RESUMEN
BACKGROUND: Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. HYPOTHESIS: We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. METHODS: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. RESULTS: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). SIGNIFICANCE: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.
RESUMEN
RATIONALE: Post-myocardial infarction ventricular remodeling is associated with the expression of a variety of factors including S100B that can potentially modulate myocyte apoptosis. OBJECTIVE: This study was undertaken to investigate the expression and function of S100B and its receptor, the receptor for advanced glycation end products (RAGE) in both postinfarction myocardium and in a rat neonatal myocyte culture model. METHODS AND RESULTS: In a rat model of myocardial infarction following coronary artery ligation, we demonstrate in periinfarct myocytes, upregulation of RAGE, induction of S100B, and release into plasma with consequent myocyte apoptosis. Using a coimmunoprecipitation strategy, we demonstrate a direct interaction between S100B and RAGE. In rat neonatal cardiac myocyte cultures, S100B at concentrations > or = 50 nmol/L induced myocyte apoptosis, as evidenced by increased terminal DNA fragmentation, TUNEL, cytochrome c release from mitochondria to cytoplasm, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p53, increased expression and activity of proapoptotic caspase-3, and decreased expression of antiapoptotic Bcl-2. Transfection of a full-length cDNA of RAGE or a dominant-negative mutant of RAGE resulted in increased or attenuated S100B-induced myocyte apoptosis, respectively. Inhibition of ERK1/2 by U0126/PD-98059 or overexpression of a dominant negative p53 comparably inhibited S100B-induced myocyte apoptosis. CONCLUSIONS: These results suggest that interaction of RAGE and its ligand S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53 signaling. This receptor-mediated mechanism is uniquely amenable to therapeutic intervention.
Asunto(s)
Apoptosis , Proteínas Musculares/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas S100/metabolismo , Animales , Butadienos/farmacología , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Citocromos c/genética , Citocromos c/metabolismo , Citosol/metabolismo , Fragmentación del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Musculares/antagonistas & inhibidores , Proteínas Musculares/genética , Infarto del Miocardio/genética , Factores de Crecimiento Nervioso/genética , Nitrilos/farmacología , Fosforilación/efectos de los fármacos , Fosforilación/genética , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/genéticaRESUMEN
We conducted two parallel studies on cryopreserved arterial homografts: a biomechanical study based on traction tests and a functional study coupled with a histology examination. Twenty-four arterial segments from 6 donors (2 iliac and 2 superficial femoral segments per donor) were cryopreserved at -150 degrees C and -80 degrees C. Cryopreservation lasted at least 6 months. Lengthening at rupture, the Young elasticity module, and rupture stress were calculated from the traction test. Results were significantly different depending on the preservation temperature. The functional properties of the cryopreserved arterial grafts were evaluated by studying the vasomotricity capacity of the vascular smooth muscle (VSM) and the endothelium. The expected results (direct contracture of VSM induced by PHE and endothelial dependent relaxation of VSM induced by ACH) were measured on fresh arteries. Cryopreserved arteries showed no response to physiological doses of PHE and ACH, whatever the preservation temperature. In one-third of the cases, a lower amplitude vasoconstriction was obtained using nonphysiological doses of PHE; there was no relaxation with ACH.
Asunto(s)
Frío , Criopreservación , Arteria Femoral/trasplante , Arteria Ilíaca/trasplante , Músculo Liso Vascular/fisiología , Sistema Vasomotor/fisiología , Adulto , Fenómenos Biomecánicos , Endotelio Vascular/citología , Arteria Femoral/patología , Humanos , Arteria Ilíaca/patología , Músculo Liso Vascular/patología , Estudios RetrospectivosRESUMEN
The purpose of this study was to establish whether carotid-revascularized patients who had preoperative vertebrobasilar insufficiency (VBI) displayed distinctive characteristics and whether a particular prognosis would ensure. From January 1985 to December 1993, 1022 carotid revascularizations were performed, of which 114 (11%) were for high-grade stenosis associated with VBI. The group with VBI and the group without VBI were compared according to a set of 121 prospectively collected variables. Of all the demographic and risk-factor variables, only female prevalence (42% vs. 27%) and hypertension (77% vs. 27%) distinguished the group with VBI, who also exhibited a significantly higher proportion of significant contralateral carotid lesions (27.2% vs. 8.9%) and vertebrosubclavian lesions (38.6% vs. 24.8%). Following isolated carotid surgery, there was no statistically significant difference between the two groups as to their cumulative rate of permanent neurological mortality and morbidity (2.6% in the group with VBI vs. 3.4% in the group without it). With an average follow-up of 60 months, VBI was cured in 82.4% and improved condition shown in 6.5% of patients. However, the proportion of good results fell to 65% in patients with a nonfunctional circle of Willis. Out of 13 cases of failure to control VBI, cure was finally effected by means of contralateral revascularization in 3 cases and by means of vertebrosubclavian revascularization in 5 cases out of 6. At 5 years, the actuarial rates of neurological event-free intervals and survival were not different from one group to another. In most cases, isolated carotid surgery is sufficient to bring vertebrobasilar insufficiency under control, except when significant vertebrosubclavian lesions and a nonpatent circle of Willis call for simultaneous carotid and vertebral artery surgery.
