RESUMO
BACKGROUND: In academic surgery publications, self-reporting of conflicts of interest (COI) has often proved to be inaccurate. Here, we review the accuracy of COI disclosures for studies related to the use of robotic technology in cardiothoracic surgery and evaluate factors associated with increased discrepancies. METHODS: A literature search identified robotic surgery-related studies with at least 1 American author published between January 2015 and December 2020 from 3 major American cardiothoracic surgery journals (The Journal of Thoracic and Cardiovascular Surgery, The Annals of Thoracic Surgery, and Annals of Cardiothoracic Surgery). Industry payments from Intuitive Surgical (Intuitive) were collected with use of the Centers for Medicare and Medicaid Open Payments database. COI discrepancies were identified by comparing author declaration statements with payments found for the year of publication and the year prior (24-month period). RESULTS: A total of 144 studies (764 authors) were identified. At least 1 author of 112 studies (78%) had received payments from Intuitive. At least 1 author of 98 studies (68%) had received an undeclared payment from Intuitive. Authors who accurately disclosed payments received significantly higher median payments compared with authors who did not ($16,511 [interquartile range, $6389-$159,035] vs $1762 [interquartile range, $338-$7500]; P < .0001). Last authors were significantly more likely to have a COI discrepancy compared with middle and first authors (P = .018; P = .0015). CONCLUSIONS: Most studies investigating the use of robotic technology in cardiothoracic surgery did not accurately declare COI with Intuitive. This study highlights the need for improved accuracy of reporting industry sponsorship by publishing authors.
Assuntos
Procedimentos Cirúrgicos Robóticos , Idoso , Humanos , Estados Unidos , Conflito de Interesses , Medicare , Revelação , IndústriasRESUMO
Conventional surgical techniques to seal and repair defects in highly stressed elastic tissues are insufficient. Therefore, this study aimed to engineer an inexpensive, highly adhesive, biocompatible, and biodegradable sealant based on a modified and naturally derived biopolymer, gelatin methacryloyl (GelMA). We tuned the degree of gelatin modification, prepolymer concentration, photoinitiator concentration, and crosslinking conditions to optimize the physical properties and adhesion of the photocrosslinked GelMA sealants. Following ASTM standard tests that target wound closure strength, shear resistance, and burst pressure, GelMA sealant was shown to exhibit adhesive properties that were superior to clinically used fibrin- and poly(ethylene glycol)-based glues. Chronic in vivo experiments in small as well as translational large animal models proved GelMA to effectively seal large lung leakages without the need for sutures or staples, presenting improved performance as compared to fibrin glue, poly(ethylene glycol) glue and sutures only. Furthermore, high biocompatibility of GelMA sealant was observed, as evidenced by a low inflammatory host response and fast in vivo degradation while allowing for adequate wound healing at the same time. Combining these results with the low costs, ease of synthesis and application of the material, GelMA sealant is envisioned to be commercialized not only as a sealant to stop air leakages, but also as a biocompatible and biodegradable hydrogel to support lung tissue regeneration.
