van Rijt, Willem G; van Goor, Harry; Ploeg, Rutger J; Leuvenink, Henri G D
The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation.
Palepu, Sneha; Prasad, G V Ramesh
Pre-kidney transplant cardiac screening has garnered particular attention from guideline committees as an approach to improving post-transplant success. Screening serves two major purposes: To more accurately inform transplant candidates of their risk for a cardiac event before and after the transplant, thereby informing decisions about proceeding with transplantation, and to guide pre-transplant management so that post-transplant success can be maximized. Transplant candidates on dialysis are more likely to be screened for coronary artery disease than those not being considered for transplantation. Thorough history and physical examination taking, resting electrocardiography and echocardiography, exercise stress testing, myocardial perfusion scintigraphy, dobutamine stress echocardiography, cardiac computed tomography, cardiac biomarker measurement, and cardiac magnetic resonance imaging all play contributory roles towards screening for cardiovascular disease before kidney transplantation. In this review, the importance of each of these screening procedures for both coronary artery disease and other forms of cardiac disease are discussed. PMID:26722655
Chow, Eric J.; Wong, Kenneth; Lee, Stephanie J.; Cushing-Haugen, Kara L.; Flowers, Mary E.D.; Friedman, Debra L.; Leisenring, Wendy M.; Martin, Paul J.; Mueller, Beth A.; Baker, K. Scott
PURPOSE To better understand the combined effects of pre-transplant, transplant, and post-transplant factors in determining risks of serious cardiovascular disease following hematopoietic cell transplantation (HCT). METHODS Hospitalizations and deaths associated with serious cardiovascular outcomes were identified among 1,379 Washington State residents who received HCT (57% allogeneic; 43% autologous) at a single center from 1985–2005, survived ≥2 years, and followed through 2008. Using a nested-case-cohort design, relationships (hazard ratios, HR) between potential risk factors and outcomes were examined among affected survivors and a randomly selected sub-cohort (n=509). RESULTS After 7.0 years median follow-up (range 2.0–23.7), the 10-year cumulative incidence of ischemic heart disease, cardiomyopathy, stroke, and all-cause cardiovascular death was 3.8%, 6.0%, 3.5%, and 3.7%, respectively. In multivariable analysis, increased pre-transplant anthracyclines was associated with cardiomyopathy. Active chronic graft vs. host disease was associated with cardiovascular death (HR 4.0, 95% CI 1.1–14.7); risk was otherwise similar between autologous vs. allogeneic HCT recipients. Independent of therapeutic exposures, pre-transplant smoking, hypertension, dyslipidemia, diabetes, and obesity conferred additional risk of all outcomes except stroke (HR ≥1.5 for each additional risk factor, p<0.03). Hypertension and dyslipidemia at one year with persistence of these conditions two or more years following HCT also were associated with independent risks of multiple outcomes. CONCLUSION Hematopoietic cell transplant survivors with pre-existing or newly developed and persistent cardiovascular risk factors remain at greater risk of subsequent serious cardiovascular disease compared with other survivors, independent of chemo- and radiotherapy exposures. These survivors should receive appropriate follow-up and be considered for primary intervention. PMID:24565992
Chow, Eric J; Wong, Kenneth; Lee, Stephanie J; Cushing-Haugen, Kara L; Flowers, Mary E D; Friedman, Debra L; Leisenring, Wendy M; Martin, Paul J; Mueller, Beth A; Baker, K Scott
The authors sought to better understand the combined effects of pretransplant, transplant, and post-transplant factors in determining risks of serious cardiovascular disease after hematopoietic cell transplantation (HCT). Hospitalizations and deaths associated with serious cardiovascular outcomes were identified among 1379 Washington State residents who received HCT (57% allogeneic and 43% autologous) at a single center from 1985 to 2005, survived ≥ 2 years, and followed through 2008. Using a nested case-cohort design, relationships (hazard ratios [HRs]) between potential risk factors and outcomes were examined among affected survivors and a randomly selected subcohort (N = 509). After 7.0 years of median follow-up (range, 2.0 to 23.7), the 10-year cumulative incidence of ischemic heart disease, cardiomyopathy, stroke, and all-cause cardiovascular death was 3.8%, 6.0%, 3.5%, and 3.7%, respectively. In multivariable analysis, increased pretransplant anthracycline was associated with cardiomyopathy. Active chronic graft-versus-host disease was associated with cardiovascular death (HR, 4.0; 95% confidence interval, 1.1 to 14.7); risk was otherwise similar between autologous versus allogeneic HCT recipients. Independent of therapeutic exposures, pretransplant smoking, hypertension, dyslipidemia, diabetes, and obesity conferred additional risk of all outcomes except stroke (HR ≥ 1.5 for each additional risk factor, P < .03). Hypertension and dyslipidemia at 1 year with persistence of these conditions 2 or more years after HCT also were associated with independent risks of multiple outcomes. HCT survivors with preexisting or newly developed and persistent cardiovascular risk factors remain at greater risk of subsequent serious cardiovascular disease compared with other survivors, independent of chemo- and radiotherapy exposures. These survivors should receive appropriate follow-up and be considered for primary intervention. Copyright © 2014 American Society for
McQuarrie, Emily P; Fellström, Bengt C; Holdaas, Hallvard; Jardine, Alan G
Renal transplant recipients have a markedly increased risk of premature cardiovascular disease (CVD) compared with the general population, although considerably lower than that of patients receiving maintenance haemodialysis. CVD in transplant recipients is poorly characterised and differs from the nonrenal population, with a much higher proportion of fatal to nonfatal cardiac events. In addition to traditional ischaemic heart disease risk factors such as age, gender, diabetes and smoking, there are additional factors to consider in this population such as the importance of hypertension, left ventricular hypertrophy and uraemic cardiomyopathy. There are factors specific to transplantation such immunosuppressive therapies and graft dysfunction which contribute to this altered risk profile. However, understanding and treatment is limited by the absence of large randomised intervention trials addressing risk factor modification, with the exception of the ALERT study. The approach to managing these patients should begin early and be multifactorial in nature.
Delville, Marianne; Sabbah, Laurent; Girard, Delphine; Elie, Caroline; Manceau, Sandra; Piketty, Marie; Martinez, Frank; Méjean, Arnaud; Legendre, Christophe; Sberro-Soussan, Rebecca
Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up. In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed. Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06-4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04-3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 -5.96], p = 0.03). Pre-transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients.
De Vito Dabbs, Annette; Song, Mi-Kyung
Transplant recipients have an unfavorable cardiovascular risk profile and experience more cardiovascular morbidity and mortality compared with the general population, primarily because of immunosuppressant-induced diabetes, hypertension, and hyperlipidemia. These discouraging prospects are even more ominous for lung transplant recipients who are more likely than other organ recipients to require intense immunosuppression and develop these conditions early and concomitantly. The purposes of this article are to heighten awareness of the prevalence, risk factors, and management of diabetes, hypertension, and hyperlipidemia in lung transplant patients, and to assist nurses to be proactive in helping recipients to reduce the likelihood of developing cardiovascular complications.
