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BACKGROUND: Doxorubicin (Doxo) is a widely prescribed drug against many malignant cancers. Unfortunately, its utility is limited by its toxicity, in particular a progressive induction of congestive heart failure. Doxo acts primarily as a mitochondrial toxin, with consequent increased production of reactive oxygen species (ROS) and attendant oxidative stress, which drives cardiac dysfunction and cell death. A diet containing a special mixture of all essential amino acids (EAAs) has been shown to increase mitochondriogenesis, and reduce oxidative stress both in skeletal muscle and heart. So, we hypothesized that such a diet could play a favorable role in preventing Doxo-induced cardiomyocyte damage. METHODS: Using transmission electron microscopy, we evaluated cells' morphology and mitochondria parameters in adult mice. In addition, by immunohistochemistry, we evaluated the expression of pro-survival marker Klotho, as well as markers of necroptosis (RIP1/3), inflammation (TNFα, IL1, NFkB), and defense against oxidative stress (SOD1, glutathione peroxidase, citrate synthase). RESULTS: Diets with excess essential amino acids (EAAs) increased the expression of Klotho and enhanced anti-oxidative and anti-inflammatory responses, thereby promoting cell survival. CONCLUSION: Our results further extend the current knowledge about the cardioprotective role of EAAs and provide a novel theoretical basis for their preemptive administration to cancer patients undergoing chemotherapy to alleviate the development and severity of Doxo-induced cardiomyopathy.
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Aminoácidos Esenciales , Miocitos Cardíacos , Ratones , Animales , Miocitos Cardíacos/metabolismo , Aminoácidos Esenciales/metabolismo , Doxorrubicina/toxicidad , Estrés Oxidativo , Dieta , Cardiotoxicidad/prevención & controlRESUMEN
Background: Many patients who have been suffering by Covid-19 suffer of long-Covid syndrome, with symptoms of fatigue and muscular weakness that characterize post-acute sequelae SARS-CoV-2 infection (PASC). However, there is limited knowledge about the molecular pathophysiology, and about the serum profile of these patients. Methods: We studied the blood serum profile of 75 selected patients, with previous confirmed Covid-19, 2 months after hospital discharge, who reported new-onset fatigue, muscle weakness and/or dyspnea not present prior to the virus infection and independently from concomitant diseases and/or clinical conditions. Results: All patients had very high serum concentrations of ferritin and D-Dimer. 87 and 72% of patients had clinically significant low levels of hemoglobin and albumin, respectively. Seventy three percentage had elevations in erythrocyte sedimentation rate and CRP. Twenty seven percentage had elevations in LDH. Conclusions: The co-existence of patient symptoms along with blood markers of coagulation, protein disarrangement and inflammation suggests ongoing alterations in the metabolism, promoting an inflammatory/hypercatabolic state which maintains a vicious circles implicated in the persistence of PASC. The persistence of altered D-Dimer levels raises the possibility of long-term risks of thromboembolic disease. All these markers levels should be accurately evaluated in the long-term follow-up, with individualized consideration for prophylactic nutritional, anti-inflammatory and/or anticoagulant therapy if indicated.
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Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.
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Autofagia , Insuficiencia Cardíaca/fisiopatología , Corazón/fisiología , Desnutrición/fisiopatología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Supervivencia Celular , Enfermedad Crónica , Citosol/metabolismo , Progresión de la Enfermedad , Insuficiencia Cardíaca/complicaciones , Humanos , Desnutrición/complicaciones , Metabolismo , Ratones , Músculo Esquelético/metabolismo , Contracción Miocárdica , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Medición de RiesgoRESUMEN
Chronic diseases are characterised by altered autophagy and protein metabolism disarrangement, resulting in sarcopenia, hypoalbuminemia and hypo-haemoglobinaemia. Hypo-haemoglobinaemia is linked to a worse prognosis independent of the target organ affected by the disease. Currently, the cornerstone of the therapy of anaemia is iron supplementation, with or without erythropoietin for the stimulation of haematopoiesis. However, treatment strategies should incorporate the promotion of the synthesis of heme, the principal constituent of haemoglobin (Hb) and of many other fundamental enzymes for human metabolism. Heme synthesis is controlled by a complex biochemical pathway. The limiting step of heme synthesis is D-amino-levulinic acid (D-ALA), whose availability and synthesis require glycine and succinil-coenzyme A (CoA) as precursor substrates. Consequently, the treatment of anaemia should not be based only on the sufficiency of iron but, also, on the availability of all precursor molecules fundamental for heme synthesis. Therefore, an adequate clinical therapeutic strategy should integrate a standard iron infusion and a supply of essential amino acids and vitamins involved in heme synthesis. We reported preliminary data in a select population of aged anaemic patients affected by congestive heart failure (CHF) and catabolic disarrangement, who, in addition to the standard iron therapy, were treated by reinforced therapeutic schedules also providing essential animo acids (AAs) and vitamins involved in the maintenance of heme. Notably, such individualised therapy resulted in a significantly faster increase in the blood concentration of haemoglobin after 30 days of treatment when compared to the nonsupplemented standard iron therapy.