Assuntos
Materiais Biocompatíveis/química , Gelatina/química , Hidrogéis/química , Metacrilatos/química , Adesivos Teciduais/química , Cicatrização , Células 3T3 , Animais , Materiais Biocompatíveis/uso terapêutico , Gelatina/uso terapêutico , Hidrogéis/uso terapêutico , Lesão Pulmonar/terapia , Masculino , Teste de Materiais , Metacrilatos/uso terapêutico , Camundongos , Ratos Wistar , Suínos , Resistência à Tração , Adesivos Teciduais/uso terapêuticoRESUMO
BACKGROUND: Postoperative formation of adhesions increases risk of complications during cardiac reoperations. We previously demonstrated that swine supplemented with vodka had a significant reduction in adhesions at sternotomy after previous thoracotomy. This follow-up study was conducted to determine reproducibility and the mechanism for adhesion reduction in swine supplemented with ethanol. METHODS: An ameroid constrictor was placed in the left circumflex in 14 male Yorkshire swine to induce chronic myocardial ischemia through left minithoracotomy. Animals were supplemented postoperatively with ethanol (45 g ETOH, n = 7) or sucrose (80 g SUC, n = 7) for 7 weeks, followed by a reoperative median sternotomy. RESULTS: The ETOH group had significantly fewer adhesions, thinner pericardial thickness, decreased intramyocardial fibrosis, and decreased myocardial collagen deposition compared with the SUC group. In the myocardium, ETOH animals had decreased expression of proadhesion proteins focal adhesion kinase, paxillin, integrin-ß1, transforming growth factor-ß1 and phosphorylated SMAD and increased expression of adhesion breakdown proteins matrix metalloproteinase (MMP) 1, MMP2, MMP3, and MMP9 compared with SUC animals. However in the pericardium, ETOH animals had increased expression of proadhesion proteins focal adhesion kinase, paxillin, phosphorylated paxillin, vinculin, integrin-ß1, tumor necrosis factor-α, transforming growth factor-ß, and phosphorylated SMAD3, and decreased expression of adhesion breakdown proteins MMP1, MMP3, MMP9, and plasmin compared with SUC animals. CONCLUSIONS: Alcohol supplementation substantially reduced postoperative pericardial adhesion formation, attenuated pericardial thickening, and reduced myocardial fibrosis in response to chronic ischemia. Alcohol supplementation modulates adhesion protein and MMP/tissue inhibitor of metalloproteinase expression, favoring a profile associated with reduced pericardial adhesions. These results suggest that the myocardium is the driving factor in reducing pericardial adhesions and mediating the postoperative healing process.
Assuntos
Bebidas Alcoólicas , Etanol/administração & dosagem , Isquemia Miocárdica/cirurgia , Miocárdio/patologia , Pericárdio/patologia , Complicações Pós-Operatórias/prevenção & controle , Esternotomia/efeitos adversos , Administração Oral , Animais , Modelos Animais de Doenças , Masculino , Complicações Pós-Operatórias/patologia , Suínos , Aderências TeciduaisRESUMO
BACKGROUND: Previous studies have demonstrated that moderate alcohol consumption is cardioprotective and reduces postoperative pericardial adhesions; however, the mechanism is not fully understood. Using proteomic analysis, we sought to objectively investigate the effects of daily moderate alcohol consumption in the pericardium and myocardium in a swine model of chronic myocardial ischemia. METHODS: Fourteen swine underwent placement of an ameroid constrictor to induce chronic myocardial ischemia. Animals were supplemented with 90 mL of ethanol daily (ETOH) or 80 g of sucrose of equal caloric value (SUC). After 7 weeks, the ischemic myocardium and pericardium were harvested for proteomics analysis. RESULTS: Pericardial proteomics analysis yielded 397 proteins, of which 23 were unique to SUC and 52 were unique to ETOH. Of the 322 common proteins, 71 were statistically significant and 23 were characterized (p < 0.05). Alcohol supplementation increased structural proteins, and decreased immune protease inhibitors and coagulation proteins in the pericardium (p < 0.01). Myocardial proteomics analysis yielded 576 proteins, of which 32 were unique to SUC and 21 were unique to ETOH. Of the 523 common proteins, 85 were significant, and 32 were characterized (p < 0.05). Alcohol supplementation decreased cardiac remodeling proteins, cell death proteins and motor proteins, and increased metabolic proteins (p < 0.05). CONCLUSIONS: The results suggest that daily moderate alcohol consumption affects numerous pathways that contribute to cardioprotection, including cardiac remodeling, metabolism, and cell death. Our findings reveal the biosignature of myocardial and pericardial protein expression in the setting of chronic myocardial ischemia and daily moderate alcohol consumption.