Boratyńska, M; Obremska, M; Małecki, R; Gacka, M; Magott, M; Kamińska, D; Banasik, M; Kusztal, M; Chełmoński, A; Jablecki, J; Klinger, M
Cardiovascular disease is a major cause of mortality in solid organ allograft recipients. Hand transplantation is not a lifesaving procedure, thus the effect of long-term immunosuppression on the cardiovascular system in these patients should be monitored. The aim of this study was to evaluate the morphology and function of heart and blood vessels in patients after hand transplantation. The study included 5 patients at ages 32 to 58 years, mean 39 years, who underwent hand transplantation between 2006 and 2010. Immunosuppressive treatment included basiliximab in induction and tacrolimus, mycophenolate mofetil, and prednisone. Cardiac status was assessed by echocardiography (according to the American Society of Echocardiography) and cardiac biomarkers. Blood vessels were estimated by carotid intima-media thickness, pulse wave velocity, and brachial artery flow-mediated dilatation (FMD). The examinations were performed at 28 to 79 (mean 43) months after transplantation. Cardiovascular risk factors were observed in all patients after transplantation: 2 had insulin-dependent diabetes, 3 developed dyslipidemia and hypertension, 2 had chronic kidney disease stage 3. Concentric left ventricular hypertrophy was found in 1 and ventricular concentric remodeling in 4 patients. Impaired diastolic function (E/e' > 8) was observed in 2 patients. The index volume of the left atrium was higher in all patients. The cardiac biomarkers N-terminal pro-brain natriuretic peptide, C-reactive protein, and troponins were within normal range. Carotid intima-media thickness was higher in 1 patient and normal in 4 patients. Arterial stiffness measured by pulse wave velocity was not increased in all patients. Native brachial artery FMD response, an index of endothelium-dependent function, was abnormal in 2 patients, but in the transplanted extremity FMD was abnormal in 4 patients. Pathologic changes in cardiac structures were found in all patients, but the arterial wall changes and endothelial
Mangels, Daniel R; Mohler, Emile R
The impact of diet on cardiovascular disease has become an increasingly relevant topic as ongoing epidemiological evidence continues to demonstrate clear associations with disease burden and mortality. Certain diets, such as those high in sodium and saturated fat, are associated with cardiovascular disease states, while other diets can be cardioprotective. However, there is limited knowledge on how the micro- and macronutrients within such cardioprotective diets afford their benefits. One such micronutrient is the catechin class, which are naturally occurring compounds in plant foods, such as teas, cocoa, wine, pears, and apples. Recent evidence reveals that catechins may be a key mediator in cardiovascular health via mechanisms of blood pressure reduction, flow-mediated vasodilation, and atherosclerosis attenuation. This review evaluates the current literature on the interplay between catechins and cardiovascular disease, which may have important implications for nutrition counseling and pharmaceutical drug development. © 2017 American Heart Association, Inc.
Mansell, Holly; Stewart, Samuel Alan; Shoker, Ahmed
Predicting cardiovascular risk is of great interest in renal transplant recipients since cardiovascular disease is the leading cause of mortality. To conduct a systematic review to assess the validity of cardiovascular risk prediction models in this population. Five databases were searched (MEDLINE, EMBASE, SCOPUS, CINAHL, and Web of Science) and cohort studies with at least one year of follow-up were included. Variables that described population characteristics, study design, and prognostic performance were extracted. The Quality in Prognostic Studies (QUIPS) tool was used to evaluate bias. Seven studies met the criteria for inclusion, of which, five investigated the Framingham risk score and three used a transplant-specific model. Sample sizes ranged from 344 to 23,575, and three studies lacked sufficient event rates to confidently reach conclusion. Four studies reported discrimination (as measured by c-statistic), which ranged from 0.701 to 0.75, while only one risk model was both internally and externally validated. The Framingham has underestimated cardiovascular events in renal transplant recipients, but these studies have not been robust. A risk prediction model has been externally validated at least on one occasion, but comprehensive validation in multiple cohorts and impact analysis are recommended before widespread clinical application is advocated.
Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation. PMID:23002428
Lindley, Eric M; Hall, Amanda K; Hess, Jordan; Abraham, Jo; Smith, Brigham; Hopkins, Paul N; Shihab, Fuad; Welt, Frederick; Owan, Theophilus; Fang, James C
Cardiovascular (CV) assessment in prerenal transplant patients varies by center. Current guidelines recommend stress testing for candidates if ≥ 3 CV risk factors exist. We evaluated the CV assessment and management in 685 patients referred for kidney transplant over a 7-year period. All patients had CV risk factors, and the most common cause of end-stage renal disease was diabetes. Thirty-three percent (n = 229) underwent coronary angiography. The sensitivity of stress testing to detect obstructive coronary artery disease (CAD) was poor (0.26). Patients who had no CAD, nonobstructive CAD, or CAD with intervention had significantly higher event-free survival compared with patients with obstructive CAD without intervention. There were no adverse clinical events (death, myocardial infarction, stroke, revascularization, and graft failure) within 30 days post-transplant in patients who had preoperative angiography (n = 77). Of the transplanted patients who did not have an angiogram (n = 289), there were 8 clinical events (6 myocardial infarctions) in the first 30 days. In conclusion, our results indicate that stress testing and usual risk factors were poor predictors of obstructive CAD and that revascularization may prove beneficial in these patients. Copyright © 2016 Elsevier Inc. All rights reserved.
Sandor, Barbara; Varga, Adam; Rabai, Miklos; Toth, Andras; Papp, Judit; Toth, Kalman; Szakaly, Peter
International surveys have shown that the leading cause of death after kidney transplantation has cardiovascular origin with a prevalence of 35-40%. As a preventive strategy these patients receive aspirin (ASA) therapy, even though their rate of aspirin resistance is still unknown. In our study, platelet aggregation measurements were performed between 2009 and 2012 investigating the laboratory effect of low-dose aspirin (100 mg) treatment using a CARAT TX4 optical aggregometer. ASA therapy was considered clinically effective in case of low ( i.e., below 40%) epinephrine-induced (10 μM) platelet aggregation index. Rate of aspirin resistance, morbidity and mortality data of kidney transplanted patients (n = 255, mean age: 49 ± 12 years) were compared to a patient population with cardio- and cerebrovascular diseases (n = 346, mean age: 52.6 ± 11 years). Rate of aspirin resistance was significantly higher in the renal transplantation group (RT) compared to the positive control group (PC) (35.9% vs. 25.6%, p < 0.002). Morbidity analysis demonstrated significantly higher incidence of myocardial infarction, hypertension and diabetes mellitus in the RT group (p < 0.05). The subgroup analysis revealed significantly higher incidence of infarction and stroke in the ASA resistant RT group compared to the RT patients without ASA resistance (p < 0.05). Furthermore, the incidence of myocardial infarction and hypertension was significantly higher in the non-resistant RT group than in the group of PC patients without ASA resistance (p < 0.05). These results may suggest that the elevated rate of aspirin resistance contributes to the high cardiovascular mortality after kidney transplantation.
