RESUMEN
Immune checkpoint inhibitor (ICI) therapy represents a ground-breaking paradigm in cancer treatment, harnessing the immune system to combat malignancies by targeting checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). The use of ICI therapy generates distinctive immune-related adverse events (irAEs) including cardiovascular toxicity, necessitating targeted research efforts. This comprehensive review explores preclinical models dedicated to ICI-mediated cardiovascular complications including myocarditis. Tailored preclinical models of ICI-mediated myocardial toxicities highlight the key role of CD8+ T cells, emphasizing the profound impact of immune checkpoints on maintaining cardiac integrity. Cytokines and macrophages were identified as possible driving factors in disease progression, and at the same time, initial data on possible cardiac antigens responsible are emerging. The implications of contributing factors including thoracic radiation, autoimmune disorder, and the presence of cancer itself are increasingly understood. Besides myocarditis, mouse models unveiled an accelerated progression of atherosclerosis, adding another layer for a thorough understanding of the diverse processes involving cardiovascular immune checkpoint signalling. This review aims to discuss current preclinical models of ICI cardiotoxicity and their potential for improving enhanced risk assessment and diagnostics, offering potential targets for innovative cardioprotective strategies. Lessons from ICI therapy can drive novel approaches in cardiovascular research, extending insights to areas such as myocardial infarction and heart failure.
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Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity.
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Antineoplásicos , Cardiomiopatías , Insuficiencia Cardíaca , Miocarditis , Neoplasias , Medicina Nuclear , Humanos , Antineoplásicos/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Cardiotoxicidad/diagnóstico por imagen , Cardiotoxicidad/etiología , Cardiotoxicidad/tratamiento farmacológico , Miocarditis/inducido químicamente , Miocarditis/tratamiento farmacológicoRESUMEN
The continuous improvement in cancer treatment leads to a growing number of long-term survivors. Arguably, the treatment of cardiovascular side effects from cancer therapy is therefore of major importance for the morbidity and mortality affected patients. The 2022 ESC guidelines on cardio-oncology of the European Society of Cardiology (ESC) aim to improve the treatment of affected patients across the entire continuum of therapy and in the long term by establishing standardized procedures for prevention, diagnostics, and treatment of cardiovascular side effects. Suitable diagnostic and therapeutic measures for specific substance classes are defined on the basis of fundamental recommendations for cardio-oncological care in individual therapy phases. Furthermore, the guidelines provide a comprehensive focus on individual risk assessment before the start of therapy as the basis for determining the type and intensity of cardio-oncological care in the further course. In addition, the risk assessment serves as a basis for the initiation of suitable preventive measures to avoid or minimize the development of cardiovascular side effects during therapy. The present article provides an overview of the most important innovations of the 2022 ESC guidelines on cardio-oncology with respect to general definitions and recommendations as well as a summary of the most important recommendations for some specific forms of therapy with relevance for cardio-oncology in the future.
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Cardiología , Enfermedades Cardiovasculares , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias , Humanos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/prevención & control , Cardiotoxicidad/diagnóstico , Cardiotoxicidad/prevención & control , Neoplasias/tratamiento farmacológico , Oncología MédicaRESUMEN
Chimeric antigen receptor (CAR)-T cell therapy is the next revolutionary advance in cancer therapy. By using ex vivo engineered T cells to specifically target antigens, a targeted immune reaction is induced. Chimeric antigen receptor-T cell therapy is approved for patients suffering from advanced and refractory B cell and plasma cell malignancies and is undergoing testing for various other haematologic and solid malignancies. In the process of triggering an anticancer immune reaction, a systemic inflammatory response can emerge as cytokine release syndrome (CRS). The severity of CRS is highly variable across patients, ranging from mild flu-like symptoms to fulminant hyperinflammatory states with excessive immune activation, associated multiorgan failure and high mortality risk. Cytokine release syndrome is also an important factor for adverse cardiovascular (CV) events. Sinus tachycardia and hypotension are the most common reflections, similar to what is seen with other systemic inflammatory response syndromes. Corrected QT interval prolongation and tachyarrhythmias, including ventricular arrhythmias and atrial fibrillation, also show a close link with CRS. Events of myocardial ischaemia and venous thromboembolism can be provoked during CAR-T cell therapy. Although not as closely related to CRS, changes in cardiac function can be observed to the point of heart failure and cardiogenic shock. This may also be encountered in patients with severe valvular heart disease in the setting of CRS. This review will discuss the pertinent CV risks of the growing field of CAR-T cell therapy for today's cardiologists, including incidence, characteristics, and treatment options, and will conclude with an integrated management algorithm.
