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1.
J Surg Res ; 283: 953-964, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36915024

RESUMO

INTRODUCTION: Endothelial dysfunction is a potential side effect of brain death (BD). Ischemia/reperfusion (IR) injury during heart transplantation may lead to further endothelial damage. Protective effects of alpha-1-antitrypsin (AAT), a human neutrophil serine protease inhibitor, have been demonstrated against IR injury. We hypothesized that AAT protects brain-dead rats' vascular grafts from IR injury. METHODS: Donor rats were subjected to BD by inflation of a subdural balloon. After 5.5 h, aortic rings were immediately mounted in organ baths (BD, n = 6 rats) or preserved in saline, supplemented either with vehicle (BD-IR, n = 8 rats) or AAT (BD-IR + AAT, n = 14 rats) for 24 h. During organ bath experiment, rings from both IR groups were exposed to hypochlorite to simulate warm reperfusion-associated endothelial injury. Endothelial function was measured ex vivo. Immunohistochemical staining for caspases was carried out and DNA-strand breaks were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Data are presented as median (interquartile range). RESULTS: AAT improved IR-induced decreased maximum endothelium-dependent vasorelaxation to acetylcholine in the BD-IR + AAT aortas compared to the BD-IR group (BD: 83 (9-28) % versus BD-IR: 49 (39-60) % versus BD-IR + AAT: 64 (24-42) %, P < 0.05). Additionally, an increase in the rings' sensitivity to acetylcholine was noted after AAT (pD2-value: BD-IR + AAT: 7.35 (7.06-7.89) versus BD-IR: 6.96 (6.65-7.21), P < 0.05). Caspase-3, -8, -9, and -12 immunoreactivity and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were significantly decreased by AAT. CONCLUSIONS: AAT alleviates endothelial dysfunction, prevents increased caspase-3, -8, -9, and -12 levels, and decreases apoptotic DNA breakage due to BD and IR injury. This suggests that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular damage.


Assuntos
Morte Encefálica , Traumatismo por Reperfusão , alfa 1-Antitripsina , Animais , Humanos , Ratos , Encéfalo , Caspase 3 , DNA Nucleotidilexotransferase , Isquemia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , alfa 1-Antitripsina/farmacologia
2.
Am J Physiol Heart Circ Physiol ; 323(1): H204-H222, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35687503

RESUMO

Investigating the effect of sex on pressure unloading therapy in a clinical scenario is limited by several nonstandardized factors. Hence, we sought to study sex-related similarities and differences under laboratory conditions. Pressure overload was induced in male and female rats by aortic banding (AB) for 6 and 12 wk. Age-matched sham-operated animals served as controls. Pressure unloading was performed by aortic debanding at week 6. Different aspects of myocardial remodeling were characterized by echocardiography, pressure-volume analysis, histology, qRT-PCR, and explorative proteomics. Hypertrophy, increased fetal gene expression, interstitial fibrosis, and prolonged active relaxation were noted in the AB groups at week 6 in both sexes. However, decompensation of systolic function and further deterioration of diastolic function only occurred in male AB rats at week 12. AB induced similar proteomic alterations in both sexes at week 6, whereas characteristic differences were found at week 12. After debanding, regression of hypertrophy and recovery of diastolic function took place to a similar extent in both sexes. Nevertheless, fibrosis, transcription of ß-myosin-to-α-myosin heavy chain ratio, and myocardial proteomic alterations were reduced to a greater degree in females than in males. Debanding exposed anti-remodeling properties in both sexes and prevented the functional decline in males. Female sex is associated with greater reversibility of fibrosis, fetal gene expression, and proteomic alterations. Nevertheless, pressure unloading exposes a more pronounced anti-remodeling effect on the functional level in males, which is attributed to the more progressive functional deterioration in AB animals.NEW & NOTEWORTHY The present study is the first to assess the role of sex on pressure unloading-induced reverse and anti-remodeling in a rat model of aortic banding and debanding. Our data indicate that female sex is associated with a greater reversibility of fibrosis, fetal gene expression, and proteomic alterations compared with males. Nevertheless, pressure unloading exposes more anti-remodeling effect on the functional level in males, which is attributed to the more rapid functional deterioration in aortic-banded animals.


Assuntos
Hipertrofia Ventricular Esquerda , Proteômica , Animais , Aorta , Feminino , Fibrose , Masculino , Miocárdio/patologia , Ratos , Remodelação Ventricular
3.
Int J Mol Sci ; 23(13)2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35806458

RESUMO

Demand for organs is increasing while the number of donors remains constant. Nevertheless, not all organs are utilized due to the limited time window for heart transplantation (HTX). Therefore, we aimed to evaluate whether an iron-chelator-supplemented Bretschneider solution could protect the graft in a clinically relevant canine model of HTX with prolonged ischemic storage. HTX was performed in foxhounds. The ischemic time was standardized to 4 h, 8 h, 12 h or 16 h, depending on the experimental group. Left ventricular (LV) and vascular function were measured. Additionally, the myocardial high energy phosphate and iron content and the in-vitro myocyte force were evaluated. Iron chelator supplementation proved superior at a routine preservation time of 4 h, as well as for prolonged times of 8 h and longer. The supplementation groups recovered quickly compared to their controls. The LV function was preserved and coronary blood flow increased. This was also confirmed by in vitro myocyte force and vasorelaxation experiments. Additionally, the biochemical results showed significantly higher adenosine triphosphate content in the supplementation groups. The iron chelator LK614 played an important role in this mechanism by reducing the chelatable iron content. This study shows that an iron-chelator-supplemented Bretschneider solution effectively prevents myocardial/endothelial damage during short- as well as long-term conservation.