Courivaud, Cécile; Bamoulid, Jamal; Crepin, Thomas; Chalopin, Jean-Marc; Tiberghien, Pierre; Saas, Philippe
T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin (ATG)–induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87±31 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio [HR], 2.36; 95% confidence interval [95% CI], 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8+ T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs. PMID:24511120
Ducloux, Didier; Courivaud, Cécile; Bamoulid, Jamal; Crepin, Thomas; Chalopin, Jean-Marc; Tiberghien, Pierre; Saas, Philippe
T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin (ATG)-induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87±31 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio [HR], 2.36; 95% confidence interval [95% CI], 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8(+) T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs. Copyright © 2014 by the American Society of Nephrology.
Chow, Eric J.; Baker, K. Scott; Lee, Stephanie J.; Flowers, Mary E.D.; Cushing-Haugen, Kara L.; Inamoto, Yoshihiro; Khera, Nandita; Leisenring, Wendy M.; Syrjala, Karen L.; Martin, Paul J.
Purpose To determine the influence of modifiable lifestyle factors on the risk of cardiovascular disease after hematopoietic cell transplantation (HCT). Patients and Methods HCT survivors of ≥ 1 year treated from 1970 to 2010 (n = 3,833) were surveyed from 2010 to 2011 on current cardiovascular health and related lifestyle factors (smoking, diet, recreational physical activity). Responses (n = 2,362) were compared with those from a matched general population sample (National Health and Nutrition Examination Survey [NHANES]; n = 1,192). Results Compared with NHANES participants, HCT survivors (median age, 55.9 years; median 10.8 years since HCT; 71.3% allogeneic) had higher rates of cardiomyopathy (4.0% v 2.6%), stroke (4.8% v 3.3%), dyslipidemia (33.9% v 22.3%), and diabetes (14.3% v 11.7%; P < .05 for all comparisons). Prevalence of hypertension was similar (27.9% v 30.0%), and survivors were less likely to have ischemic heart disease (6.1% v 8.9%; P < .01). Among HCT survivors, hypertension, dyslipidemia, and diabetes were independent risk factors for ischemic heart disease and cardiomyopathy, and smoking was associated with ischemic heart disease and diabetes (odds ratios [ORs], 1.8 to 2.1; P = .02). Obesity was a risk factor for post-transplantation hypertension, dyslipidemia, and diabetes (ORs ≥ 2.0; P < .001). In contrast, lower fruit/vegetable intake was associated with greater risk of dyslipidemia and diabetes (ORs, 1.4 to 1.8; P ≤ .01), and lower physical activity level was associated with greater risk of hypertension and diabetes (ORs, 1.4 to 1.5; P < .05). Healthier lifestyle characteristics among HCT survivors attenuated risk of all cardiovascular conditions assessed. Conclusion Attention of clinicians to conventional cardiovascular risk factors and modifiable lifestyle characteristics offers hope of reducing serious cardiovascular morbidity after HCT. PMID:24297944
Ballesteros, Fabián; Allard, Julie; Durand, Céline; Cardinal, Héloïse; Lalonde, Lyne; Fortin, Marie-Chantal
Background Cardiovascular disease (CVD) is a major cause of mortality among kidney transplant recipients (KTRs). These patients have a high prevalence of risk factors, such as hypertension, diabetes, and dyslipidemia. Despite regular medical care, few of them reach the recommended therapeutic targets. The objective of this study is to describe KTRs' perspectives on CVD and related risk factors, as well as their priorities for posttransplant care. Methods Twenty-six KTRs participated in a semistructured interview about their personal experience and offered their perspectives on CVD risk factors posttransplant. The interview was digitally recorded and the transcripts were analyzed using a thematic and content methodology. Results CVD and related risk factors appear to be underestimated and trivialized. Only 2 of 26 patients identified CVD prevention and treatment as a priority. The most important posttransplant priorities identified by patients were related to immunosuppressive drugs (13 of 26), posttransplant follow-up (10) and graft survival (9). However, 21 of 26 patients stated they wanted to be better informed about posttransplant CVD risk factors. Conclusions CVD and related risk factors are not a priority for KTRs, and the importance of CVD is underestimated and trivialized. KTRs did recommend that tailored information be provided by various professionals and at several points in the transplantation process. This knowledge will help us develop a new approach to increase awareness of posttransplant CVD and related risk factors. PMID:28620646
Knechtle, Stuart J; Kwun, Jean; Iwakoshi, Neal
Belying the spectacular success of solid organ transplantation and improvements in immunosuppressive therapy is the reality that long-term graft survival rates remain relatively unchanged, in large part due to chronic and insidious alloantibody-mediated graft injury. Half of heart transplant recipients develop chronic rejection within 10 years - a daunting statistic, particularly for young patients expecting to achieve longevity by enduring the rigors of a transplant. The current immunosuppressive pharmacopeia is relatively ineffective in preventing late alloantibody-associated chronic rejection. In this issue of the JCI, Kelishadi et al. report that preemptive deletion of B cells prior to heart transplantation in cynomolgus monkeys, in addition to conventional posttransplant immunosuppressive therapy with cyclosporine, markedly attenuated not only acute graft rejection but also alloantibody elaboration and chronic graft rejection. The success of this preemptive strike implies a central role for B cells in graft rejection, and this approach may help to delay or prevent chronic rejection after solid organ transplantation.