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Neoplasias , Receptores Quiméricos de Antígenos , Cardiotoxicidad/etiología , Tratamiento Basado en Trasplante de Células y Tejidos , Síndrome de Liberación de Citoquinas/etiología , Humanos , Neoplasias/complicaciones , Neoplasias/terapia , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
AIMS: Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. METHODS AND RESULTS: We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure-volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. CONCLUSIONS: Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Animales , Cardiotoxicidad/etiología , Células Endoteliales , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Ratones , Receptor de Muerte Celular Programada 1/uso terapéuticoRESUMEN
Cancer survival rates have increased significantly because of improvements in therapy regimes and novel immunomodulatory drugs. Recently, combination therapies of anthracyclines and immune checkpoint inhibitors (ICIs) have been proposed to maximize neoplastic cell removal. However, it has been speculated that a priori anthracycline exposure may prone the heart vulnerable to increased toxicity from subsequent ICI therapy, such as an anti-programmed cell death protein 1 (PD1) inhibitor. Here, we used a high-dose anthracycline mouse model to characterize the role of the PD1 immune checkpoint signaling pathway in cardiac tissue using flow cytometry and immunostaining. Anthracycline treatment led to decreased heart function, increased concentration of markers of cell death after six days and a change in heart cell population composition with fewer cardiomyocytes. At the same time point, the number of PD1 ligand (PDL1)-positive immune cells and endothelial cells in the heart decreased significantly. The results suggest that PD1/PDL1 signaling is affected after anthracycline treatment, which may contribute to an increased susceptibility to immune-related adverse events of subsequent anti-PD1/PDL1 cancer therapy.
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Antraciclinas , Neoplasias , Animales , Ratones , Antraciclinas/farmacología , Antraciclinas/uso terapéutico , Células Endoteliales/metabolismo , Inmunoterapia/métodos , Transducción de Señal , Antígeno B7-H1/metabolismoRESUMEN
The programmed cell death protein 1 (PD1) immune checkpoint prevents inflammatory tissue damage by inhibiting immune reactions. Understanding the relevance of cardiac PD1 signaling may provide new insights into the inflammatory events under baseline conditions and disease. Here, we demonstrate distinct immunological changes upon PD1 deficiency in healthy hearts and during reperfused acute myocardial infarction (repAMI). In PD1-deficient mice, upregulated inflammatory cytokines were identified under baseline conditions including cardiac interleukins and extracellular signal-related kinase 1/2 (ERK1/2). A murine in vivo repAMI model to determine inflammatory changes in the early phase showed downregulation of the ligand PDL1, paralleled by an endothelial injury, indicated by loss of the CD31 signal. Immunofluorescence imaging showed decreased PDL1 expression specifically in the infarct zone, highlighting an involvement in PDL1 in myocardial injury response. Pharmacological depletion of PD1 prior to repAMI did not alter the area of infarction but led to increased numbers of CD8+ T cells in treated mice. We conclude that PD1/PDL1 signaling plays a significant role in healthy hearts and repAMI, emphasizing the relevance of adaptive immunity during myocardial injury. The findings highlight the risk for adverse outcomes from acute myocardial infarction in the growing group of patients receiving immune checkpoint inhibitor therapy.
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Infarto del Miocardio , Receptor de Muerte Celular Programada 1 , Inmunidad Adaptativa/genética , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Ratones , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
BACKGROUND/OBJECTIVES: Coronary microvascular dysfunction (CMD) is a common disorder, leading to symptoms similar to obstructive coronary artery disease and bears important prognostic implications. Local inflammation is suggested to promote development of CMD. Epicardial adipose tissue (EAT) is a local visceral fat depot surrounding the heart and the coronary arteries, modifying the inflammatory environment of the heart. We compared EAT in patients with and without CMD. METHODS: We retrospectively included consecutive patients undergoing diagnostic coronary angiography as well as transthoracic echocardiography between March and October 2016. EAT thickness was defined as space between the epicardial wall of the myocardium and the visceral layer of the pericardium and EAT index was calculated as EAT thickness/body surface area. Logistic regression analysis was used to determine the association of EAT index with the presence of CMD. RESULTS: Overall, 399 patients (mean age 60.2 ± 14.0 years, 46% male) were included. EAT thickness was significantly higher in patients with CMD compared to patients without CMD (EAT thickness 4.4 ± 1.8 vs. 4.9 ± 2.4 mm, p = 0,048 for patients without and with CMD, respectively). In univariate regression analysis, EAT index was associated with a 30% higher frequency of CMD (odds ratio [95% confidence interval]: 1.30 [1.001-1.69], p = 0.049). Effect sizes remained stable upon adjustment for body mass index (BMI, 1.30 [1.003-1.70], p = 0.048), but were attenuated when ancillary adjusting for age and gender (1.17 [0.90-1.54, p = 0.25). The effect was more pronounced in patients >65 years of age and independent of BMI and sex (1.85 [1.14-3.00], p = 0.013). CONCLUSION: EAT thickness is independently associated with CMD and can differentiate between patients with and without CMD especially in older age groups. Our results support the hypothesis that modulation of local inflammation by epicardial fat is involved in the development of CMD.