Assuntos
Transplante de Coração , Preservação de Órgãos , Animais , Suplementos Nutricionais , Cães , Glucose , Coração , Ferro , Quelantes de Ferro/farmacologia , Manitol , Miocárdio , Preservação de Órgãos/métodos , Cloreto de Potássio , Procaína , Função Ventricular Esquerda
4.
Crit Care ; 25(1): 141, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849618

RESUMO

BACKGROUND: Intensive care unit (ICU) physicians have extended the minimum alveolar concentration (MAC) to deliver and monitor long-term volatile sedation in critically ill patients. There is limited evidence of MAC's reliability in controlling sedation depth in this setting. We hypothesized that sedation depth, measured by the electroencephalography (EEG)-derived Narcotrend-Index (burst-suppression N_Index 0-awake N_Index 100), might drift downward over time despite constant MAC values. METHODS: This prospective single-centre randomized clinical study was conducted at a University Hospital Surgical Intensive Care Unit and included consecutive, postoperative ICU patients fulfilling the inclusion criteria. Patients were randomly assigned to receive uninterrupted inhalational sedation with isoflurane, sevoflurane, or desflurane. The end-expiratory concentration of the anaesthetics and the EEG-derived index were measured continuously in time-stamped pairs. Sedation depth was also monitored using Richmond-Agitation-Sedation-Scale (RASS). The paired t-test and linear models (bootstrapped or multilevel) have been employed to analyze MAC, N_Index and RASS across the three groups. RESULTS: Thirty patients were recruited (female/male: 10/20, age 64 ± 11, Simplified Acute Physiology Score II 30 ± 10). In the first 24 h, 21.208 pairs of data points (N_Index and MAC) were recorded. The median MAC of 0.58 ± 0.06 remained stable over the sedation time in all three groups. The t-test indicated in the isoflurane and sevoflurane groups a significant drop in RASS and EEG-derived N_Index in the first versus last two sedation hours. We applied a multilevel linear model on the entire longitudinal data, nested per patient, which produced the formula N_Index = 43 - 0.7·h (R2 = 0.76), showing a strong negative correlation between sedation's duration and the N_Index. Bootstrapped linear models applied for each sedation group produced: N_Index of 43-0.9, 45-0.8, and 43-0.4·h for isoflurane, sevoflurane, and desflurane, respectively. The regression coefficient for desflurane was almost half of those for isoflurane and sevoflurane, indicating a less pronounced time-effect in this group. CONCLUSIONS: Maintaining constant MAC does not guarantee stable sedation depth. Thus, the patients necessitate frequent clinical assessments or, when unfeasible, continuous EEG monitoring. The differences across different volatile anaesthetics regarding their time-dependent negative drift requires further exploration. TRIAL REGISTRATION: NCT03860129.


Assuntos
Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/classificação , Idoso , Estado Terminal/epidemiologia , Estado Terminal/terapia , Desflurano/administração & dosagem , Desflurano/uso terapêutico , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Eletroencefalografia/métodos , Eletroencefalografia/estatística & dados numéricos , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Isoflurano/administração & dosagem , Isoflurano/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Sevoflurano/administração & dosagem , Sevoflurano/uso terapêutico
5.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360539

RESUMO

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9-10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8-10 rats) or 50µM CANA (IR + CANA, n = 9-11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.


Assuntos
Canagliflozina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Doenças Vasculares/prevenção & controle , Vasodilatação/efeitos dos fármacos , Animais , Endotélio Vascular/patologia , Técnicas In Vitro , Masculino , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ratos , Ratos Wistar , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia
6.
Am J Transplant ; 20(10): 2847-2856, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32162462

RESUMO

Hearts are usually procured from brain-dead (BD) donors. However, brain death may induce hemodynamic instability, which may contribute to posttransplant graft dysfunction. We hypothesized that BD-donor heart preservation with a conditioned medium (CM) from mesenchymal stem cells (MSCs) would improve graft function after transplantation. Additionally, we explored the PI3K pathway's potential role. Rat MSCs-derived CM was used for conservation purposes. Donor rats were either exposed to sham operation or brain death by inflation of a subdural balloon-catheter for 5.5 hours. Then, the hearts were explanted, stored in cardioplegic solution-supplemented with either a medium vehicle (BD and sham), CM (BD + CM), or LY294002, an inhibitor of PI3K (BD + CM + LY), and finally transplanted. Systolic performance and relaxation parameters were significantly reduced in BD-donors compared to sham. After transplantation, systolic and diastolic functions were significantly decreased, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and endonuclease G positive cells were increased in the BD-group compared to sham. Preservation of BD-donor hearts with CM resulted in a recovery of systolic graft function (dP/dtmax : BD + CM: 3148 ± 178 vs BD: 2192 ± 94 mm Hg/s at 110 µL, P < .05) and reduced apoptosis. LY294002 partially lowered graft protection afforded by CM in the BD group. Our data suggest that PI3K/Akt pathway is not the primary mechanism of action of CM in improving posttransplant cardiac contractility and preventing caspase-independent apoptosis.