Chaikriangkrai, Kongkiat; Jyothula, Soma; Jhun, Hye Yeon; Estep, Jerry; Loebe, Matthias; Scheinin, Scott; Torre-Amione, Guillermo
This study examined the correlation between pre-operative coronary artery disease (CAD) and post-operative cardiovascular events in lung transplant recipients. Consecutive isolated lung transplant recipients from 2007 to 2013 in our institution were identified and categorized as having significant CAD (≥ 50% coronary stenosis in at least 1 artery or history of coronary revascularization) or no-mild CAD. Patient records and death index data were analyzed for a median of 2 years for death or cardiovascular events, including coronary, cerebrovascular, and peripheral artery events. The study comprised 280 patients (62% male) with mean age of 60 ± 10 years. Cardiovascular events occurred in 5.7% (16 of 280) of the entire cohort. Patients with significant CAD had a higher annualized rate of cardiovascular events than those with no-mild CAD (11.9% vs 0.6%; p < 0.001). Significant CAD was an independent predictor of cardiovascular events (hazard ratio, 20.32; 95% confidence interval, 5.79-71.26; p < 0.001) but not all-cause mortality (log-rank p = 0.66). Adding significant CAD to clinical risk factors gave incremental prognostic performance compared with clinical risk factors alone (p < 0.001 for increase in global chi-square). Selected lung transplant candidates with significant CAD can undergo transplantation with equal mortality risk to those without CAD but are at a higher risk of non-fatal cardiovascular events. These data support the current practice of accepting a selected group of patients with CAD for lung transplantation and suggest that they should be monitored early and treated to prevent cardiovascular complications. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Cheng, Judy W M; Frishman, William H; Aronow, Wilbert S
Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in the metabolism of steroid hormones, fatty acids, and many medications. Many agents used for management of cardiovascular diseases are substrates, inhibitors, or inducers of CYP450 enzymes.When two agents that are substrates, inhibitors, or inducers of CYP450 are administered together, drug interactions with significant clinical consequences may occur. This review discusses CYP450-mediated cardiovascular drug interactions as well as noncardiovascular drug interactions that produced significant cardiovascular side effects. The principles in predicting drug interactions are also discussed.
Chow, Eric J; Mueller, Beth A; Baker, K Scott; Cushing-Haugen, Kara L; Flowers, Mary E D; Martin, Paul J; Friedman, Debra L; Lee, Stephanie J
Hematopoietic stem cell transplantation (HSCT) is increasingly used to treat multiple malignant and nonmalignant conditions. The risk for cardiovascular disease after the procedure has not been well-described. To compare rates and hazards of cardiovascular-related hospitalization and death among persons who were still alive at least 2 years after HSCT with those in a population-based sample. Retrospective cohort study. Comprehensive cancer center. 1491 patients who had survived 2 years or longer after HSCT received between 1985 and 2006, and frequency-matched persons who were randomly selected from drivers' license files in the state of Washington. Cardiovascular hospitalizations and death, as determined from statewide hospital discharge records and death registries in Washington. Compared with the general population, transplant recipients experienced increased cardiovascular death (adjusted incidence rate difference, 3.6 per 1000 person-years [95% CI, 1.7 to 5.5]). Recipients also had an increased cumulative incidence of ischemic heart disease, cardiomyopathy or heart failure, stroke, vascular diseases, and rhythm disorders and an increased incidence of related conditions that predispose toward more serious cardiovascular disease (hypertension, renal disease, dyslipidemia, and diabetes). No consistent differences in hazards were observed after total-body irradiation or receipt of an allogeneic versus an autologous graft, aside from an increased rate of hypertension among recipients of allogeneic grafts. Disease relapse after transplantation was associated with an increased hazard of cardiovascular death (hazard ratio, 2.3 [CI, 1.1 to 4.8]). All patients received HSCT at a single institution, and no information was available on pretransplantation treatment and lifestyle factors that may influence risk for cardiovascular disease. Increased rates of cardiovascular disease should be taken into account when caring for patients who have received HSCT. Future efforts
Roe, Peter; Wolfe, Megan; Joffe, Marshall; Rosas, Sylvia E
Objective Coronary artery calcification (CAC) predicts cardiovascular events in the general population. We conducted a prospective study to determine if inflammatory markers were predictive of CAC and if CAC predicted cardiovascular events and mortality in incident renal transplant recipients. Methods A prospective cohort of 112 asymptomatic incident renal transplant recipients who had no prior history of coronary artery revascularization or myocardial infarction had coronary calcifications measured early post-transplant and at least 18 months later by Agatston score and volume method. Results The mean CAC score was 367.7 (682.3). Inflammatory markers such as WBC and CRP were predictive of CAC severity. Recipients with cardiovascular events (n=11) or death (n=12) during the follow-up period had higher mean [675.1 (669.3) vs. 296.8(669.0), p=0.02] and median [434.8 vs. 28.9, p=0.01] CAC score compared to those without them. Recipients with CAC score less than 100 had a better cumulative survival rate compared to the recipients with CAC score greater than 100 [95.1 vs. 82.3%, p=0.03]. We found a significant unadjusted and adjusted association between CAC score and cardiovascular events and mortality. A quarter (25.9%) of recipients had CAC progression. Coronary calcification progression also predicted cardiovascular events and mortality after adjustment for diabetes, age, dialysis vintage and presence of CAC at time of transplant. Conclusion CAC is prevalent in renal recipients and is predictive of cardiovascular events and mortality. Changes in coronary calcification are common and predict clinical outcomes. Inflammatory markers are predictive of CAC severity at time of transplant, but are not predictive of future cardiovascular event or mortality. PMID:20934074
Mengel, Michael; Husain, Sufia; Hidalgo, Luis; Sis, Banu
Antibody-mediated hyperacute rejection was the first rejection phenotype observed in human organ transplants. This devastating phenotype was eliminated by reliable crossmatch technologies. Since then, the focus was on T-cell-mediated rejection and de novo donor-specific antibodies were considered an epiphenomenon of cognate T-cell activation. The immune theory was that controlling the T-cell response would entail elimination of antibody-mediated rejection (ABMR). With modern immunosuppressive drugs, T-cell-mediated rejection is essentially treatable. However, this did not prevent ABMR from emerging as a significant phenotype in all types of organ transplants. It became obvious that both rejection types require distinct treatment and thus reliable diagnosis. This is the current challenge. ABMR, depending on stage, grade, time course, organ type or prior treatment, can present with a wide spectrum of phenotypes. This review summarizes the current diagnostic consensus for ABMR, describes unmet needs and challenges in diagnostics, and proposes new approaches for consideration. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.
Kuo, Hsiao-Hsuan; Fan, Ran; Dvorina, Nina; Chiesa-Vottero, Andres
Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. PMID:25145937
Laurés, A S; Gómez, E; Baltar, J; Alvarez-Grande, J
The aim of the present study was to assess the role of cardiovascular risk factors in the occurrence of cardiovascular events among 100 consecutive renal transplant recipients during the first 2 years after transplantation. The following parameters were analyzed: (1) demographic data (gender, age, dialysis duration, preexistent diabetes, and pretransplantation events) as well as (2) basal 1-year, and 2-year posttransplantation data for events, body mass index, arterial hypertension, number of drugs for hypertension control, use of ACE or ARA II inhibitors, treatment with lipid- lowering drugs, de novo diabetes, anemia, immunosuppression with cyclosporine versus tacrolimus, and homocysteine, folic acid, serum creatinine, uric acid, PTH-i, and cholesterol total, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels. At the end of the second posttransplantation year, 14 patients versus 86 who did not experience a new cardiovascular event. Patients in the event group had more events pretransplantation and during the first posttransplantation year than those in the non event group (57.1% vs 17.4%; P = .003 and 78.6% vs 2.3%; P = .000, respectively). Furthermore, the former cohort of patients were older, had greater ventricular hypertrophy and had higher triglyceride and serum creatinine concentrations during the 2 years after transplantation. A multiple logistic regression analysis confirmed the relationship between events within 1 year of transplantation and serum creatinine level at the end of 2 years as well as the development of cardiovascular disease within 2 years. In conclusion, our data suggest the need for aggressive intervention during the first year to prevent the development of new cardiovascular events. Renoprotective strategies may also contribute to reduce the cardiovascular risk of renal transplant recipients.