Assuntos
Etanol/farmacologia , Isquemia Miocárdica/patologia , Miocárdio/patologia , Pericárdio/efeitos dos fármacos , Proteômica/métodos , Animais , Morte Celular , Modelos Animais de Doenças , Masculino , Isquemia Miocárdica/etiologia , Pericárdio/patologia , Suínos , Porco MiniaturaRESUMO
OBJECTIVE: Impaired angiogenesis is a known consequence of metabolic syndrome (MetS); however, the mechanism is not fully understood. Recent studies have shown that the notch signaling pathway is an integral component of cardiac angiogenesis. We tested, in a clinically relevant swine model, the effects of MetS on notch and apoptosis signaling in chronically ischemic myocardium. METHODS: Ossabaw swine were fed either a regular diet (control [CTL], n = 8) or a high-cholesterol diet (MetS, n = 8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, the wine underwent cardiac harvest of the ischemic myocardium. RESULTS: Downregulation of pro-angiogenesis proteins notch2, notch4, jagged2, angiopoietin 1, and endothelial nitric oxide synthase were found in the MetS group compared with the CTL group. Also, upregulation of pro-apoptosis protein caspase 8 and downregulation of anti-angiogenesis protein phosphorylated forkhead box transcription factor 03 and pro-survival proteins phosphorylated P38 and heat shock protein 90 were present in the MetS group. Cell death was increased in the MetS group compared with the CTL group. Both CTL and MetS groups had a similar arteriolar count and capillary density, and notch3 and jagged1 were both similarly concentrated in the smooth muscle wall. CONCLUSIONS: MetS in chronic myocardial ischemia significantly impairs notch signaling by downregulating notch receptors, ligands, and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling, and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, suggesting that inhibition of notch signaling might underlie the decreased angiogenesis in later stages of MetS.
Assuntos
Apoptose , Síndrome Metabólica/complicações , Isquemia Miocárdica/complicações , Miocárdio/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Proteínas Angiogênicas/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Doença Crônica , Modelos Animais de Doenças , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Miocárdio/patologia , Neovascularização Fisiológica , Suínos , Porco Miniatura , Fatores de TempoRESUMO
BACKGROUND: Epidemiologic data has shown that metformin confers a survival advantage in patients with cardiovascular disease. Although the underlying cardioprotective mechanism is unclear, it appears to be independent of metformin's insulin-sensitizing effect. The purpose of this study was to evaluate the effect of metformin on the apoptosis pathway in the ischemic and nonischemic cardiac tissue in a swine model of metabolic syndrome. MATERIALS AND METHODS: Ossabaw miniswine were fed either a regular diet (Ossabaw control, n = 8), a high-cholesterol diet (Ossabaw high cholesterol, n = 8), or a high-cholesterol diet supplemented with metformin (Ossabaw high-cholesterol metformin, n = 8). After 9 wk, all animals underwent placement of an ameroid constrictor to the left circumflex coronary artery to induce chronic ischemia. Seven weeks after ameroid placement, animals underwent cardiac harvest. RESULTS: In the chronically ischemic myocardium, metformin significantly upregulates prosurvival proteins: extracellular signal-regulated kinases, nuclear factor κB, phosphorylated endothelial nitric oxide synthase, and P38. Metformin also significantly inhibits or downregulates proapoptosis proteins: FOXO3 and caspase 3. Metformin decreased the percent apoptotic cells in the ischemic and nonischemic myocardium. There was no difference in arteriolar density, capillary density, intramyocardial fibrosis, or collagen deposition in the ischemic or nonischemic myocardium. CONCLUSIONS: Metformin selectively alters the apoptosis pathway by inhibiting FOXO3 and decreasing the active form of caspase 3, cleaved caspase 3. Metformin also upregulates mitogen-activated kinase proteins p38 and extracellular signal-regulated protein kinases 1 and 2, which are considered cardioprotective during ischemic preconditioning. Perhaps, the altered activation of the apoptosis pathway in ischemic myocardium is one mechanism by which metformin is cardioprotective.
Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Metformina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco MiniaturaRESUMO
BACKGROUND: Epidemiologic studies have shown that individuals who consume low to moderate alcohol have a lower risk of cardiovascular disease developing compared with abstainers. Although experimental studies confirmed this observation, the effect of alcohol on ischemic myocardium is still unclear. We developed a clinically relevant animal model of chronic myocardial ischemia to investigate the effects of moderate alcohol consumption on the myocardium. STUDY DESIGN: Fourteen Yorkshire swine underwent placement of an ameroid constrictor to induce chronic myocardial ischemia. Postoperatively, one group was supplemented with 90 mL 50% EtOH daily (n = 7) and one group was supplemented with 80 g sucrose daily to normalize caloric intake between groups (n = 7). After 7 weeks, all animals underwent sternotomy, and harvest of the chronically ischemic myocardium and nonischemic myocardium. Tissues were analyzed for protein expression and stained for apoptosis quantification. RESULTS: In the ischemic myocardium, alcohol down-regulated the following proapoptotic proteins: tumor necrosis factor-α, forkhead box protein 03, BCL2-associated death promoter, and cysteine aspartic acid-specific protease 9; up-regulated the following prosurvival proteins: 5'adenosine monophosphate-activated protein kinase, phosphorylated 5'adenosine monophosphate-activated protein kinase, and phosphorylated forkhead box protein 03; and down-regulated mammalian target of rapamycin (MTOR) signaling by down-regulating MTOR, phosphorylated MTOR, and up-regulating Deptor. In the nonischemic myocardium, alcohol up-regulated prosurvival proteins: protein kinase B, phosphorylated protein kinase B, phosphorylated B-cell CLL/lymphoma 2, 5'adenosine monophosphate-activated protein kinase, phosphorylated BCL2-associated death promoter, phosphorylated forkhead box protein 03, and down-regulated MTOR signaling by down-regulating phosphorylated MTOR and up-regulating Deptor. Alcohol also decreased cell death as measured by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling staining in the ischemic and nonischemic myocardium. CONCLUSIONS: Alcohol consumption down-regulates apoptosis and promotes cell survival in the ischemic and nonischemic myocardium. Alcohol also modulates MTOR signaling, which regulates senescence and apoptosis. Perhaps MTOR and apoptosis regulation is another mechanism by which moderate EtOH consumption is cardioprotective.
Assuntos
Consumo de Bebidas Alcoólicas , Apoptose/efeitos dos fármacos , Etanol/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Isquemia Miocárdica/prevenção & controle , Miocárdio , Suínos , Porco MiniaturaRESUMO
BACKGROUND: Notch signaling is a highly conserved pathway that promotes vascular and myocardial growth. The hypothesis that exogenous vascular endothelial growth factor (VEGF) administration to ischemic myocardium would enhance the neovascular response and upregulate Notch signaling was assessed. METHODS AND RESULTS: Fourteen male Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia with half of the animals receiving perivascular VEGF to the ischemic area. The remote territory served as the normal ventricle control (NV), while the 2 experimental groups consisted of the area at risk of the non-VEGF animals (AAR) and the area at risk of animals treated with VEGF (VEGF). Capillary and arteriolar density was significantly increased in the VEGF group as compared to both NV and AAR. Expression of Notch receptors and pro-neovascular Notch ligands was significantly higher in the VEGF group. Both Jagged 1 and Notch 3 were the most highly concentrated in the smooth muscle wall of arterioles. CONCLUSIONS: VEGF administration to chronically ischemic myocardium significantly augmented the neovascular response by an increase in both capillary and arteriolar density, and resulted in an upregulation of several Notch receptors and ligands, which were not upregulated with ischemia alone. These findings suggest that the augmented neovascular response seen with VEGF administration was through the VEGF-induced upregulation of Notch signaling.
Assuntos
Isquemia Miocárdica/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Receptores Notch/biossíntese , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Arteríolas/metabolismo , Arteríolas/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Capilares/metabolismo , Capilares/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/patologia , Proteínas Serrate-Jagged , Suínos , Porco MiniaturaRESUMO
Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary artery (IMA), however, is much lower than in nearly all other arteries. The etiology of this IMA disease resistance is not well understood. Here, using paired primary IMA and coronary artery SMCs, serum stimulation, siRNA knockdowns, and verifications in porcine vessels in vivo, we investigate the molecular mechanisms that could account for this increased disease resistance of internal mammary SMCs. We show that the residue-specific phosphorylation profile of the retinoblastoma tumor suppressor protein (Rb) appears to differ significantly between IMA and coronary artery SMCs in cultured human cells. We also report that the differential profile of Rb phosphorylation may follow as a consequence of differences in the content of cyclin-dependent kinase 2 (CDK2) and the CDK4 phosphorylation inhibitor p15. Finally, we present evidence that siRNA-mediated CDK2 knockdown alters the profile of Rb phosphorylation in coronary artery SMCs, as well as the proliferative response of these cells to mitogenic stimulation. The intrinsic functional and protein composition specificity of the SMCs population in the coronary artery may contribute to the increased prevalence of restenosis and atherosclerosis in the coronary arteries as compared with the internal mammary arteries.
Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , Mitógenos/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína do Retinoblastoma/metabolismo , Animais , Movimento Celular , Proliferação de Células , Vasos Coronários/citologia , Vasos Coronários/metabolismo , Meios de Cultura Livres de Soro , Quinase 2 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Masculino , Artéria Torácica Interna/citologia , Artéria Torácica Interna/metabolismo , Fosforilação , Cultura Primária de Células , Soro , Suínos , Fator de Transcrição YY1/metabolismoRESUMO
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplantation. However, it has other nonimmune functions: in the cardiovascular system, it is a regulator of heart hypertrophy and locally, in coated vascular stents, it inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism, and survival, we hypothesized that inhibiting it with rapamycin before an acute myocardial ischemia-reperfusion injury (IRI) would confer cardioprotection by virtue of slowing down cardiac function and metabolism. METHODS: Yorkshire pigs received either placebo or 4 mg/d rapamycin orally for 7 days before the IRI. All animals underwent median sternotomy, and the mid-left anterior descending coronary artery was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data were collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively, and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by Western blotting with specific antibodies against mTOR substrates phosphorylating sites. RESULTS: Rapamycin before treatment impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities. CONCLUSIONS: Acute myocardial IRI, in healthy pigs treated with rapamycin, is associated with decreased cardiac function and higher myocardial necrosis.
Assuntos
Imunossupressores/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Sirolimo/uso terapêutico , Doença Aguda , Animais , Imunossupressores/efeitos adversos , Masculino , Necrose/induzido quimicamente , Sirolimo/efeitos adversos , SuínosRESUMO
Resveratrol is a naturally occurring polyphenol found in the skin of red grapes, peanuts, and red wine that has been shown to modify many cardiovascular risk factors. Small animal models have been extensively used to investigate cardiovascular disease, but the results often fail to translate in clinical trials. Disease-specific pig models are emerging as clinically useful tools that may offer insight into cardiovascular disease and the effect of drugs such as resveratrol on cardiovascular health. In this paper, we discuss the advantage of using clinically relevant pig models of diabetes, hypercholesterolemia, and myocardial ischemia to investigate the role of resveratrol in cardiovascular disease prevention.
Assuntos
Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Estilbenos/uso terapêutico , Animais , Cardiotônicos/metabolismo , Doenças Cardiovasculares/metabolismo , Humanos , Resveratrol , Especificidade da Espécie , Estilbenos/metabolismo , Suínos , Resultado do TratamentoRESUMO
BACKGROUND: In a previous study, we demonstrated that swine with metabolic syndrome treated with alcohol had improved insulin signaling. We developed a follow-up study to evaluate the effects of alcohol on ischemic myocardium in animals without metabolic syndrome. METHODS: Fourteen Yorkshire swine underwent placement of an ameroid constrictor to induce chronic myocardial ischemia. Postoperatively, one group was supplemented with ethanol (ETOH), and one group was supplemented with sucrose (SUC) daily to normalize caloric intake. After 7 weeks, all animals underwent dextrose challenge and harvest of nonischemic and ischemic myocardium. Tissues were analyzed for protein expression and histologic analysis. RESULTS: There was no difference in body mass index, serum glucose or insulin levels. However, ethanol supplementation up-regulated phosphoinostitide 3-kinase, phosphorylated protein kinase B, protein kinase B, and phosphorylated Forkhead Box 01 expression, which may promote insulin signaling, and down-regulated inhibitors of insulin signaling pIRS1 and pIRS2. There was no difference in intramyocardial glycogen but there was increased GLUT4 expression in the ETOH group, which may promote glucose use. CONCLUSION: Despite similar serum glucose and insulin levels, alcohol consumption up-regulates the insulin signaling pathway in the absence of metabolic syndrome in both nonischemic and chronically ischemic myocardium. These results suggest that alcohol selectively up-regulates the insulin signaling pathway despite normoglycemia.