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Anemia/diagnóstico , Anemia/terapia , Anciano , Anciano de 80 o más Años , Anemia/etiología , Anemia/metabolismo , Biomarcadores/sangre , Vías Biosintéticas , Enfermedad Crónica , Terapia Combinada , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Índices de Eritrocitos , Femenino , Hemo/química , Hemo/metabolismo , Humanos , Hierro/química , Hierro/metabolismo , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND In humans, wood dust is a carcinogen. Indeed, a strong association between wood dust and lung cancer risk has been reported in woodworkers, as well as in the general population. CASE REPORT The patient was a 58-year-old man with follicular B-cell lymphoma. In the 10 years preceding the cancer diagnosis, he lived within 1/4 mile of a paper mill, where wood was processed. Computed tomography of the chest, abdomen, and pelvis revealed right hilar, mediastinal, abdominal, and retroperitoneal lymphadenopathy, bilateral pleural effusions, and a large soft-tissue mass infiltrating the small bowel mesentery. Analysis of the pleural fluid revealed the presence of a web of thin filopodia-like filaments, which trapped clusters of mesothelial cells and atypical lymphocytes. Single tubular filaments, morphologically similar to tunneling nanotubes, were seen originating from atypical lymphocytes and reaching neighboring cells. Furthermore, long, thick, cylindrical fibers of unknown nature, probably from the external environment, were also observed. CONCLUSIONS Because the patient lived in an unhealthy environment for many years, the possibility that his clinical condition was related to exposure to toxic emissions should be entertained. Considered in this context, the foreign fibers in his pleural fluid could be a direct consequence of inhalation of contaminants in the polluted air.
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Exposición a Riesgos Ambientales/efectos adversos , Linfoma de Células B/inducido químicamente , Material Particulado/toxicidad , Madera/toxicidad , Humanos , Masculino , Persona de Mediana Edad , Derrame Pleural Maligno/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
In this systematic review article, we aim to summarize the most up-to-date evidence regarding elevations of cardiac troponin, especially in clinical scenarios other than obstructive coronary artery disease. The accurate interpretation of raised cardiac troponin is challenging because it relies on unconfirmed postulations and dogmatic knowledge (e.g., the exclusive provenience of cardiac troponin from cardiac myocytes), based on which every troponin elevation is assumed to definitely indicate myocardial damage. Indeed, the investigation of the pathophysiologic mechanism leading to the release in the bloodstream of cardiac biomarkers should be the first step of the diagnostic process to fully understand the clinical significance of the elevated serum levels and identify the best management. A prominent effort should be put in place to identify the contribution of potential confounding factors, both cardiac and non-cardiac in etiology, with the ability to affect synthesis and clearance of cardiac biomarkers. Regardless of the underlying cause, it is well established that cardiovascular biomarkers are increasingly useful to further risk stratification and prognosticate patients. Accordingly, we sought to clarify the meaning and impact of elevated cardiac troponin in those frequently encountered real-world scenarios presenting clinicians with a diagnostic dilemma, with the final goal of facilitating the diagnosis and help optimize individually tailored treatment strategies.