Ting, Stephen M S; Iqbal, Hasan; Kanji, Hemali; Hamborg, Thomas; Aldridge, Nicolas; Krishnan, Nithya; Imray, Chris H E; Banerjee, Prithwish; Bland, Rosemary; Higgins, Robert; Zehnder, Daniel
Exercise intolerance is an important comorbidity in patients with CKD. Anaerobic threshold (AT) determines the upper limits of aerobic exercise and is a measure of cardiovascular reserve. This study investigated the prognostic capacity of AT on survival in patients with advanced CKD and the effect of kidney transplantation on survival in those with reduced cardiovascular reserve. Using cardiopulmonary exercise testing, cardiovascular reserve was evaluated in 240 patients who were waitlisted for kidney transplantation between 2008 and 2010, and patients were followed for ≤5 years. Survival time was the primary endpoint. Cumulative survival for the entire cohort was 72.6% (24 deaths), with cardiovascular events being the most common cause of death (54.2%). According to Kaplan-Meier estimates, patients with AT <40% of predicted peak VO2 had a significantly reduced 5-year cumulative overall survival rate compared with those with AT ≥40% (P<0.001). Regarding the cohort with AT <40%, patients who underwent kidney transplantation (6 deaths) had significantly better survival compared with nontransplanted patients (17 deaths) (hazard ratio, 4.48; 95% confidence interval, 1.78 to 11.38; P=0.002). Survival did not differ significantly among patients with AT ≥40%, with one death in the nontransplanted group and no deaths in the transplanted group. In summary, this is the first prospective study to demonstrate a significant association of AT, as the objective index of cardiovascular reserve, with survival in patients with advanced CKD. High-risk patients with reduced cardiovascular reserve had a better survival rate after receiving a kidney transplant.
Reed, Elaine F; Demetris, Anthony J; Hammond, Elizabeth; Itescu, Silviu; Kobashigawa, Jon A; Reinsmoen, Nancy L; Rodriguez, E Rene; Rose, Marlene; Stewart, Susan; Suciu-Foca, Nicole; Zeevi, Adriana; Fishbein, Michael C
Under the direction of the International Society for Heart and Lung Transplantation, a multidisciplinary review of the cardiac biopsy grading system was undertaken in 2004, with task forces examining the areas of histopathology of rejection, clinical issues, and research. An important new area addressed by the Immunopathology Task Force sub-committee was the clinical and diagnostic criteria for antibody-mediated rejection. This article is a companion paper to the revised working formulation for the standardization of nomenclature in the diagnosis of heart rejection and reviews the published literature documenting the serologic and morphologic evidence that antibody-mediated rejection is clinically significant and associated with graft loss, accelerated transplant-associated coronary artery disease, and death. This article also provides a more in-depth analysis of antibody-mediated rejection developed by the Immunopathology Task Force for revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.
Tsirigotis, Panagiotis D; Resnick, Igor B; Or, Reuven; Elad, Sharon; Zilberman, Irina; Yoffe, Luba; Levovic, Alexander; Miron, Svetlana; Gesundheit, Benjamin; Slavin, Shimon; Shapira, Michael-Yechiel
Immune-mediated cytopenias after allogeneic stem cell transplantation can be categorized as either alloimmune when host or donor immunity reacts against donor or host elements, respectively, or autoimmune when donor immunity reacts against donor hematopoietic tissue, owing to poorly understood mechanisms that result in severe impairment of central and peripheral tolerance. Immune cytopenias are manifested as monolineage or more rarely as bilineage cytopenias, and are usually mediated through humoral immune mechanisms. On the contrary, immune-mediated pancytopenia is a rare event with only few cases reported in the literature. The exact pathogenesis of immune pancytopenia is not well known although it is possible that cellular immunity may play a significant role. The importance of these syndromes lies in the fact that they can cause severe morbidity and mortality. Differential diagnosis from other causes of post-transplant pancytopenia is of extreme value because these disorders can respond to various treatment modalities.
Hartog, Jasper W L; de Vries, Aiko P J; Bakker, Stephan J L; Graaff, Reindert; van Son, Willem J; van der Heide, Jaap J Homan; Gans, Reinold O B; Wolffenbuttel, Bruce H R; de Jong, Paul E; Smit, Andries J
Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal transplant recipients. The AGE accumulation was assessed using a validated skin-autofluorescence reader (AFR) in 285 consecutive renal transplant recipients (57% male, aged 50+/-12 years) visiting the outpatient clinic at a median (interquartile range) time of 73 (32-143) months after transplantation. Furthermore, various transplant- and recipient-related factors of interest were collected. Average skin-autofluorescence of lower arm and leg was 2.7+/-0.8 a.u. Skin-autofluorescence was positively determined by recipient age, systolic blood pressure, smoking, high-sensitivity C-reactive protein, duration of pre-transplant dialysis, and negatively by plasma vitamin C levels, creatinine clearance at baseline, and change in creatinine clearance since one year after transplantation in linear multivariate regression analysis. Together, these factors explained 41% of the variance of skin-autofluorescence. Skin-autofluorescence was associated with several risk factors for cardiovascular disease and chronic renal transplant dysfunction. These results are in line with the hypothesis that AGEs play a role in the pathogenesis of these conditions in renal transplant recipients. Prospective studies are required to investigate whether the AFR can be used as a simple, non-invasive tool to identify and monitor patients at risk for chronic renal transplant dysfunction and cardiovascular disease.
Kolonko, A; Chudek, J; Szotowska, M; Kuczera, P; Wiecek, A
There is limited evidence regarding the risk factors influencing vascular injury in kidney transplant recipients, except for accelerated vasculopathy and endothelial dysfunction in the pre-transplantation period of end-stage renal failure. Therefore, we performed a cross-sectional study to evaluate the role of traditional and novel or potential nontraditional risk factors in vascular and endothelial dysfunction in a cohort of stable kidney transplant recipients. One hundred forty-two kidney transplant recipients at 8.4 ± 1.8 years after transplantation were enrolled into the study. Different markers of vascular injury, such as carotid intima-media thickness (IMT), pulse wave velocity (PWV), and peripheral arterial tonometry (PAT), were assessed. Inflammatory markers, oxidative stress and endothelial function surrogate markers, adhesion molecules, and parathormone and osteoprotegerin levels were measured. Among traditional risk factors, only age, pre-transplantation diabetes, left ventricular hypertrophy (LVH) and cardiovascular disease (CVD) were related to increased IMT and PWV, whereas PAT values were significantly decreased only in diabetics and patients with CVD and were similar in patients with and without LVH. In multivariate regression analysis, IMT was explained by age, previous CVD episodes, and higher high-sensitivity C-reactive protein levels, and PWV by age and pre-transplantation diabetes. The regression analysis failed to find any significant explanatory variables for PAT. 1. In stable kidney transplant recipients, age, pre-transplantation diabetes, previous cardiovascular episode, and systemic microinflammation were predictors of vascular injury. 2. PAT is poorly associated with traditional CV risk factors and does not correspond with levels of biochemical markers of endothelial dysfunction in those patients. Copyright © 2016 Elsevier Inc. All rights reserved.