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Tejido Adiposo/fisiopatología , Microcirculación/fisiología , Pericardio/anomalías , Anciano , Ecocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pericardio/metabolismo , Pericardio/fisiopatología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Platelets are components of the blood that are highly reactive, and they quickly respond to multiple physiological and pathophysiological processes. In the last decade, it became clear that platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity. Protein composition, localization, and activity are crucial for platelet function and regulation. The current state of mass spectrometry-based proteomics has tremendous potential to identify and quantify thousands of proteins from a minimal amount of material, unravel multiple post-translational modifications, and monitor platelet activity during drug treatments. This review focuses on the role of proteomics in understanding the molecular basics of the classical and newly emerging functions of platelets. including the recently described role of platelets in immunology and the development of COVID-19.The state-of-the-art proteomic technologies and their application in studying platelet biogenesis, signaling, and storage are described, and the potential of newly appeared trapped ion mobility spectrometry (TIMS) is highlighted. Additionally, implementing proteomic methods in platelet transfusion medicine, and as a diagnostic and prognostic tool, is discussed.
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Plaquetas/metabolismo , Espectrometría de Masas/métodos , Pruebas de Función Plaquetaria/métodos , Proteómica/métodos , Animales , Plaquetas/citología , Plaquetas/inmunología , COVID-19/inmunología , COVID-19/metabolismo , Humanos , Transfusión de Plaquetas , Procesamiento Proteico-Postraduccional , Transducción de Señal , Medicina Transfusional/métodosRESUMEN
BACKGROUND: Parameters that mark the timing of left ventricular (LV) reverse remodeling following transcatheter aortic valve replacement (TAVR) are incompletely defined. This study aims to identify the dynamics of LV strain derived from speckle tracking echocardiography in a cohort of patients with severe aortic stenosis (AS) who underwent TAVR and its correlation with postprocedural outcomes. METHODS: We selected 150 consecutive patients (82 ± 4 years old, STS score 6.4 ± 6.2) who underwent transfemoral TAVR between 07/2016 and 12/2017 at our tertiary care center. All patients were evaluated at baseline, 1 week after TAVR, and 3 months following TAVR. RESULTS: The global longitudinal strain (GLS) 1 week following TAVR was comparable to that at baseline (- 15,9 ± 4.3 vs - 16.8 ± 4.1; p = NS) but significantly improved at 3 months following TAVR (- 15.9 ± 4.3% vs. -19.5 ± 3.5%; p < 0.001). No significant changes in global circumferential strain (GCS) and global radial strain (GRS) were detectable. The ejection fraction was significantly improved 1 week after the TAVR procedure. The baseline GLS correlated directly with the complication rate (R = 0.36, p = 0.005). The linear regression analysis showed that the main predictors of the improvement in the GLS at 3 months in our cohort were baseline GRS and GCS. CONCLUSION: GLS improves at 3 months after TAVR, while LV ejection fraction does not show a substantial change, signaling an early recovery of LV longitudinal function after the intervention. Additionally, GLS has a direct correlation with the postprocedural outcomes. GLS improvement might emerge as a valuable parameter for a tailored follow-up in TAVR patients.
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Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Volumen Sistólico , Reemplazo de la Válvula Aórtica Transcatéter , Función Ventricular Izquierda , Remodelación Ventricular , Anciano , Anciano de 80 o más Años , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/fisiopatología , Femenino , Humanos , Masculino , Recuperación de la Función , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del TratamientoRESUMEN
Cardiotoxic side effects can significantly limit the quality of life and survival of tumor patients under treatment. Acute and chronic effects include hypertension, venous and arterial thromboembolic events, acute and chronic coronary syndromes, heart failure and arrhythmias. Patients with previous cardiovascular diseases are often more frequently affected by side effects. The triggers are not only irradiation and conventional chemotherapy but increasingly also newer forms of cancer treatment. These include targeted therapy and immune checkpoint inhibitors (ICI). The goals of oncological cardiology are the prevention, timely diagnosis and treatment of these side effects in order to optimize patient outcomes.