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Enfermedad de la Arteria Coronaria/metabolismo , Miocardio/metabolismo , Troponina/metabolismo , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/fisiopatología , Humanos , Modelos BiológicosRESUMEN
BACKGROUND Urocortin (Ucn) is a member of the hypothalamic corticotrophin-releasing factor family and has been shown to reduce cell death in the heart caused by ischemia/reperfusion (I/R) injury. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor known to function as a pro-survival and anti-apoptotic factor, whose activation depends on a variety of cytokines, including IL-6. A recent study demonstrated that urocortin induced IL-6 release from cardiomyocytes in a CRF-R2-dependent manner, suggesting a possible link between CRF-R2 stimulation and STAT3 activation. MATERIAL AND METHODS Experimental work was carried out in HL-1 cardiac myocytes exposed to serum starvation for 16-24 h. RESULTS Ucn stimulation led to IL-6 expression and release from mouse atrial HL-1 cardiomyocytes. Ucn treatment led to rapid phosphorylation of JAK2, which was blocked by the protein synthesis inhibitor cycloheximide or the JAK inhibitor AG490. Urocortin treatment induced STAT3 phosphorylation at Y705 and S727 through transactivation of JAK2 in an IL-6-dependent manner, but had no effect on STAT1 activity. Kinase inhibition experiments revealed that urocortin induces STAT3 S727 phosphorylation through ERK1/2 and Y705 phosphorylation through Src tyrosine kinase. In line with this finding, urocortin failed to induce phosphorylation of Y705 residue in SYF cells bearing null mutation of Src, while phosphorylation of S727 residue was unchanged. CONCLUSIONS Here, we have shown that Ucn induces activation of STAT3 through diverging signaling pathways. Full understanding of these signaling pathways will help fully exploit the cardioprotective properties of endogenous and exogenous Ucn.
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Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Urocortinas/metabolismo , Animales , Línea Celular , ADN/metabolismo , Interleucina-6/metabolismo , Janus Quinasa 2/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Modelos Biológicos , Fosforilación/efectos de los fármacos , Fosfoserina/metabolismo , Fosfotirosina/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Urocortinas/farmacologíaRESUMEN
BACKGROUND Although originally described as a survival mechanism, it is unknown whether and to what extent autophagy is implicated in the terminal stages of heart failure. Here, we studied magnitude and evolution of autophagy in patients with intractable heart failure. MATERIAL AND METHODS Myocardial samples were obtained from 22 patients with ischemic cardiomyopathy and idiopathic dilated cardiomyopathy who were undergoing cardiac transplantation. Hearts from 11 patients who died from non-cardiac causes were used as control samples. Autophagy was evaluated by immunostaining with a monoclonal microtubule associated protein light chain 3 (LC3)-II antibody, while the relationship of autophagy with apoptosis and oncosis was assessed by double staining with TUNEL (terminal deoxynucleotidyl transferase - mediated deoxyuridine triphosphate nick end labeling) assay and complement 9 (C9) immunological staining, respectively. In addition, several necroptotic markers, including RIP1 and RIP3 (receptor interacting protein kinase 1 and 3), anti-C3 (cleaved-caspase-3), and anti-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) were assessed by immunohistochemistry. RESULTS Anti-LC3-II staining was detected in 8.7±1.6% of the heart failure patient heart samples and in 1.2±0.3% of control patient heart samples. Vacuole formation started at one nuclear pole, before becoming bipolar and involving the cytosol. Subsequently, the autophagic process extended also to the nuclei, which underwent a progressive vacuolization and disintegration, assuming a peculiar "strawberry like appearance". Myocytes with extensive vacuole formation exhibited nuclear degeneration, which was associated with TUNEL, C3, C9, RIP1, and RIP3 positive staining. Conversely, myocytes with less extensive vacuole formation showed RIP1 and NF-κB positive staining, though not positivity for other cell death markers. CONCLUSIONS Autophagy was extensively detected in end-stage heart failure and its progression, resulted in secondary cell death, with occurrence of oncosis and necroptosis exceeding that of apoptosis. Conversely, activation of the RIP1/NF-κB pathway was associated with cell survival.