Northcott, Josette M; Yeganeh, Azadeh; Taylor, Carla G; Zahradka, Peter; Wigle, Jeffrey T
This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.
Knechtle, Stuart J.; Kwun, Jean; Iwakoshi, Neal
Belying the spectacular success of solid organ transplantation and improvements in immunosuppressive therapy is the reality that long-term graft survival rates remain relatively unchanged, in large part due to chronic and insidious alloantibody-mediated graft injury. Half of heart transplant recipients develop chronic rejection within 10 years — a daunting statistic, particularly for young patients expecting to achieve longevity by enduring the rigors of a transplant. The current immunosuppressive pharmacopeia is relatively ineffective in preventing late alloantibody-associated chronic rejection. In this issue of the JCI, Kelishadi et al. report that preemptive deletion of B cells prior to heart transplantation in cynomolgus monkeys, in addition to conventional posttransplant immunosuppressive therapy with cyclosporine, markedly attenuated not only acute graft rejection but also alloantibody elaboration and chronic graft rejection. The success of this preemptive strike implies a central role for B cells in graft rejection, and this approach may help to delay or prevent chronic rejection after solid organ transplantation. PMID:20335653
Sharma, Jagdish N
All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction, and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin-converting enzyme inhibitors is primarily mediated via the kinin-releasing pathway, which may cause regression of left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.
Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic effect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound targeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and drug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may spew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles increase the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and cell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully investigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss the current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to cardiovascular system by UTMD. PMID:23594865
Mathur, Amit K.; Chang, Yu-Hui; Steidley, D. Eric; Heilman, Raymond; Khurmi, Narjeet; Wasif, Nabil; Etzioni, David; Moss, Adyr A.
Background Cardiovascular disease (CVD) is an important driver of mortality after kidney transplantation. Its broader impact on posttransplant health care utilization in US hospitals is unknown. Methods We used administrative claims data from the Nationwide Inpatient Sample and the American Hospital Association Annual Survey to identify hospitalizations for kidney transplant patients with a cardiovascular diagnosis from 2005 to 2011. CVD hospitalizations were stratified by transplant hospital status to characterize patterns in inpatient health care utilization and outcomes. Based on these analyses, the domestic burden of treatment for posttransplant CVD (myocardial infarction, stroke, congestive heart failure, dysrhythmia, cardiac arrest, malignant hypertension) was estimated. Results The total domestic burden of post-kidney transplant hospitalization between 2005 and 2011 is estimated at 389 138 of which 26.5% of episodes were related to CVD (n = 103 118). CVD was responsible for a growing proportion of post-transplant hospitalizations over time (24.4%-30.4%, P < 0.001). Compared with nontransplant hospitals, transplant hospitals had similar length of stay (median length of stay, 3.7 days), higher median costs per hospitalization (US $10 364 vs US $8606, overall US $9324), and lower adjusted mortality (3.2% vs 3.9%, overall 3.6%; P = 0.003). Conclusions Inpatient CVD care is increasing over time for kidney transplant patients, accounting for 30% of all post-transplant hospitalizations. Variation exists in the inpatient care, outcomes, and costs between by hospital type. Further studies are needed to better understand the mechanisms behind these phenomena. PMID:28361110
Pihlstrøm, Hege; Mjøen, Geir; März, Winfried; Olav Dahle, Dag; Abedini, Sadollah; Holme, Ingar; Fellström, Bengt; Jardine, Alan; Pilz, Stefan; Holdaaas, Hallvard
Inflammatory markers show significant associations with cardiovascular events and all-cause mortality after kidney transplantation. Neopterin, reflecting interferon-γ-release, may better reflect the proinflammatory state of recipients than less specific markers. Kidney transplant recipients in the Assessment of LEscol in Renal Transplant (ALERT) trial were examined and investigated for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all-cause mortality. After adjustment for established and emerging risk factors neopterin expressed as neopterin-to-creatinine ratio was significantly associated with MACE (p = 0.009) and all-cause mortality (p = 0.002). Endpoints were more frequent with increasing quartiles of neopterin-to-creatinine ratio. The incidence rates of MACE and all-cause mortality were significantly increased in the upper quartiles compared with the first. This long-term prospective analysis in stable kidney allograft recipients suggests that neopterin is associated with long-term risk of cardiovascular events and all-cause mortality, but not renal outcomes. © 2013 The Authors Clinical Transplantation Published by John Wiley & Sons Ltd.
Davis, Scott; Cooper, James E
Antibody-mediated rejection has now been recognized as one of the most important causes of graft loss. Transplantation across HLA barriers and nonadherence can result in acute antibody-mediated rejection, which is associated with particularly worse graft outcomes. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of acute antibody-mediated rejection but have engendered many questions about the clinical application of these tests in the prognosis and prevention of this protean disease process. In this article, we review the pathophysiology of acute antibody-mediated rejection, the evolving diagnostic criteria, and specific challenges related to its prognosis, treatment, and prevention.
Foster, M C; Weiner, D E; Bostom, A G; Carpenter, M A; Inker, L A; Jarolim, P; Joseph, A A; Kusek, J W; Pesavento, T; Pfeffer, M A; Rao, M; Solomon, S D; Levey, A S
Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in non-transplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N=508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% non-white race) with enrichment for cardiovascular events (N=306; 54 within the subcohort), mortality (N=208; 68 within the subcohort), and kidney failure (N=208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m(2), respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 vs. 60+ were 2.02 (95% CI 1.09-3.76; p=0.03) and 2.56 (1.35-4.88; p=0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p<0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p<0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients. This article is protected by copyright. All rights reserved.
Harrison, Neil A.; Cooper, Ella; Voon, Valerie; Miles, Ken; Critchley, Hugo D.