Asunto(s)
Estenosis Carotídea/cirugía , Endarterectomía Carotidea , Insuficiencia Vertebrobasilar/prevención & control , Anciano , Estenosis Carotídea/complicaciones , Estenosis Carotídea/epidemiología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Morbilidad , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Insuficiencia Vertebrobasilar/epidemiología , Insuficiencia Vertebrobasilar/etiologíaRESUMEN
Orthotopic liver transplantation is the most effective treatment for fulminant hepatic failure. As an alternative treatment, an efficient extracorporeal bioartificial liver should contain a large yield of functional hepatocytes with an immunoprotective barrier, for providing temporary adequate metabolic support to allow spontaneous liver regeneration or for acting as a bridge toward transplantation. Survival, proliferation, and functions of porcine hepatocytes were evaluated in primary cultures and after embedding in alginate beads, which were subsequently coated with a membrane made by a transacylation reaction between propylene glycol alginate and human serum albumin. Disruption of total pig livers by collagenase perfusion/recirculation allowed the obtention of up to 10(11) hepatocytes with a viability greater than 95%. Hepatocytes in conventional cultures or embedded in coated alginate beads survived for about 10 days, secreted proteins, particularly albumin, and maintained several phase I and II enzymatic activities, namely ethoxyresorufin-O-deethylase, oxidation of nifedipine to pyridine, phenacetin deethylation to paracetamol, glucuroconjugation of paracetamol, and N-acetylation of procainamide. Typical features of mitosis and [3H]thymidine incorporation indicated that porcine hepatocytes proliferated in both conventional cultures and alginate beads. The efficacy of the membrane surrounding alginate beads for protecting cells from immunoglobulins was tested by embedding HLA-typed human lymphocytes, which were subsequently incubated with specific anti-HLA immunoglobulin G and complement. These data show that large yields of porcine hepatocytes that are embedded in coated alginate beads remain functional and are isolated from large molecular weight molecules, such as immunoglobulins. This system represents a promising tool for the design of an extracorporeal bioartificial liver, containing xenogeneic hepatocytes, to treat acute liver disease in humans.
Asunto(s)
Hígado Artificial , Hígado/citología , Hígado/fisiología , Acetaminofén/farmacocinética , Alginatos , Animales , Biotransformación , Cápsulas , División Celular , Supervivencia Celular , Células Cultivadas , Técnicas de Cultivo/métodos , Sistema Enzimático del Citocromo P-450/metabolismo , ADN/biosíntesis , Femenino , Ácido Glucurónico , Ácidos Hexurónicos , Humanos , Hígado/ultraestructura , Hepatopatías/terapia , Microscopía Electrónica , Microscopía Electrónica de Rastreo , Procainamida/farmacocinética , Biosíntesis de Proteínas , Albúmina Sérica/biosíntesis , PorcinosRESUMEN
The need for an alternative treatment to orthotopic liver transplantation for acute liver failure is a major issue, and systems capable of temporarily providing liver functions are being actively tested. Liver assist devices based on detoxication by dialysis or hemoperfusion through various membranes or cartridges proved to be inefficient because of their lack of metabolic function. An extracorporeal hybrid bioartificial liver might be an appropriate treatment, since it can provide liver-specific functions, maintain the patient alive, and allow spontaneous recovery of the patient's own liver or act as a bridge toward liver transplantation. Many devices have been proposed, including flat culture substrates, hollow-fiber bioreactors, or microcarriers, using xenogenic hepatocytes or hepatoma cell lines. Various drawbacks of these devices led us to attempt to develop a reliable extracorporeal bioartificial liver based on alginate bead-entrapped hepatocytes. This system was used successfully for the correction of the Gunn rat genetic defect, which results in lack of bilirubin conjugation. The development of this system for clinical purposes requires large yields of functional hepatocytes. We have isolated normal porcine hepatocytes by collagenase perfusion of the liver. Cells were immobilized in membrane-coated alginate gel beads, which were subsequently inoculated into a bioreactor. Porcine hepatocytes expressed liver-specific functions at high levels, particularly protein neosynthesis and enzymatic activities involved in detoxication and biotransformation processes. In addition, hepatocytes entrapped in coated alginate beads were isolated from immunoglobulins. This system represents a promising tool for the design of an extracorporeal bioartificial liver in human beings.