Assuntos
Transplante de Coração , Células-Tronco Mesenquimais , Animais , Encéfalo , Morte Encefálica , Meios de Cultivo Condicionados , Humanos , Fosfatidilinositol 3-Quinases , Ratos , Doadores de Tecidos , Função Ventricular Esquerda
7.
J Mol Cell Cardiol ; 129: 208-218, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30844361

RESUMO

AIM: Here we aimed at investigating the relation between left ventricular (LV) contractility and myofilament function during the development and progression of pressure overload (PO)-induced LV myocardial hypertrophy (LVH). METHODS: Abdominal aortic banding (AB) was performed to induce PO in rats for 6, 12 and 18 weeks. Sham operated animals served as controls. Structural and molecular alterations were investigated by serial echocardiography, histology, quantitative real-time PCR and western blot. LV function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes. RESULTS: AB resulted in the development of pathological LVH as indicated by increased heart weight-to-tibial length ratio, LV mass index, cardiomyocyte diameter and fetal gene expression. These alterations were already present at early stage of LVH (AB-week6). Furthermore, at more advanced stages (AB-week12, AB-week18), myocardial fibrosis and chamber dilatation were also observed. From a hemodynamic point of view, the AB-wk6 group was associated with increased LV contractility, maintained ventriculo-arterial coupling (VAC) and preserved systolic function. In the same experimental group, increased myofilament Ca2+ sensitivity (pCa50) and hyperphosphorylation of cardiac troponin-I (cTnI) at Threonine-144 was detected. In contrast, in the AB-wk12 and AB-wk18 groups, the initial augmentation of LV contractility, as well as the increased myofilament Ca2+ sensitivity and cTnI (Threonine-144) hyperphosphorylation diminished, leading to impaired VAC and reduced systolic performance. Strong correlation was found between LV contractility parameters and myofilament Ca2+-sensitivity among the study groups. CONCLUSION: Changes in myofilament Ca2+ sensitivity might underlie the alterations in LV contractility during the development and progression of PO-induced LVH.


Assuntos
Cálcio/metabolismo , Progressão da Doença , Hipertrofia Ventricular Esquerda/fisiopatologia , Contração Miocárdica , Miofibrilas/metabolismo , Pressão , Função Ventricular Esquerda , Animais , Artérias/fisiopatologia , Biomarcadores/metabolismo , Proteínas de Transporte/metabolismo , Diástole , Fibrose , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Fosforilação , Ratos Sprague-Dawley , Sístole , Troponina I/metabolismo
8.
J Transl Med ; 17(1): 127, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992077

RESUMO

BACKGROUND: The sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. METHODS: Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure-volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. RESULTS: Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia-reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. CONCLUSIONS: Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.


Assuntos
Canagliflozina/uso terapêutico , Cardiotônicos/uso terapêutico , Endotélio/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Vasodilatação , Aldeídos/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Glicemia/metabolismo , Canagliflozina/farmacologia , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Endotélio/fisiopatologia , Glicosúria/complicações , Glicosúria/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sístole/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
9.
Pharmacol Res ; 150: 104503, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31629091

RESUMO

The major source of heart transplantation comes from brain-dead (BD) donors. However, brain death and myocardial ischemia/reperfusion injury during transplantation may lead to cardiac dysfunction and hemodynamic instability. A previous work demonstrated that pre-treatment of BD donors with dopamine improved the graft survival of heart allograft in recipient after transplantation. However, low-dose dopamine treatment might result in tachycardia and hypertension. Our previous experimental study showed that pre-treatment of BD donor rats with the dopamine derivate N-octanoyl dopamine (NOD), devoid of any hemodynamic effects, improved graft function after transplantation. Herein, we hypothesized that NOD confers superior myocardial protection than dopamine, in terms of graft function. Male Lewis donor rats were either subjected to sham-operation or brain death via a subdurally placed balloon followed by 5.5 h monitoring. Then, the hearts were explanted and heterotopically transplanted into Lewis recipient rats. Shortly before the onset of reperfusion, continuous intravenous infusion of either NOD (14.7 µg/kg/min, BD + NOD group, n = 9), dopamine (10 µg/kg/min, BD + Dopamine group, n = 8) or physiological saline vehicle (sham, n = 9 and BD group, n = 9) were administered to the recipient rats. In vivo left-ventricular (LV) graft function was evaluated after 1.5 h reperfusion. Additionally, immunohistochemical detection of 4-hydroxy-2-nonenal (HNE, an indicator of oxidative stress) and nitrotyrosine (a nitro-oxidative stress marker), was performed. After heart transplantation, systolic and diastolic functions were significantly decreased in the BD group compared to sham. Treatment with NOD but not dopamine, resulted in better LV graft systolic functional recovery (LV systolic pressure BD + NOD 90 ±â€¯8 vs BD + Dopamine 66 ±â€¯5 vs BD 65 ±â€¯4 mmHg; maximum rate of rise of LV pressure dP/dtmax BD + NOD 2686 ±â€¯225 vs BD + Dopamine 2243 ±â€¯70 vs BD 1999 ±â€¯147 mmHg/s, at an intraventricular volume of 140 µl, p < 0.05) and myocardial work compared to BD group. The re-beating time (time to restoration of heartbeat) was significantly shorter in BD + NOD group than that of BD hearts (32 ±â€¯4 s vs. 48 ±â€¯6 s, p < 0.05), Dopamine treatment had no impact on all of these parameters. Furthermore, NOD as well as dopamine decreased HNE and nitrotyrosine immunoreactivity to the same level. NOD is superior to dopamine in terms of protecting LV graft contractile function when administered to the heart transplant recipients from BD donors.