Assuntos
Etanol/farmacologia , Insulina/fisiologia , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia/análise , Transportador de Glucose Tipo 4/análise , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Suínos , Porco MiniaturaAssuntos
Divertículo/diagnóstico por imagem , Impacção Fecal/diagnóstico por imagem , Perfuração Intestinal/diagnóstico por imagem , Doenças do Jejuno/diagnóstico por imagem , Divertículo/complicações , Divertículo/cirurgia , Impacção Fecal/complicações , Impacção Fecal/cirurgia , Humanos , Perfuração Intestinal/etiologia , Perfuração Intestinal/cirurgia , Doenças do Jejuno/complicações , Doenças do Jejuno/cirurgia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: The purpose of this study is to evaluate the effect of metformin on insulin signaling in ischemic cardiac tissue in a swine model of metabolic syndrome. METHODS: Ossabaw miniswine were fed either a regular diet (Ossabaw control [OC]) or a hypercaloric diet (Ossabaw high cholesterol [OHC], Ossabaw high cholesterol with metformin [OHCM]). After 9 weeks, all animals underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. OHC animals were continued on a hypercaloric diet alone; the OHCM group was supplemented with metformin in addition to the hypercaloric diet. Seven weeks after ameroid placement, myocardial perfusion was measured and ischemic cardiac tissue was harvested for protein expression and histologic analysis. RESULTS: The OHC and OHCM groups had significantly higher body mass indices and serum insulin levels compared with the OC group. There were no differences in myocardial perfusion in the chronically ischemic territories. In the OHC group, there was upregulation of both an activator of insulin signaling insulin receptor substrate 1, and an inhibitor of insulin signaling phosphorylated insulin receptor substrate 2. In the OHCM group, there was upregulation of activators of insulin signaling including phosphorylated adenosine monophosphate-activated protein kinase α, protein kinase B, phosphorylated protein kinase B, mammalian target of rapamycin, phosphorylated mammalian target of rapamycin, and phosphoinostitide 3-kinase, and upregulation of inhibitors including phosphorylated insulin receptor substrate 1, phosphorylated insulin receptor substrate 2, and retinol binding protein 4. Histologic analysis demonstrated increased expression of glucose transporter 1 at the plasma membrane in the OHCM group, but there was no difference in cardiomyocyte glycogen stores among groups. CONCLUSIONS: Metformin treatment in the context of metabolic syndrome and myocardial ischemia dramatically upregulates the insulin signaling pathway in chronically ischemic myocardium, which is at the crossroads of known metabolic and survival benefits of metformin.
Assuntos
Hipoglicemiantes/farmacologia , Insulina/sangue , Síndrome Metabólica/tratamento farmacológico , Metformina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Circulação Coronária , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Isquemia Miocárdica/sangue , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Suínos , Porco Miniatura , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: Previous experiments in Yorkshire swine demonstrated significantly fewer pericardial adhesions and intramyocardial collagen deposition at reoperative sternotomy in animals supplemented with vodka but not with red wine. The purpose of this experiment was to determine a mechanism for adhesion reduction. METHODS: Twenty-seven male Yorkshire swine were fed a high-cholesterol diet to simulate conditions of coronary artery disease followed by the surgical placement of an ameroid constrictor to the left circumflex coronary artery to induce chronic ischaemia. Postoperatively, control pigs continued their high-fat/cholesterol diet alone, whereas the two experimental groups had diets supplemented with either red wine or vodka for 7 weeks followed by reoperative sternotomy and cardiac harvest. RESULTS: The expression of related adhesion focal tyrosine kinase (RAFTK) and caspase 3 in the sodium dodecyl sulphate (SDS)-soluble myocardial fraction was significantly higher only in the vodka-supplemented group. In the more soluble fraction, the expression of caspase 3, cleaved caspase 3 and caspase 9 was lower in both the vodka and red wine treatment groups. CONCLUSIONS: In the SDS-soluble lysate fraction, likely representing the transmembrane/cell-extracellular matrix (ECM), a significant increase in RAFTK and caspase 3 expression was seen only in the vodka-treated animals, which may explain why this group demonstrated significantly fewer pericardial adhesions. Caspase expression/signalling was not increased in the more soluble myocardial lysate, suggesting that the increased apoptotic signalling was specific to the epicardial-ECM.
