9 research outputs found
Oral treatment with a zinc complex of acetylsalicylic acid prevents diabetic cardiomyopathy in a rat model of type-2 diabetes: activation of the Akt pathway.
BACKGROUND: Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)2, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy. METHODS: Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 29-30 weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot. RESULTS: Zn(ASA)2-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0 +/- 3.6 vs 49.4 +/- 2.8 mM, P < 0.05) while serum insulin-levels were similar among the groups. Data from cardiac catheterization showed that Zn(ASA)2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure-volume relationship: 0.064 +/- 0.008 vs 0.084 +/- 0.014 mmHg/microl; end-diastolic pressure: 6.5 +/- 0.6 vs 7.9 +/- 0.7 mmHg, P < 0.05). Furthermore, ECG-recordings revealed a restoration of prolonged QT-intervals (63 +/- 3 vs 83 +/- 4 ms, P < 0.05) with Zn(ASA)2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes' transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)2-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)2-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)2 significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)2 reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)2 had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression. CONCLUSIONS: We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)2 reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)2. The oral administration of Zn(ASA)2 may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients
Improvement of Left Ventricular Graft Function Using an Iron-Chelator-Supplemented Bretschneider Solution in a Canine Model of Orthotopic Heart Transplantation
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
Left ventricular pressure-volume measurements and myocardial gene expression profile in type 2 diabetic Goto-Kakizaki rats
Influence of concomitant ablation of nonparoxysmal atrial fibrillation during coronary artery bypass grafting on mortality and readmissionsCentral MessagePerspective
Objective: We determined the utilization rate of surgical ablation (SA) during coronary artery bypass grafting (CABG) and compared outcomes between CABG with or without SA in a national cohort. Methods: The January 2016 to December 2018 Nationwide Readmissions Database was searched for all patients undergoing isolated CABG with preoperative persistent or chronic atrial fibrillation by using the International Classification of Diseases, 10th Revision classification. Propensity score matching and multivariate logistic regressions were performed to compare outcomes, and Cox proportional hazards model was used to assess risk factors for 1-year readmission. Results: Of 18,899 patients undergoing CABG with nonparoxysmal atrial fibrillation, 78% (n = 14,776) underwent CABG alone and 22% (n = 4123) underwent CABG with SA. In the propensity score-matched cohort (n = 8116), CABG with SA (n = 4054) (vs CABG alone [n = 4112]) was not associated with increased in-hospital mortality (3.4% [139 out of 4112] vs 3.9% [159 ut of 4054]; P = .4), index-hospitalization length of stay (10 days vs 10 days; P = .3), 30-day readmission (19.1% [693 out of 3362] vs 17.2% [609 out of 3537]; P = .2), or 90-day readmission (28.9% [840 out of 2911] vs 26.2% [752 out of 2875]; P = .1). Index hospitalization costs were significantly higher for those undergoing SA (47,433; P < .001). Rates of readmission at 300 days were similar between patients receiving SA (43.8%) and no SA (42.8%; log-rank P = .3). The 3 most common causes of readmission were not different between groups and included heart failure (24.3% [594 out of 2444]; P = .6), infection (16.8% [411 out of 2444]; P = .5), and arrhythmia (11.7% [286 out of 2444]; P = .2). Conclusions: In patients with nonparoxysmal atrial fibrillation, utilization of SA during CABG remains low. SA during CABG did not adversely influence mortality or short-term readmissions. These findings support increased use of SA during CABG
Socioeconomic disparities in procedural choice and outcomes after aortic valve replacementCentral MessagePerspective
Objective: To identify potential socioeconomic disparities in the procedural choice of patients undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve replacement (TAVR) and in readmission outcomes after SAVR or TAVR. Methods: The Nationwide Readmissions Database was queried to identify a total of 243,691 patients who underwent isolated SAVR and TAVR between January 2016 and December 2018. Patients were stratified according to a tiered socioeconomic status (SES) metric comprising patient factors including education, literacy, housing, employment, insurance status, and neighborhood median income. Multivariable analyses were used to assess the effect of SES on procedural choice and risk-adjusted readmission outcomes. Results: SAVR (41.4%; 100,833 of 243,619) was performed less frequently than TAVR (58.6%; 142,786 of 243,619). Lower SES was more frequent among patients undergoing SAVR (20.2% [20,379 of 100,833] vs 19.4% [27,791 of 142,786]; PÂ <Â .001). Along with such variables as small hospital size, drug abuse, arrhythmia, and obesity, lower SES was independently associated with SAVR relative to TAVR (adjusted odds ratio [aOR], 1.17; 95% confidence interval [CI], 1.11 to 1.24). After SAVR, but not after TAVR, lower SES was independently associated with increased readmission at 30Â days (aOR, 1.19; 95% CI, 1.07-1.32), 90Â days (aOR, 1.27; 95% CI, 1.15-1.41), and 1Â year (adjusted hazard ratio, 1.19; 95% CI, 1.11 to 1.28; PÂ <Â .05 for all). Conclusions: Our study findings indicate that socioeconomic disparities exist in the procedural choice for patients undergoing AVR. Patients with lower SES had increased odds of undergoing SAVR, as well as increased odds of readmission after SAVR, but not after TAVR, supporting that health inequities exist in the surgical care of socioeconomically disadvantaged patients
Impairment of the Akt pathway in transplanted Type 1 diabetic hearts is associated with post-transplant graft injuryâ
Dimethyloxalylglycine treatment of brain-dead donor rats improves both donor and graft left ventricular function after heart transplantation.