Assuntos
Dopamina/análogos & derivados , Transplante de Coração , Substâncias Protetoras/uso terapêutico , Animais , Morte Encefálica , Dopamina/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Masculino , Ratos Endogâmicos Lew , Doadores de Tecidos , Função Ventricular Esquerda/efeitos dos fármacos
10.
Am J Physiol Heart Circ Physiol ; 315(3): H502-H511, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29799277

RESUMO

Sex differences in pressure overload (PO)-induced left ventricular (LV) myocardial hypertrophy (LVH) have been intensely investigated. Nevertheless, sex-related disparities of LV hemodynamics in LVH were not examined in detail. Therefore, we aimed to provide a detailed characterization of distinct aspects of LV function in male and female rats during different stages of LVH. Banding of the abdominal aorta (AB) was performed to induce PO for 6 or 12 wk in male and female rats. Control animals underwent sham operation. The development of LVH was followed by serial echocardiography. Cardiac function was assessed by pressure-volume analysis. Cardiomyocyte hypertrophy and fibrosis were evaluated by histology. At week 6, increased LV mass index, heart weight-to-tibial length, cardiomyocyte diameter, concentric LV geometry, and moderate interstitial fibrosis were detected in both male and female AB rats, indicating the development of an early stage of LVH. Functionally, at this time, impaired active relaxation, increased contractility, and preserved ventricular-arterial coupling were observed in the AB groups in both sexes. In contrast, at week 12, progressive deterioration of LVH-associated structural and functional alterations occurred in male but not female animals with sustained PO. Accordingly, at this later stage, LVH was associated with eccentric remodeling, exacerbated fibrosis, and increased chamber stiffness in male AB rats. Furthermore, augmented contractility declined in male but not female AB animals, resulting in contractility-afterload mismatch. Maintained contractility augmentation, preserved ventricular-arterial coupling, and better myocardial compliance in female rats contribute to sex differences in LV function during the progression of PO-induced LVH. NEW & NOTEWORTHY We investigated sex differences in pressure overload-induced left ventricular myocardial hypertrophy for the first time on the functional level by pressure-volume analysis. We found that left ventricular hypertrophy was initially characterized by prolonged active relaxation, increased contractility, and maintained ventricular-arterial coupling in both sexes. However, at a later stage, augmented contractility declined in mate but not female rats, resulting in contractility-afterload mismatch. Furthermore, in male rats, increased myocardial stiffness also contributed to hypertrophy-associated diastolic dysfunction.


Assuntos
Hipertrofia Ventricular Esquerda/fisiopatologia , Animais , Feminino , Fibrose , Hemodinâmica , Hipertrofia Ventricular Esquerda/patologia , Masculino , Contração Miocárdica , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
11.
Eur J Vasc Endovasc Surg ; 56(2): 256-263, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724533