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Antineoplásicos , Enfermedades Cardiovasculares , Neoplasias , Antineoplásicos/efectos adversos , Cardiólogos , Enfermedades Cardiovasculares/epidemiología , Humanos , Neoplasias/tratamiento farmacológico , Calidad de Vida , Factores de RiesgoRESUMEN
Immune checkpoint inhibitor (ICI) therapy induces an immune response against cancer cells. Immune checkpoint inhibitor therapy has tremendously improved the prognosis for a large number of cancers, but is associated with considerable immune-related adverse events (irAEs). Cardiovascular complications from ICI therapy occur in a modest proportion of patients, but show the highest lethality rates of all ICI-related complications. While ICI-related myocarditis is the most dangerous complication, its clinical manifestation varies, e.g., asymptomatic reduction of left ventricular function, isolated increase in cardiac troponins, and arrhythmias. This review delineates current data on cardiovascular complications of ICI therapy. The effects of ICI therapy on the cardiovascular system are classified in the context of preclinical data on the biochemical and immunological function of the immune checkpoint signaling pathways in the heart and the vascular system. Incidence, suspected pathomechanisms, typical symptoms, as well as recommended diagnostics are summarized. Current therapy recommendations for ICI-related cardiotoxicity are outlined and innovative new approaches with high potential for improving outcome in ICI-related myocarditis are delineated. A better understanding of cardiovascular complications is essential for the best possible oncocardiology care of the growing number of patients undergoing ICI therapy.
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Antineoplásicos Inmunológicos , Sistema Cardiovascular , Miocarditis , Neoplasias , Cardiotoxicidad , Humanos , Miocarditis/inducido químicamente , Miocarditis/diagnóstico , Miocarditis/tratamiento farmacológico , Neoplasias/tratamiento farmacológicoRESUMEN
OBJECTIVES: To evaluate the impact of baseline left ventricular ejection fraction (LVEF) and its interaction with low-gradient aortic stenosis (LGAS) on all-cause mortality after transfemoral aortic valve implantation (TF-TAVI). METHODS: We reviewed mortality data of 624 consecutive single center TF-TAVI patients and categorized LVEF according to current ASE/EACVI recommendations (normal, mildly-, moderately-, and severely abnormal). RESULTS: Baseline LVEF was normal in 336 (53.8%), mildly abnormal in 160 (25.6%), moderately abnormal in 91 (14.6%), and severely abnormal in 37 (5.9%) patients, and 1-year mortality was 19%, 17%, 23%, and 43% (P = 0.002), respectively. Patients with LGAS had a similar 1-year mortality compared to those without LGAS in groups with normal (19% vs 19%, P = 0.899) and mildly abnormal LVEF (16% vs 17%, P = 0.898). One-year mortality of patients with LGAS was significantly greater than in those without LGAS in presence of moderately abnormal LVEF (31% vs 11%, P = 0.022), and it was numerically greater than in those without LGAS in presence of severely abnormal LVEF (48% vs 25%, P = 0.219). In multivariate analysis, only the combination of moderately/severely abnormal LVEF and LGAS predicted increased 1-year mortality (HR: 2.12, 95% CI: 1.4-3.2, P < 0.001). Other variables, including EuroSCORE I did not affect this result. CONCLUSIONS: Moderately/severely abnormal LVEF (≤40%) at baseline is associated with increased mortality after TF-TAVI, especially when the mean transvalvular aortic gradient is <40 mm Hg (LGAS), while outcomes in patients with normal and mildly abnormal LVEF are comparable regardless of the pressure gradient across the native aortic valve. (DRKS00013729).