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Autofagia/fisiología , Insuficiencia Cardíaca/fisiopatología , Miocitos Cardíacos/fisiología , Apoptosis/fisiología , Caspasa 3/fisiología , Humanos , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , FN-kappa B/fisiología , Necrosis/fisiopatología , Proteínas de Complejo Poro Nuclear/fisiología , Proteínas de Unión al ARN/fisiología , Transducción de SeñalRESUMEN
BACKGROUND: There has been a constant pursuit for development of newer therapies which can contribute to the relatively nascent field of cardioprotection in the setting of myocardial ischemiareperfusion injury. One novel cardioprotective agent among others, that has shown promising results in the limited number of research studies undertaken till now, is Urocortin. Urocortins are peptides belonging to the Corticotropin-Releasing Hormone family. RESULTS: Acting through a variety of downstream mechanisms, urocortin has been shown to alter cellular metabolism and modulate the mechanism of cell death occurring as a result of ischemia-reperfusion injury. New evidence continues to accumulate in support of urocortin's beneficial role in cytoprotection. CONCLUSION: We present here an updated review largely focused on the various mechanisms through which urocortin alters cellular metabolism, and discuss the clinical potential of urocortin's cardioprotective ability in myocardial ischemia-reperfusion injury.
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Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Urocortinas/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Cardiomegalia/tratamiento farmacológico , Cardiotónicos/farmacología , Humanos , Urocortinas/genética , Urocortinas/farmacologíaRESUMEN
The Heart Rhythm Society (HRS) has been developing clinical practice documents in collaboration and partnership with other professional medical societies since 1996. The HRS formed a Scientific and Clinical Documents Committee (SCDC) with the sole purpose of managing the development of these documents from conception through publication. The SCDC oversees the process for developing clinical practice documents, with input and approval from the HRS Executive Committee and the Board of Trustees. As of May 2017, the HRS has produced more than 80 publications with other professional organizations. This process manual is produced to publicly and transparently declare the standards by which the HRS develops clinical practice documents, which include clinical practice guidelines, expert consensus statements, scientific statements, clinical competency statements, task force policy statements, and proceedings statements. The foundation for this process is informed by the Institute of Medicine's standards for developing trustworthy clinical practice guidelines; the new criteria from the National Guidelines Clearinghouse, effective June 2014; SCDC member discussions; and a review of guideline policies and methodologies used by other professional organizations.
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Arritmias Cardíacas/terapia , Cardiología/organización & administración , Consenso , Formulación de Políticas , Sociedades Médicas , Humanos , Estados UnidosRESUMEN
BACKGROUND: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials. AIM OF STUDY: To test the effects of CFZ (10-9 to 10-7mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta. METHODS AND RESULTS: CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p<0.05). CONCLUSIONS: CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents. Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm.
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Presión Arterial/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Oligopéptidos/farmacología , Inhibidores de Proteasoma/farmacología , Resistencia Vascular/efectos de los fármacos , Acetilcolina/farmacología , Animales , Frecuencia Cardíaca/efectos de los fármacos , Nitroglicerina/farmacología , ConejosRESUMEN
Cancer and cardiovascular disease are the two leading causes of mortality worldwide. Evolving oncologic therapy, including the use of newer targeted agents, has led to an improvement in survival from childhood- and adult-onset cancers. Consequently, there has been a growing realization of cardiotoxic complications related to cancer therapy, with some complications manifesting over months to decades after completion of cancer treatment. This paper reviews cancer therapeutics-related cardiovascular toxicity and its manifestations, multimodality imaging techniques for surveillance and detection of this complication, and the current state of knowledge in this emerging field.
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Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Cardiopatías/inducido químicamente , Cardiopatías/diagnóstico por imagen , Imagen Multimodal/métodos , Neoplasias/complicaciones , Neoplasias/diagnóstico por imagen , Cardiología/métodos , Medicina Basada en la Evidencia , Humanos , Oncología Médica/métodosRESUMEN
BACKGROUND: Klotho proteins (α- and ß) are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors (FGFs). Recent data has shown that higher plasma circulating Klotho levels reduce cardiovascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and FGFs, and whether high cardiovascular risk could affect cardiac expression of Klotho, FGFs and other molecules. METHODS: We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age-matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyocytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxidative stress, inflammation and fibrosis. RESULTS: Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis. CONCLUSIONS: This study showed for the first time that Klotho proteins are expressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress-related molecules were significantly increased.