileum and the liver. Tissue ATP-levels were higher following iRIC (Liver: 1.34 ± 0.12 vs. 0.97 ± 0.20 µmol/g, p = 0.04) and hepatocellular injury was reduced significantly (ALT: 2409 ± 447 vs. 6613 ± 1117 IU/L, p = 0.003). Systemic- and portal venous IL-6 and TNF-alpha levels were markedly lower following iRIC, demonstrating a reduced inflammatory response. iRIC led to a structural and functional preservation of the intestinal barrier. These results suggest that iRIC might confer a potent protection against the detrimental effects of THI in rats via reducing IRI and systemic inflammatory responses and at the same time by mitigating the dramatic consequences of severe intestinal congestion and bacterial translocation.
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Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9-T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.
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Capsaicina/uso terapéutico , Cardiotónicos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Nocicepción , Fármacos del Sistema Sensorial/uso terapéutico , Piel/inervación , Animales , Capsaicina/farmacología , Cardiotónicos/farmacología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/fisiología , Proteína Quinasa C/metabolismo , Receptor de Bradiquinina B2/metabolismo , Reflejo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Fármacos del Sistema Sensorial/farmacologíaRESUMEN
Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.
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Cardiotoxicidad/prevención & control , Cardiotoxinas , Desarrollo de Medicamentos/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Seguridad del Paciente , Animales , Comorbilidad , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Humanos , RatonesRESUMEN
Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit.
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Cardiología/métodos , Fraccionamiento Celular/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/trasplante , Técnicas de Diagnóstico Cardiovascular , Exosomas/metabolismo , Exosomas/trasplante , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/terapia , Animales , Biomarcadores/metabolismo , Cardiología/normas , Fraccionamiento Celular/normas , Tratamiento Basado en Trasplante de Células y Tejidos/normas , Micropartículas Derivadas de Células/patología , Consenso , Técnicas de Diagnóstico Cardiovascular/normas , Exosomas/patología , Humanos , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Valor Predictivo de las PruebasRESUMEN
Remote ischemic conditioning (RIC) is at a pivotal point in its evolution, both in terms of its adoption as a therapy and its viability commercially. The most usual way of inducing RIC, with a standard blood pressure cuff and a stopwatch, is time-consuming and potentially inaccurate and unsafe. Development of automated devices have facilitated large-scale randomized trials and will make clinical deployment of the technique more straightforward. Both the medical and commercial future of RIC will depend on the results of upcoming phase 3 pivotal trials.
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Precondicionamiento Isquémico Miocárdico , Procedimientos Quirúrgicos Cardíacos , Humanos , Intervención Coronaria PercutáneaRESUMEN
BACKGROUND: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI. METHODS AND RESULTS: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 × 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 × 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 × 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO. CONCLUSION: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis.
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Cardiotónicos/metabolismo , Poscondicionamiento Isquémico , Precondicionamiento Isquémico Miocárdico , Imagen por Resonancia Magnética/métodos , Microvasos/patología , Daño por Reperfusión Miocárdica/diagnóstico , Animales , Edema/patología , Electrocardiografía , Femenino , Pruebas de Función Cardíaca , Hemodinámica , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Necrosis , Coloración y Etiquetado , Sus scrofaRESUMEN
The incidence of ST segment elevation myocardial infarction (STEMI) has decreased over the last two decades in developed countries, but mortality from STEMI despite widespread access to reperfusion therapy is still substantial as is the development of heart failure, particularly among an expanding older population. In developing countries, the incidence of STEMI is increasing and interventional reperfusion is often not available. We here review the pathophysiology of acute myocardial infarction and reperfusion, notably the temporal and spatial evolution of ischaemic and reperfusion injury, the different modes of cell death, and the resulting coronary microvascular dysfunction. We then go on to briefly characterize the cardioprotective phenomena of ischaemic preconditioning, ischaemic postconditioning, and remote ischaemic conditioning and their underlying signal transduction pathways. We discuss in detail the attempts to translate conditioning strategies and drug therapy into the clinical setting. Most attempts have failed so far to reduce infarct size and improve clinical outcomes in STEMI patients, and we discuss potential reasons for such failure. Currently, it appears that remote ischaemic conditioning and a few drugs (atrial natriuretic peptide, exenatide, metoprolol, and esmolol) reduce infarct size, but studies with clinical outcome as primary endpoint are still underway.
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Reperfusión Miocárdica/métodos , Infarto del Miocardio con Elevación del ST/etiología , Animales , Cardiotónicos/uso terapéutico , Circulación Coronaria/fisiología , Modelos Animales de Enfermedad , Humanos , Poscondicionamiento Isquémico/métodos , Precondicionamiento Isquémico Miocárdico/métodos , Angina Microvascular/etiología , Reperfusión Miocárdica/efectos adversos , Daño por Reperfusión Miocárdica/prevención & control , Intervención Coronaria Percutánea/métodos , Infarto del Miocardio con Elevación del ST/fisiopatología , Infarto del Miocardio con Elevación del ST/terapia , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Resultado del TratamientoRESUMEN
Cardioprotective strategies aim to salvage myocardium from ischemia/reperfusion injury and to reduce infarct size and its consequences. Different stimuli, acting at sites remote from the heart (remote conditioning), activate molecular self-defense mechanisms at the target organ heart as well as in other parenchymal organs. Remote conditioning of the heart has been established in many experimental studies and successfully translated to patients. Remote ischemic conditioning by short repetitive cycles of ischemia/reperfusion on an extremity reduces infarct size and improves the prognosis of patients with reperfused myocardial infarction. The present review focuses on three levels of remote conditioning and its resulting cardioprotection: I) at the stimulus level, electrical stimulation, chemical/pharmacological substances, mechanical trauma and cycles of ischemia/reperfusion act at sites remote from the heart, II) at the transfer level, neuronal and humoral mediators transfer the protective signal from the periphery to the heart, and III) at the target level, receptor activation and intracellular signal transduction ultimately affect protection of the myocardium and other organs, as established in different animal models and humans/patients. Remote conditioning is obviously a systemic response. Further mechanistic understanding is mandatory to translate the protection by remote conditioning more successfully to patients with cardiovascular disease.