Abstract
OBJECTIVE:
Hypoxia inducible factor (HIF)-1 pathway signalling has a protective effect against ischemia/reperfusion injury. The prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) activates the HIF-1 pathway by stabilizing HIF-1α. In a rat model of brain death (BD)-associated donor heart dysfunction we tested the hypothesis that pre-treatment of brain-dead donors with DMOG would result in a better graft heart condition.
METHODS:
BD was induced in anesthetized Lewis rats by inflating a subdurally placed balloon catheter. Controls underwent sham operations. Then, rats were injected with an intravenous dose of DMOG (30 mg/kg) or an equal volume of physiologic saline. After 5 hours of BD or sham operation, hearts were perfused with a cold (4°C) preservation solution (Custodiol; Dr. Franz Köhler Chemie GmbH; Germany), explanted, stored at 4°C in Custodiol, and heterotopically transplanted. Graft function was evaluated 1.5 hours after transplantation.
RESULTS:
Compared with control, BD was associated with decreased left ventricular systolic and diastolic function. DMOG treatment after BD improved contractility (end-systolic pressure volume relationship E'max: 3.7 ± 0.6 vs 3.1 ± 0.5 mm Hg/”1; p < 0.05) and left ventricular stiffness (end-diastolic pressure volume relationship: 0.13 ± 0.03 vs 0.31 ± 0.06 mm Hg/”1; p < 0.05) 5 hours later compared with the brain-dead group. After heart transplantation, DMOG treatment of brain-dead donors significantly improved the altered systolic function and decreased inflammatory infiltration, cardiomyocyte necrosis, and DNA strand breakage. In addition, compared with the brain-dead group, DMOG treatment moderated the pro-apoptotic changes in the gene and protein expression.
CONCLUSIONS:
In a rat model of potential brain-dead heart donors, pre-treatment with DMOG resulted in improved early recovery of graft function after transplantation. These results support the hypothesis that activation of the HIF-1 pathway has a protective role against BD-associated cardiac dysfunction
N-octanoyl dopamine is superior to dopamine in protecting graft contractile function when administered to the heart transplant recipients from brain-dead donors
Administration of zinc complex of acetylsalicylic acid after the onset of myocardial injury protects the heart by upregulation of antioxidant enzymes
We recently demonstrated that the pre-treatment of rats with zinc and acetylsalicylic acid complex in the form of bis(aspirinato)zinc(II) [Zn(ASA)2] is superior to acetylsalicylic acid in protecting the heart from acute myocardial ischemia. Herein, we hypothesized that Zn(ASA)2 treatment after the onset of an acute myocardial injury could protect the heart. The rats were treated with a vehicle or Zn(ASA)2 after an isoproterenol injection. Isoproterenol-induced cardiac damage [inflammatory infiltration into myocardial tissue, DNA-strand breakage evidenced by TUNEL-assay, increased 11-dehydro thromboxane (TX)B2-levels, elevated ST-segment, widened QRS complex and prolonged QT-interval] was prevented by the Zn(ASA)2 treatment. In isoproterenol-treated rats, load-independent left ventricular contractility parameters were significantly improved after Zn(ASA)2. Furthermore, Zn(ASA)2 significantly increased the myocardial mRNA-expression of superoxide dismutase-1, glutathione peroxidase-4 and decreased the level of Na+/K+/ATPase. Postconditioning with Zn(ASA)2 protects the heart from acute myocardial ischemia. Its mechanisms of action might involve inhibition of pro-inflammatory prostanoids and upregulation of antioxidant enzymes