RESUMO

OBJECTIVES: Ischaemia reperfusion (IR) injury occurs during vascular graft harvesting and implantation during vascular/cardiac surgery. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective endothelial protection in different pathophysiological conditions. The hypothesis that the phosphodiesterase-5 inhibitor vardenafil would protect vascular grafts against IR injury by upregulating the nitric oxide-cGMP pathway in the vessel wall of the bypass graft was investigated. METHODS: Lewis rats (n = 6-7/group) were divided into Group 1, control; Group 2, donor rats received intravenous saline; Group 3, received intravenous vardenafil (30 µg/kg) 2 h before explantation. Whereas aortic arches of Group 1 were immediately mounted in an organ bath, aortic segments of Groups 2 and 3 were stored for 2 h in saline and transplanted into the abdominal aorta of the recipient. Two hours after transplantation, the implanted grafts were harvested. Endothelium dependent and independent vasorelaxations were investigated. TUNEL, CD-31, ICAM-1, VCAM-1, α-SMA, nitrotyrosine, dihydroethidium and cGMP immunochemistry were also performed. RESULTS: Compared with the control, the saline group showed significantly attenuated endothelium dependent maximal relaxation (Rmax) 2 h after reperfusion, which was significantly improved by vardenafil supplementation (Rmax control, 91 ± 2%; saline 22 ± 2% vs. vardenafil 39 ± 4%, p < .001). Vardenafil pre-treatment significantly reduced DNA fragmentation (control 9 ± 1%, saline 66 ± 8% vs. vardenafil 13 ± 1%, p < .001), nitro-oxidative stress (control 0.8 ± 0.3, saline 7.6 ± 1.3 vs. vardenafil 3.8 ± 1, p = .036), reactive oxygen species level (vardenafil 36 ± 4, control 34 ± 2 vs. saline 43 ± 2, p = .049), prevented vascular smooth muscle cell damage (control 8.5 ± 0.7, saline 4.3 ± 0.6 vs. vardenafil 6.7 ± 0.6, p = .013), decreased ICAM-1 (control 4.1 ± 0.5, saline 7.0 ± 0.9 vs. vardenafil 4.4 ± 0.6, p = .031), and VCAM-1 score (control 4.4 ± 0.4, saline 7.3 ± 1.0 vs. vardenafil 5.2 ± 0.4, p = .046) and increased cGMP score in the aortic wall (control 11.2 ± 0.8, saline 6.5 ± 0.8 vs. vardenafil 8.9 ± 0.6, p = .016). The marker for endothelial integrity (CD-31) was also higher in the vardenafil group (control 74 ± 4%, saline 22 ± 2% vs. vardenafil 40 ± 3%, p = .008). CONCLUSIONS: The results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction of an arterial graft after bypass surgery, which can effectively be prevented by vardenafil. Its clinical use as preconditioning drug could be a novel approach in vascular/cardiac surgery.


Assuntos
Aorta Torácica/efeitos dos fármacos , Aorta Torácica/transplante , Inibidores da Fosfodiesterase 5/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Coleta de Tecidos e Órgãos , Dicloridrato de Vardenafila/farmacologia , Lesões do Sistema Vascular/prevenção & controle , Vasodilatadores/farmacologia , Actinas/metabolismo , Animais , Aorta Torácica/enzimologia , Aorta Torácica/fisiopatologia , Isquemia Fria , GMP Cíclico/metabolismo , Citoproteção , Dano ao DNA/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Estresse Nitrosativo/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Coleta de Tecidos e Órgãos/efeitos adversos , Tirosina/análogos & derivados , Tirosina/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Lesões do Sistema Vascular/enzimologia , Lesões do Sistema Vascular/fisiopatologia , Isquemia Quente
12.
J Surg Res ; 195(1): 315-24, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25592272

RESUMO

BACKGROUND: Heart transplantation represents the only curative treatment for end-stage heart failure. Presently, the donor pool is restricted to brain-dead donors. Based on the lack of suitable donors and the increasing number of patients, we investigated some molecular pathomechanisms of the potential use of hearts after circulatory determination of death (DCDD) in transplantation. MATERIALS AND METHODS: Rats were either maintained brain death for 5 h by inflation of a subdurally placed balloon catheter (n = 6) or subjected to cardiac arrest by exsanguinations (n = 6). Additionally, a control group was used (n = 9). Then the hearts were perfused with a cold preservation solution (Custodiol), explanted, stored at 4°C in Custodiol, and heterotopically transplanted. RESULTS: Brain death was associated with decreased left-ventricular contractility (dP/dtmax: 4895 ± 505 versus 8037 ± 565 mm Hg/s; ejection fraction: 27 ± 5 versus 44 ± 5%; Emax: 2.2 ± 0.3 versus 4.2 ± 0.3 mm Hg/µL; preload recruitable stroke work: 59 ± 5 versus 96 ± 6 mm Hg; 5 h after brain death versus before brain death; P < 0.05) and impaired cardiac relaxation (dP/dtmin: -4734 ± 575 versus -9404 ± 550 mm Hg/s and prolonged Tau, P < 0.05) compared with controls. After transplantation, significantly decreased systolic function and prolonged Tau were observed in brain-dead and DCDD groups compared with those in controls. Tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor-κB, inducible-NOS, and caspase-3 messenger RNA and protein-levels were significantly increased in the brain-dead compared with both control and DCDD groups. Additionally, marked myocardial inflammatory cell infiltration, edema, necrosis, and DNA-strand breaks were observed in the brain-dead group. CONCLUSIONS: Our results show that despite the similar functional outcome in DCDD and brain-dead groups, brain-dead hearts showed marked myocardial inflammatory cell infiltration, edema, necrosis, DNA-strand breaks, and increased transcriptional and posttranscriptional expression for markers of apoptosis and inflammatory signaling pathways.


Assuntos
Morte Encefálica , Transplante de Coração , Animais , Quebras de DNA , Masculino , Modelos Animais , Miocárdio/metabolismo , Miocárdio/patologia , Distribuição Aleatória , Ratos Endogâmicos Lew , Função Ventricular Esquerda
13.
Sci Rep ; 14(1): 15174, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956161

RESUMO

Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7-9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p < 0.05). Immunohistochemical analysis revealed decreased intercellular adhesion molecule-1, 4-hydroxy-2-nonenal, caspase-3 and caspase-8 expression, while endothelial cell adhesion molecule-1 immunoreactivity was increased in the IR + DuraGraft grafts compared to the IR-group. DuraGraft mitigates endothelial dysfunction following IR injury in a rat bypass model. Its protective effect may be attributed, at least in part, to its ability to reduce the inflammatory response, oxidative stress, and apoptosis.