Assuntos
Bebidas Alcoólicas , Álcoois/farmacologia , Cardiopatias/prevenção & controle , Hipercolesterolemia/metabolismo , Esternotomia/métodos , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Dieta Hiperlipídica , Quinase 2 de Adesão Focal/metabolismo , Hipercolesterolemia/induzido quimicamente , Masculino , Isquemia Miocárdica/metabolismo , Pericárdio/efeitos dos fármacos , Proteína Quinase C-épsilon/metabolismo , Ensaio de Radioimunoprecipitação , Reoperação , Transdução de Sinais/efeitos dos fármacos , Esternotomia/efeitos adversos , Suínos , Aderências Teciduais/prevenção & controleRESUMO
BACKGROUND: The purpose of this study was to examine the effects of alcohol in the context of metabolic syndrome on insulin signaling pathways in the liver and skeletal muscle. METHODS: Twenty-six Yorkshire swine were fed a hypercaloric, high-fat diet for 4 weeks then split into 3 groups: hypercholesterolemic diet alone (HCC, n = 9), hypercholesterolemic diet with vodka (HCVOD, n = 9), and hypercholesterolemic diet with wine (HCW, n = 8) for 7 weeks. Animals underwent intravenous dextrose challenge before euthanasia and tissue collection. RESULTS: HCC, HCVOD, and HCW groups had similar blood fasting glucose levels, liver function test, and body mass index. Thirty and 60 minutes after dextrose infusion, HCVOD and HCW groups had significantly increased blood glucose levels compared with the HCC group. The HCW group had significantly increased levels of insulin compared with the HCC group. Immunoblotting in skeletal muscle demonstrated that alcohol up-regulates p-IRS1, IRS2, AKT, AMPKα, PPARα, Fox01, and GLUT4. In the liver, HCW had up-regulation of AKT, AMPKα, and GLUT4 compared with HCC. Skeletal muscle immunohistochemistry demonstrated increased sarcolemmal expression of GLUT4 in both alcohol groups compared with HCC. CONCLUSION: Moderate alcohol consumption in a swine model of metabolic syndrome worsens glucose metabolism by altering activation of the insulin signaling pathway in the liver and skeletal muscle.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Etanol/farmacologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Fígado/metabolismo , Síndrome Metabólica/metabolismo , Músculo Esquelético/metabolismo , Bebidas Alcoólicas , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Transportador de Glucose Tipo 4/metabolismo , Imuno-Histoquímica , Proteínas Substratos do Receptor de Insulina/metabolismo , Testes de Função Hepática , Masculino , PPAR alfa/efeitos dos fármacos , PPAR alfa/metabolismo , Resveratrol , Estilbenos/metabolismo , Estilbenos/farmacologia , Suínos , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: The purpose of the present study was to evaluate the effect of atorvastatin on oxidative stress and angiogenesis in ischemic myocardium in a clinically relevant porcine model of the metabolic syndrome. METHODS: Sixteen Ossabaw pigs were fed either a high-fat diet alone or a high-fat diet supplemented with atorvastatin (1.5 mg/kg daily) for 14 weeks. Chronic myocardial ischemia was induced by ameroid constrictor placement around the circumflex artery. After 6 months of the diet, myocardial perfusion was measured at rest and with demand pacing. The heart was harvested for analysis of perfusion, microvessel relaxation, protein expression, and oxidative stress. RESULTS: Both groups had similar endothelium-dependent microvessel relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside. Myocardial perfusion in the ischemic territory was also not significantly different either at rest or with demand pacing. Atorvastatin treatment increased total myocardial protein oxidation and serum lipid peroxidation. However, the expression of markers of oxidative stress, including NOX2, RAC1, myeloperoxidase, and superoxide dismutase 1, 2, and 3, were not statistically different. The expression of proangiogenic proteins endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase (Ser 1177), phosphorylated adenosine monophosphate kinase (Thr 172), phosphorylated extracellular signal-regulated kinase (T202, Y204), and vascular endothelial growth factor were all upregulated in the atorvastatin group. CONCLUSIONS: Atorvastatin increased the capillary and arteriolar density and upregulated the proangiogenic proteins endothelial nitric oxide synthase and phosphorylated endothelial nitric oxide synthase, phosphorylated adenosine monophosphate kinase, phosphorylated extracellular signal-regulated kinase, and vascular endothelial growth factor in a swine model of the metabolic syndrome. However, it failed to increase myocardial perfusion. Atorvastatin treatment was associated with increased myocardial and serum oxidative stress, which might contribute to the lack of collateral-dependent perfusion in the setting of angiogenesis.