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Estenosis de la Válvula Aórtica/complicaciones , Ecocardiografía/métodos , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/fisiopatología , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Disfunción Ventricular Izquierda/complicaciones , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/fisiopatología , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Complicaciones Posoperatorias/diagnóstico por imagen , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/mortalidadRESUMEN
BACKGROUND: Myocardial infarction remains the single leading cause of death worldwide. Upon reperfusion of occluded arteries, deleterious cellular mediators particularly located at the mitochondria level can be activated, thus limiting the outcome in patients. This may lead to the so-called ischemia/reperfusion (I/R) injury. Calpains are cysteine proteases and mediators of caspase-independent cell death. Recently, they have emerged as central transmitters of cellular injury in several cardiac pathologies e.g. hypertrophy and acute I/R injury. METHODS: Here we investigated the role of cardiac calpains in acute I/R in relation to mitochondrial integrity and whether calpains can be effectively inhibited by posttranslational modification by S-nitrosation. Taking advantage of the a cardiomyocyte cell line (HL1), we determined S-nitrosation by the Biotin-switch approach, cell viability and intracellular calcium concentration after simulated ischemia and reoxygenation - all in dependence of supplementation with nitrite, which is known as an 'hypoxic nitric oxide (NO) donor'. Likewise, using an in vivo I/R model, calpain S-nitrosation, calpain activity and myocardial I/R injury were characterized in vivo. RESULTS: Nitrite administration resulted in an increased S-nitrosation of calpains, and this was associated with an improved cell-survival. No impact was detected on calcium levels. In line with these in vitro experiments, nitrite initiated calpain S-nitrosation in vivo and caused an infarct sparing effect in an in vivo myocardial I/R model. Using electron microscopy in combination with immuno-gold labeling we determined that calpain 10 increased, while calpain 2 decreased in the course of I/R. Nitrite, in turn, prevented an I/R induced increase of calpains 10 at mitochondria and reduced levels of calpain 1. CONCLUSION: Lethal myocardial injury remains a key aspect of myocardial I/R. We show that calpains, as key players in caspase-independent apoptosis, increasingly locate at mitochondria following I/R. Inhibitory post-translational modification by S-nitrosation of calpains reduces deleterious calpain activity in murine cardiomyocytes and in vivo.
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Calpaína/antagonistas & inhibidores , Isquemia Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Nitratos/química , Animales , Calpaína/química , Calpaína/metabolismo , Línea Celular , Masculino , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Infarto del Miocardio/metabolismo , Nitritos/administración & dosificación , NitrosaciónRESUMEN
Cardioprotective strategies to prevent damage to mitochondria in acute myocardial infarction are warranted to reduce lethal myocardial ischemia/reperfusion (I/R) injury. Mitochondrial antagonists in I/R are reactive oxygen species (ROS), deteriorated calcium signaling, permeabilization of the mitochondrial outer membrane (MOM) and deranged mitochondrial structural dynamism (fusion and fission). Nitric oxide (NO) related signaling can protect hearts from I/R. Albeit the underlying signaling is incompletely resolved, recent data point to a particular involvement of protective posttranslational modification of mitochondrial elements. We and others have demonstrated that hypoxic NO signaling in cardiomyocytes is associated with a posttranslational mitochondrial complex I modification to reduce the burden of ROS. Induction of cardioprotective NO signaling may occur through several pathways. These include (i) the supplementation with mitochondria unspecific and specific NO-donors, (ii) the administration of the 'hypoxic-NO donors nitrate and nitrite' and (iii) the enhancement of endogenous NO formation, e.g. by remote ischemic preconditioning maneuvers (rIPC). In this chapter, we outline how NO signaling is activated in the cardiomyocyte, characterize the downstream signaling pathways and discuss how this could translate into a tractable therapeutic approach in patients requiring cardioprotection.
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Precondicionamiento Isquémico Miocárdico/métodos , Mitocondrias Cardíacas/efectos de los fármacos , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Citoprotección , Humanos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Donantes de Óxido Nítrico/metabolismoRESUMEN
RATIONALE: Remote ischemic preconditioning (rIPC) with short episodes of ischemia/reperfusion (I/R) of an organ remote from the heart is a powerful approach to protect against myocardial I/R injury. The signal transduction pathways for the cross talk between the remote site and the heart remain unclear in detail. OBJECTIVE: To elucidate the role of circulating nitrite in cardioprotection by rIPC. METHODS AND RESULTS: Mice were subjected to 4 cycles of no-flow ischemia with subsequent reactive hyperemia within the femoral region and underwent in vivo myocardial I/R (30 minutes/5 minutes or 24 hours). The mouse experiments were conducted using genetic and pharmacological approaches. Shear stress-dependent stimulation of endothelial nitric oxide synthase within the femoral artery during reactive hyperemia yielded substantial release of nitric oxide, subsequently oxidized to nitrite and transferred humorally to the myocardium. Within the heart, reduction of nitrite to nitric oxide by cardiac myoglobin and subsequent S-nitrosation of mitochondrial membrane proteins reduced mitochondrial respiration, reactive oxygen species formation, and myocardial infarct size. Pharmacological and genetic inhibition of nitric oxide/nitrite generation by endothelial nitric oxide synthase at the remote site or nitrite bioactivation by myoglobin within the target organ abrogated the cardioprotection by rIPC. Transfer experiments of plasma from healthy volunteers subjected to rIPC of the arm identified plasma nitrite as a cardioprotective agent in isolated Langendorff mouse heart preparations exposed to I/R. CONCLUSIONS: Circulating nitrite derived from shear stress-dependent stimulation of endothelial nitric oxide synthase at the remote site of rIPC contributes to cardioprotection during I/R. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01259739.