Assuntos
Endotélio Vascular , Ratos Endogâmicos Lew , Traumatismo por Reperfusão , Animais , Ratos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Traumatismo por Reperfusão/metabolismo , Masculino , Ponte de Artéria Coronária/métodos , Ponte de Artéria Coronária/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Modelos Animais de Doenças , Aldeídos/metabolismo , Aldeídos/farmacologia , Caspase 3/metabolismo , Vasodilatação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Acetilcolina/farmacologia
14.
Circ J ; 77(1): 207-16, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23001070

RESUMO

BACKGROUND: Heart valve tissue engineering represents a concept for improving the current methods of valvular heart disease therapy. The aim of this study was to develop tissue engineered heart valves combining human umbilical vein endothelial cells (HUVECs) and decellularized human heart valve matrices. METHODS AND RESULTS: Pulmonary (n=9) and aortic (n=6) human allografts were harvested from explanted hearts from heart transplant recipients and were decellularized using a detergent-based cell extraction method. Analysis of decellularization success was performed with light microscopy, transmission electron microscopy and quantitative analysis of collagen and elastin content. The decellularization method resulted in full removal of native cells while the mechanical stability and the quantitative composition of the neoscaffolds was maintained. The luminal surface of the human matrix could be successfully recellularized with in vitro expanded HUVECs under dynamic flow conditions. The surface appeared as a confluent cell monolayer of positively labeled cells for von Willebrand factor and CD 31, indicating their endothelial nature. CONCLUSIONS: Human heart valves can be decellularized by the described method. Recellularization of the human matrix resulted in the formation of a confluent HUVEC monolayer. The in vitro construction of tissue-engineered heart valves based on decellularized human matrices followed by endothelialization using HUVECs is a feasible and safe method, leading to the development of future clinical strategies in the treatment of heart valve disease.


Assuntos
Bioprótese , Próteses Valvulares Cardíacas , Células Endoteliais da Veia Umbilical Humana/citologia , Engenharia Tecidual/métodos , Alicerces Teciduais , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino
15.
Circ J ; 77(7): 1817-26, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23575364

RESUMO

BACKGROUND: Reperfusion of ischemic myocardium may contribute to substantial cardiac tissue damage, but the addition of iron chelators, zinc or zinc complexes has been shown to prevent heart from reperfusion injury. We investigated the possible beneficial effects of an iron-chelating and zinc-complexing agent, Q50, in rat models of ischemia/reperfusion (I/R)-induced myocardial infarction and on global reversible myocardial I/R injury after heart transplantation. METHODS AND RESULTS: Rats underwent 45-min myocardial ischemia by left anterior descending coronary artery ligation followed by 24h reperfusion. Vehicle or Q50 (10 mg/kg, IV) were given 5 min before reperfusion. In a heart transplantation model, donor rats received vehicle or Q50 (30 mg/kg, IV) 1h before the onset of ischemia. In myocardial infarcted rats, increased left ventricular end-systolic and end-diastolic volumes were significantly decreased by Q50 post treatment as compared with the sham group. Moreover, in I/R rat hearts, the decreased dP/dtmax and load-independent contractility parameters were significantly increased after Q50. However, Q50 treatment did not reduce infarct size or have any effect on increased plasma cardiac troponin-T-levels. In the rat model of heart transplantation, 1h after reperfusion, decreased left ventricular systolic pressure, dP/dt(max), dP/dt(min) and myocardial ATP content were significantly increased and myocardial protein expression of superoxide dismutase-1 was upregulated after Q50 treatment. CONCLUSIONS: In 2 experimental models of I/R, administration of Q50 improved myocardial function. Its mechanisms of action implicate in part the restoration of myocardial high-energy phosphates and upregulation of antioxidant enzymes.


Assuntos
Quelantes de Ferro/farmacologia , Traumatismo por Reperfusão Miocárdica , Miocárdio/metabolismo , Zinco , Animais , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Fatores de Tempo , Troponina T/sangue
16.
Aging Clin Exp Res ; 25(5): 597-600, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23949977