Asunto(s)
Fallo Hepático Agudo/terapia , Trasplante de Hígado/métodos , Hígado Artificial , Hígado/citología , Animales , Humanos , Hígado/metabolismo , Fallo Hepático Agudo/patologíaRESUMEN
The mortality rate of fulminant hepatic failure is about 80%. Besides orthotopic liver transplantation, specific therapies are not currently available. Indeed, not only removal of toxins is required, by means of dialysis or hemoperfusion, but specific hepatic functions must be provided to allow spontaneous liver regeneration or as a bridge before liver transplantation. Treatment with an extracorporeal bioartificial liver is an attractive approach. This system was successfully used for the correction of the Gunn rat genetic defect which results in the lack of bilirubin conjugation. The development of this system for clinical purpose requires both a large yield of functional hepatocytes and their immunoprotection in an appropriate device. We have isolated normal porcine hepatocytes by collagenase perfusion of the liver; cells are subsequently entrapped within membrane-coated alginate beads which are inoculated in a bioreactor. Plasma from an animal undergoing fulminant hepatic failure by end-to-site portocaval shunt and whole porta hepatic tightening circulates within the bioreactor. Porcine hepatocytes express liver-specific functions at high levels, particularly secretion of plasma proteins and several enzyme activities involved in the detoxication and biotransformation of xenobiotics. In addition, hepatocytes are immunoseparated from circulating immunoglobulins. Ethical concerns are discussed in the field of physiopathology, immunopathology and public health, as a prerequisite to create departments of Cell Therapy, in the near future.
Asunto(s)
Circulación Extracorporea , Encefalopatía Hepática/terapia , Hígado Artificial , Hígado/citología , Animales , Trasplante de Células , Ratas , Ratas Gunn , PorcinosAsunto(s)
Enfermedades de las Vías Biliares/etiología , Criopreservación , Rechazo de Injerto/prevención & control , Isquemia/etiología , Trasplante de Hígado/efectos adversos , Preservación de Órganos/métodos , Conductos Biliares/irrigación sanguínea , Enfermedades de las Vías Biliares/prevención & control , Células Cultivadas , Humanos , Isquemia/prevención & controlRESUMEN
Venous thrombosis of the portal system following splenectomy for haematological diseases is uncommon, being reported with an incidence of 0.2 to 6%. Diagnosis may be difficult and the clinical presentation varies greatly. We report 4 cases, included in a consecutive series of 350 splenectomies for hematological diseases. Case 1: a man of 22 years, operated on for autoimmune hemolytic anemia developed severe and generalized abdominal pain 20 days after splenectomy. The coeliac arteriography showed a thrombosis of the portal system. The laparotomy revealed segmentary small bowel necrosis. Outcome after intestinal resection was uneventful. Case 2: a man of 56 years, operated on for essential thrombocythemia had the laboratory findings of acute hepatic failure 28 days after splenectomy. Doppler ultrasonography revealed a portal vein thrombosis. He was treated with heparin. Case 3: a man of 69 years, operated on for acquired idiopathic anemia, developed asthenia and fever 23 days after splenectomy. The ultrasonography showed a portal vein thrombosis. He was successfully treated with heparin. Case 4: a man of 20 years, operated on for Minkowsky-Chauffard hemolytic anemia developed a severe and generalized abdominal pain and fever 13 days after splenectomy. The CT-scan showed a thrombosis of the portal system. Outcome after thrombectomy and regional thrombolysis was uneventful. The aim of this presentation is to review the pathophysiological diagnosis, therapeutic and prophylactic aspects of this serious complication of splenectomy.