Assuntos
Indutores da Angiogênese/farmacologia , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Síndrome Metabólica/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pirróis/farmacologia , Proteínas Angiogênicas/metabolismo , Animais , Atorvastatina , Biomarcadores/sangue , Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/fisiopatologia , Isquemia Miocárdica/sangue , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Imagem de Perfusão do Miocárdio , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco Miniatura , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Moderate consumption of alcohol, particularly red wine, has been shown to decrease cardiac risk. We used a hypercholesterolemic swine model of chronic ischemia to examine the effects of 2 alcoholic beverages on the heart. METHODS AND RESULTS: Yorkshire swine fed a high-cholesterol diet underwent left circumflex ameroid constrictor placement to induce chronic ischemia at 8 weeks of age. One group (HCC, n=9) continued on the diet alone, the second (HCW, n=8) was supplemented with red wine (pinot noir, 12.5% alcohol, 375 mL daily), and the third (HCV, n=9) was supplemented with vodka (40% alcohol, 112 mL daily). After 7 weeks, cardiac function was measured, and ischemic myocardium was harvested for analysis of perfusion, myocardial fibrosis, vessel function, protein expression, oxidative stress, and capillary density. Platelet function was measured by aggregometry. Perfusion to the ischemic territory as measured by microsphere injection was significantly increased in both HCW and HCV compared with HCC at rest, but in only the HCW group under ventricular pacing. Microvessel relaxation response to adenosine 5'-diphosphate was improved in the HCW group alone as was regional contractility in the ischemic territory, although myocardial fibrosis was decreased in both HCW and HCV. Expression of proangiogenic proteins phospho-endothelial nitric oxide synthase and vascular endothelial growth factor was increased in both HCW and HCV, whereas phospho-mammalian target of rapamycin was increased only in the HCV group. Expression of Sirt-1 and downstream antioxidant phospho-FoxO1 was increased only in the HCW group. Protein oxidative stress was decreased in the HCW group alone, whereas capillary density was increased only in the HCV group. There was no significant difference in platelet function between groups. CONCLUSION: Moderate consumption of red wine and vodka may reduce cardiovascular risk by improving collateral-dependent perfusion through different mechanisms. Red wine may offer increased cardioprotection related to its antioxidant properties.
Assuntos
Bebidas Alcoólicas , Circulação Colateral , Circulação Coronária , Hipercolesterolemia/terapia , Isquemia Miocárdica/terapia , Vinho , Animais , Estimulação Cardíaca Artificial , Vasos Coronários/patologia , Dieta Aterogênica , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Indução Enzimática , Etanol/sangue , Regulação da Expressão Gênica , Hemodinâmica , Hipercolesterolemia/complicações , Hipercolesterolemia/fisiopatologia , Masculino , Modelos Cardiovasculares , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo , Sus scrofa , Suínos , Serina-Treonina Quinases TOR/biossíntese , Serina-Treonina Quinases TOR/genética , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Moderate alcohol consumption is largely believed to be cardioprotective, while red wine is hypothesized to offer benefit in part due to the proangiogenic and antioxidant properties of polyphenols. We investigated the cardiovascular effects of both red wine and vodka in a swine model of endothelial dysfunction. METHODS: Twenty-seven male Yorkshire swine fed a high-fat/cholesterol diet were divided into three groups and received either no alcohol (Control), red wine, or vodka. After 7 wk, myocardial perfusion was measured, and ventricular tissue was analyzed for microvascular reactivity and immunohistochemical studies. RESULTS: There were no differences in myocardial perfusion, in arteriolar or capillary density, or in VEGF expression among groups. Total protein oxidation as well as expression of superoxide dismutase-1 and -2 and NADPH oxidase was decreased in both treatment groups compared to controls. Endothelium-dependent microvessel relaxation, however, was significantly improved only in the red wine-supplemented group. CONCLUSIONS: Supplementation with both red wine and vodka decreased oxidative stress by several measures, implicating the effects of ethanol in reducing oxidative stress in the myocardium. However, it was only in the red wine-supplemented group that an improvement in microvessel function was observed. This suggests that a component of red wine, independent of ethanol, possibly a polyphenol such as resveratrol, may confer cardioprotection by normalizing endothelial dysfunction induced by an atherogenic diet.