Inflammation is a risk factor for both depression and cardiovascular disease. Depressed mood is also a cardiovascular risk factor. To date, research into mechanisms through which inflammation impacts cardiovascular health rarely takes into account central effects on autonomic cardiovascular control, instead emphasizing direct effects of peripheral inflammatory responses on endothelial reactivity and myocardial function. However, brain responses to inflammation engage neural systems for motivational and homeostatic control and are expressed through depressed mood state and changes in autonomic cardiovascular regulation. Here we combined an inflammatory challenge, known to evoke an acute reduction in mood, with neuroimaging to identify the functional brain substrates underlying potentially detrimental changes in autonomic cardiovascular control. We first demonstrated that alterations in the balance of low to high frequency (LF/HF) changes in heart rate variability (a measure of baroreflex sensitivity) could account for some of the inflammation-evoked changes in diastolic blood pressure, indicating a central (rather than solely local endothelial) origin. Accompanying alterations in regional brain metabolism (measured using 18FDG-PET) were analysed to localise central mechanisms of inflammation-induced changes in cardiovascular state: three discrete regions previously implicated in stressor-evoked blood pressure reactivity, the dorsal anterior and posterior cingulate and pons, strongly mediated the relationship between inflammation and blood pressure. Moreover, activity changes within each region predicted the inflammation-induced shift in LF/HF balance. These data are consistent with a centrally-driven component originating within brain areas supporting stressor evoked blood pressure reactivity. Together our findings highlight mechanisms binding psychological and physiological well-being and their perturbation by peripheral inflammation. PMID:23416033
Schrör, Karsten; Rauch, Bernhard H
Aspirin is an unique compound because it bears two active moieties within one and the same molecule: a reactive acetyl group and the salicylate metabolite. Salicylate has some effects similar to aspirin, however only at higher concentrations, usually in the millimolar range, which are not obtained at conventional antiplatelet aspirin doses of 100-300 mg/day. Pharmacological actions of aspirin in the cardiovascular system at these doses are largely if not entirely due to target structure acetylation. Several classes of lipid mediators become affected: Best known is the cyclooxygenase-1 (COX-1) in platelets with subsequent inhibition of thromboxane and, possibly, thrombin formation. By this action, aspirin also inhibits paracrine thromboxane functions on other lipid mediators, such as the platelet storage product sphingosine-1-phosphate (S1P), an inflammatory mediator. Acetylation of COX-2 allows for generation of 15-(R)HETE and subsequent formation of "aspirin-triggered lipoxin" (ATL) by interaction with white cell lipoxygenases. In the cardiovascular system, aspirin also acetylates eNOS with subsequent upregulation of NO formation and enhanced expression of the antioxidans heme-oxygenase-1. This action is possibly also COX-2/ATL mediated. Many more acetylation targets have been identified in live cells by quantitative acid-cleavable activity-based protein profiling and might result in discovery of even more aspirin targets in the near future.
Baskar, Shankar; George, Peggy L; Eghtesad, Bijan; Radhakrishnan, Kadakkal; Hupertz, Vera; Aziz, Peter F; Alkhouri, Naim
The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single-center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post-transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty-eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow-up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow-up being significant risk factors. Fifty-three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Allison, Beth J.; Kaandorp, Joepe J.; Kane, Andrew D.; Camm, Emily J.; Lusby, Ciara; Cross, Christine M.; Nevin-Dolan, Rhianon; Thakor, Avnesh S.; Derks, Jan B.; Tarry-Adkins, Jane L.; Ozanne, Susan E.; Giussani, Dino A.
Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 ± 3 vs. 55 ± 3%) and increased vascular short telomere abundance (4.2–1.3 kb) 43.0 ± 1.5 vs. 55.1 ± 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 ± 2.5 vs. 48.2 ± 2.6%) and of plasma proinflammatory chemokine (24.6 ± 2.8 vs. 36.8 ± 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.—Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. PMID:26932929
Allison, Beth J; Kaandorp, Joepe J; Kane, Andrew D; Camm, Emily J; Lusby, Ciara; Cross, Christine M; Nevin-Dolan, Rhianon; Thakor, Avnesh S; Derks, Jan B; Tarry-Adkins, Jane L; Ozanne, Susan E; Giussani, Dino A
Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 ± 3 vs. 55 ± 3%) and increased vascular short telomere abundance (4.2-1.3 kb) 43.0 ± 1.5 vs. 55.1 ± 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 ± 2.5 vs. 48.2 ± 2.6%) and of plasma proinflammatory chemokine (24.6 ± 2.8 vs. 36.8 ± 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.-Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. © FASEB.
Sanchez-Torrijos, Yolanda; Ampuero, Javier; Romero-Gómez, Manuel
Non-alcoholic fatty liver disease (NAFLD) is increasing considerably due to the current lifestyle, which means that it is becoming one of the main indications for liver transplantation. On the other hand, there is a strong association between NAFLD and cardiovascular disease. This has been evidenced in many studies revealing a higher presence of carotid plaques or carotid intima-media thickness, leading to cardiovascular events and, ultimately, mortality. According to the liver transplant guidelines, screening for heart disease in transplant candidates should be performed by electrocardiogram and transthoracic echocardiography while a stress echocardiogram should be reserved for those with more than two cardiovascular risk factors or greater than 50 years old. However, there are no specific recommendations in NAFLD patients requiring a liver transplantation, despite its well-known cardiovascular risk association. Many studies have shown that these patients probably require a more exhaustive assessment and a global approach including other specialists such as cardiologists or nutritionists. Also, the incidence of cardiovascular disease is also increased in NAFLD patients in the post-transplantation period in comparison with other etiologies, because of the pre-existent risk factors together with the immunosuppressive therapy. Therefore, an early intervention on the lifestyle and the individualized selection of the immunosuppressive regimen could lead to a modification of the cardiovascular risk factors in NAFLD patients requiring a liver transplantation. PMID:28596817
Pihlstrøm, Hege; Mjøen, Geir; März, Winfried; Olav Dahle, Dag; Abedini, Sadollah; Holme, Ingar; Fellström, Bengt; Jardine, Alan; Pilz, Stefan; Holdaas, Hallvard
Background Inflammatory markers show significant associations with cardiovascular events and all-cause mortality after kidney transplantation. Neopterin, reflecting interferon-γ-release, may better reflect the proinflammatory state of recipients than less specific markers. Methods Kidney transplant recipients in the Assessment of LEscol in Renal Transplant (ALERT) trial were examined and investigated for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all-cause mortality. Results After adjustment for established and emerging risk factors neopterin expressed as neopterin-to-creatinine ratio was significantly associated with MACE (p = 0.009) and all-cause mortality (p = 0.002). Endpoints were more frequent with increasing quartiles of neopterin-to-creatinine ratio. The incidence rates of MACE and all-cause mortality were significantly increased in the upper quartiles compared with the first. Conclusions This long-term prospective analysis in stable kidney allograft recipients suggests that neopterin is associated with long-term risk of cardiovascular events and all-cause mortality, but not renal outcomes. PMID:24372612
Organ transplants are not regarded as an exclusively medical process, because they involve financial, religious, philosophic, and bioethical parameters. It becomes clear that if they are to achieve their purpose, which we believe extends well beyond the medical dimension, the creation of a comprehensive framework of communication between the involved parties is of paramount importance. The aim of this paper is to present an outline and a number of considerations regarding the communicational, bioethical, and legal issues that arise from a rather dramatic state of affairs in Greece today: In 2012 the rate of organ transplants stood at only 7 per 1 million of the population. The outdated legal framework and the lack of trust on the part of patients and the public have led to a highly inefficient system that is lagging behind in many respects. The proposition made in this paper is that there is a need for a new system of communication between doctors, patients, relatives of patients, and hospitals: bioethical mediation. This is a system that has played a vital role and has produced astounding results in other countries. There is also every indication that the introduction of such a system is crucial for Greece, especially as the symptoms of the acute financial crisis are become fully visible and tangible. Mediation aims to identify solutions that are oriented toward the interests and wishes of patients, are acknowledged and accepted by all parties involved, and are in tune with the values and the principles of medical practice.