RESUMO

BACKGROUND AND AIMS: Both advanced donor age and prolonged ischemic time are significant risk factors for the 1-year mortality. However, its functional consequences have not been fully evaluated in the early-phase after transplantation; even early graft dysfunction is the main determinant of long-term outcome following transplantation. We evaluated in vivo left-ventricular (LV) cardiac and coronary vascular function of old-donor grafts after short and prolonged cold ischemic times in rats 1 h after heart transplantation. METHODS: The hearts were excised from young donor (3-month-old) or old donor (18-month-old) rats, stored in cold preservation solution for either 1 or 8 h, and heterotopically transplanted. RESULTS: After 1 h of ischemic period, in the old-donor group, LV pressure, maximum pressure development (dP/dt max), time constant of LV pressure decay (τ), LV end-diastolic pressure and coronary blood flow did not differ compared with young donors. However, endothelium-dependent vasodilatation to acetylcholine resulted in a significantly lower response of coronary blood flow in the old-donor group (33 ± 4 vs. 51 ± 15 %, p < 0.05). After 8 h preservation, two of the old-donor hearts showed no mechanical activity upon reperfusion. LV pressure (55 ± 6 vs. 72 ± 5 mmHg, p < 0.05), dP/dt max (899 ± 221 vs. 1530 ± 217 mmHg/s, p < 0.05), coronary blood flow and response to acetylcholine were significantly reduced and τ was increased in the old-donor group in comparison to young controls. CONCLUSIONS: During the early-phase after transplantation, the ischemic tolerance of older-donor hearts is reduced after prolonged preservation time and the endothelium is more vulnerable to ischemia/reperfusion.


Assuntos
Isquemia Fria/efeitos adversos , Temperatura Baixa/efeitos adversos , Transplante de Coração/efeitos adversos , Coração/fisiologia , Animais , Circulação Coronária/fisiologia , Masculino , Soluções para Preservação de Órgãos , Ratos , Ratos Endogâmicos Lew , Vasodilatação/fisiologia , Função Ventricular Esquerda/fisiologia
17.
Front Immunol ; 14: 1155343, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37426668

RESUMO

Introduction: The shortage of available donor hearts and the risk of ischemia/reperfusion injury restrict heart transplantation (HTX). Alpha-1-antitrypsin (AAT), a well-characterized inhibitor of neutrophil serine protease, is used in augmentation therapy to treat emphysema due to severe AAT deficiency. Evidence demonstrates its additional anti-inflammatory and tissue-protective effects. We hypothesized that adding human AAT in a preservation solution reduces graft dysfunction in a rat model of HTX following extended cold ischemic storage. Methods: The hearts from isogenic Lewis donor rats were explanted, stored for either 1h or 5h in cold Custodiol supplemented with either vehicle (1h ischemia, n=7 or 5h ischemia, n=7 groups) or 1 mg/ml AAT (1h ischemia+AAT, n=7 or 5h ischemia+AAT, n=9 groups) before heterotopic HTX. Left-ventricular (LV) graft function was evaluated in vivo 1.5h after HTX. Immunohistochemical detection of myeloperoxydase (MPO) was performed in myocardial tissue and expression of 88 gene quantified with PCR was analyzed both statistical and with machine-learning methods. Results: After HTX, LV systolic function (dP/dtmax 1h ischemia+AAT 4197 ± 256 vs 1h ischemia 3123 ± 110; 5h ischemia+AAT 2858 ± 154 vs 5h ischemia 1843 ± 104mmHg/s, p<0.05) and diastolic function (dP/dtmin 5h ischemia+AAT 1516 ± 68 vs 5h ischemia 1095 ± 67mmHg/s, p<0.05) at an intraventricular volume of 90µl were improved in the AAT groups compared with the corresponding vehicle groups. In addition, the rate pressure product (1h ischemia+AAT 53 ± 4 vs 1h ischemia 26 ± 1; 5h ischemia+AAT 37 ± 3 vs 5h ischemia 21 ± 1mmHg*beats/min at an intraventricular volume of 90µl; p<0.05) was increased in the AAT groups compared with the corresponding vehicle groups. Moreover, the 5h ischemia+AAT hearts exhibited a significant reduction in MPO-positive cell infiltration in comparison to the 5h ischemia group. Our computational analysis shows that ischemia+AAT network displays higher homogeneity, more positive and fewer negative gene correlations than the ischemia+placebo network. Discussion: We provided experimental evidence that AAT protects cardiac grafts from prolonged cold ischemia during HTX in rats.


Assuntos
Transplante de Coração , Soluções para Preservação de Órgãos , Animais , Humanos , Ratos , Coração , Isquemia , Ratos Endogâmicos Lew , Doadores de Tecidos
18.
Front Cardiovasc Med ; 10: 1288128, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38239873

RESUMO

Introduction: Coronary artery bypass grafting (CABG) is the most common cardiac surgical procedure. The prognosis of revascularization via CABG is determined by the patency of the used grafts, for which an intact endothelium is essential. The degree of ischemia-reperfusion injury (IRI), which occurs during the harvest and implantation of the grafts, is an important determinant of graft patency. Preconditioning with aspirin, a nonsteroidal anti-inflammatory drug has been shown to reduce the functional and molecular damage of arterial grafts in a rodent model. Studies have found that the zinc-aspirin complex may be able to exert an even better protective effect in pathological cardiovascular conditions. Thus, our aim was to characterize the protective effect of zinc-aspirin complex on free arterial grafts in a rodent model of revascularization. Methods: Donor Lewis rats were treated with either zinc-aspirin, aspirin, or placebo (n = 8) for 5 days, then the aortic arches were harvested and stored in cold preservation solution and implanted heterotopically in the abdominal cavity of the recipient rats, followed by 2 h of reperfusion. There was also a non-ischemia-reperfusion control group (n = 8). Functional measurements using organ bath and histomorphological changes using immunohistochemistry were analyzed. Results: The endothelium dependent maximal vasorelaxation was improved (non-transplanted control group: 82% ± 3%, transplanted control group: 14% ± 2%, aspirin group: 31% ± 4%, zinc-aspirin group: 52% ± 4%), the nitro-oxidative stress and cell apoptosis decreased, and significant endothelial protection was shown in the groups preconditioned with aspirin or zinc-aspirin. However, zinc-aspirin proved to be more effective in the reduction of IRI, than aspirin alone. Discussion: Preconditioning with zinc-aspirin could be a promising way to protect the function and structural integrity of free arterial grafts, thus improving the outcomes of CABG.

19.
Thorac Cardiovasc Surg ; 60(4): 247-54, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22252326

RESUMO

BACKGROUND: Recent studies have shown the potential of PDE-5 inhibition on acute and chronic heart failure. Nevertheless it remained unclear, how far load-reducing properties and direct effects on myocardial contractility are responsible for these observations. In the present study, we investigated the effects of vardenafil on myocardial contractility and vascular function in a dose-response study. METHODS: We performed left ventricular pressure-volume analysis in young adult rats by using a Millar microtip conductance catheter. Pressure-volume loops were recorded before and after intravenous injection of vardenafil (3, 10, 30, 100, 300 µg/kg, n = 6/group). RESULTS: Treatment with vardenafil resulted in a significant (p < 0.05) increase in the load-independent cardiac contractility parameters reaching its maximum at the dose of 100µg/kg (ESPVR: 2.15 ± 0.15 vs. 3.29 ± 0.26 mm Hg/µL; PRSW: 93.28 ± 4.04 vs. 134.90 ± 6.27 mm Hg; peak positive dP/dt/EDV: 38.73 ± 7.97 vs. 53.02 ± 3.74 mm Hg·s-1·µL-1; before versus after 100 µg/kg vardenafil). Results of the in vitro organ-bath experiments showed an augmented vasorelaxation of precontracted aortic rings after vardenafil treatment. CONCLUSION: Our data supports the hypothesis that the usage of vardenafil as "inodilators" could have beneficial effects in heart failure patients.


Assuntos
Aorta/efeitos dos fármacos , Cardiotônicos/farmacologia , Imidazóis/farmacologia , Contração Miocárdica/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Cateterismo Cardíaco , Cardiotônicos/administração & dosagem , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/administração & dosagem , Técnicas In Vitro , Injeções Intravenosas , Masculino , Miografia , Inibidores da Fosfodiesterase 5/administração & dosagem , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacos , Sulfonas/administração & dosagem , Sulfonas/farmacologia , Fatores de Tempo , Triazinas/administração & dosagem , Triazinas/farmacologia , Dicloridrato de Vardenafila , Vasodilatadores/administração & dosagem , Pressão Ventricular/efeitos dos fármacos
20.
Eur J Cardiothorac Surg ; 62(5)2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-35579350

RESUMO

OBJECTIVES: HTK-Solution (Custodiol) is a well-established cardioplegic and organ preservation solution. We currently developed a novel HTK-based solution, Custodiol-N, which includes iron chelators to reduce oxidative injury, as well as l-arginine, to improve endothelial function. In this first-in-human study, Custodiol-N was compared to Custodiol in patients undergoing elective coronary artery bypass surgery. The aim of this comparison was to evaluate the safety and ability of Custodiol-N to protect cardiac tissue. METHODS: The study was designed as a prospective randomized double-blind non-inferiority trial. Primary end point was area under the curve (AUC) of creatine kinase muscle-brain (CK-MB) within the first 24 h after surgery. Secondary end points included peak CK-MB and troponin-T and AUC of troponin-T release, cardiac index, cumulative catecholamine dose, intensive care unit stay and mortality. All values in the abstract are given as mean ± SD, P < 0.05 was considered statistically significant. RESULTS: Early termination of the trial was performed per protocol as the primary non-inferiority end-point was reached after inclusion of 101 patients. CK-MB AUC (878±549 vs 779±439 h U/l, non-inferiority P < 0.001, Custodiol vs Custodiol-N) and troponin-T AUC (12990±8347 vs 13498±6513 h pg/ml, noninferiority P < 0.001, Custodiol vs Custodiol-N) were similar in both groups. Although the trial was designed for non-inferiority, peak CK-MB (52±40 vs 42±28 U/l, superiority P < 0.03, Custodiol vs Custodiol-N) was significantly lower in the Custodiol-N group. CONCLUSIONS: This study shows that Custodiol-N is safe and provides similar cardiac protection as the established HTK-Custodiol solution. Significantly reduced peak CK-MB levels in the Custodiol-N group in the full analysis set may implicate a beneficial effect on ischaemia/reperfusion injury in the setting of coronary bypass surgery.


Assuntos
Ponte de Artéria Coronária , Soluções para Preservação de Órgãos , Humanos , Ponte de Artéria Coronária/métodos , Estudos Prospectivos , Troponina T
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