Fernández-Gutiérrez, Benjamín; Perrotti, Pedro P.; Gisbert, Javier P.; Domènech, Eugeni; Fernández-Nebro, Antonio; Cañete, Juan D.; Ferrándiz, Carlos; Tornero, Jesús; García-Sánchez, Valle; Panés, Julián; Fonseca, Eduardo; Blanco, Francisco; Rodríguez-Moreno, Jesús; Carreira, Patricia; Julià, Antonio; Marsal, Sara; Rodriguez-Rodriguez, Luis
Abstract To analyze in several immune-mediated inflammatory diseases (IMIDs) the influence of demographic and clinical-related variables on the prevalence of cardiovascular disease (CVD), and compare their standardized prevalences. Cross-sectional study, including consecutive patients diagnosed with rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn disease, or ulcerative colitis, from rheumatology, gastroenterology, and dermatology tertiary care outpatient clinics located throughout Spain, between 2007 and 2010. Our main outcome was defined as previous diagnosis of angina, myocardial infarction, peripheral vascular disease, and/or stroke. Bivariate and multivariate logistic and mixed-effects logistic regression models were performed for each condition and the overall cohort, respectively. Standardized prevalences (in subjects per 100 patients, with 95% confidence intervals) were calculated using marginal analysis. We included 9951 patients. For each IMID, traditional cardiovascular risk factors had a different contribution to CVD. Overall, older age, longer disease duration, presence of traditional cardiovascular risk factors, and male sex were independently associated with a higher CVD prevalence. After adjusting for demographic and traditional cardiovascular risk factors, systemic lupus erythematosus exhibited the highest CVD standardized prevalence, followed by rheumatoid arthritis, psoriasis, Crohn disease, psoriatic arthritis, and ulcerative colitis (4.5 [95% confidence interval (CI): 2.2, 6.8], 1.3 [95% CI: 0.8, 1.8], 0.9 [95% CI: 0.5, 1.2], 0.8 [95% CI: 0.2, 1.3], 0.6 [95% CI: 0.2, 1.0], and 0.5 [95% CI: 0.1, 0.8], respectively). Systemic lupus erythematosus, rheumatoid arthritis, and psoriasis are associated with higher prevalence of CVD compared with other IMIDs. Specific prevention programs should be established in subjects affected with these conditions to prevent CVD. PMID:28658137
Wu, Guo-Sheng; Cruz Jr, Ruy J; Cai, Jun-Chao
AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection (ABMR) after intestinal transplantation (ITx). METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody (DSA), acute tissue damage, C4d deposition, and allograft dysfunction. RESULTS Acute ABMR was identified in 18 (10.3%) out of 175 intestinal allografts with an average occurrence of 10 d (range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class I and/or II antigens with a detectable DSA. A positive cross-match was seen in 14 (77.8%) cases and twelve of 18 patients (66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibody as a significant independent risk factor. Despite initial improvement after therapy, eleven recipients (61.1%) lost transplant secondary to rejection. Of those, 9 (50%) underwent graft removal and 4 (22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo (range, 13.3-76.4), 8 (44.4%) recipients died. CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes. PMID:28058223
Mosquera Reboredo, J M; Vázquez Martul, E
The diagnosis and treatment of anti-donor antibody-mediated rejection or humoral rejection (ABMR) is one of the main discussions at the moment in kidney transplantation. The search for histopathological markers that help us to diagnose ABMR has been more problematic, in contrast to the histological expression of cellular or tubulointerstitial rejection. Although the relationship between post-transplant anti-donor antibodies and the allograft's prognosis has been a topic of discussion for a long time, led in the main by P.Terasaki, it was not until the beginning of 1990s when P. Halloran studied the humoral mechanisms of rejection in greater depth. Feutch described the importance of C4d deposits as a marker that shows a humoral mechanism of allograft rejection in 1993. As a result of many studies carried out, the Banff consensus group established some diagnostic histopathological criteria of acute (ABMR) in 2003. These have been modified slightly in later meetings of the group. Furthermore, in 2005 this same working group looked at the physiopathological mechanisms causing chronic allograft failure in more detail and established the criteria defining chronic humoral rejection. In this review, we are trying to update any useful histopathological criteria for diagnosing acute and chronic ABMR.
Lindahl, Jørn P; Hartmann, Anders; Aakhus, Svend; Endresen, Knut; Midtvedt, Karsten; Holdaas, Hallvard; Leivestad, Torbjørn; Horneland, Rune; Øyen, Ole; Jenssen, Trond
Mortality due to cardiovascular disease (CVD), particularly coronary artery disease (CAD), is high in type 1 diabetic patients with end-stage renal disease (ESRD). We aimed to determine whether normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, could improve long-term outcomes compared with living donor kidney-alone (LDK) transplantation. We studied 486 type 1 diabetic patients with ESRD who underwent a first SPK (n = 256) or LDK (n = 230) transplant between 1983 and 2012 and were followed to the end of 2014. Data were retrieved from the Norwegian Renal Registry and hospital records. Kaplan-Meier plots and multivariate Cox regression, with correction for recipient, donor and transplant factors, were used to examine potential associations between transplant type and all-cause and CVD- and CAD-related mortality. Median follow-up time was 7.9 years (interquartile range 4.3, 12.9). The adjusted HR for CVD-related deaths in SPK recipients compared with LDK recipients was 0.63 (95% CI 0.40, 0.99; p = 0.047), while the HRs for all-cause and CAD-related mortality were 0.81 (95% CI 0.57, 1.16; p = 0.25) and 0.63 (95% CI 0.36, 1.12; p = 0.12), respectively. Compared with the LDK group, SPK recipients were younger and received grafts from younger donors. Cardiovascular mortality was higher in patients transplanted between 1983 and 1999 compared with those who received their grafts in subsequent years. In patients with type 1 diabetes and ESRD, SPK transplantation was associated with reduced long-term cardiovascular mortality compared with LDK transplantation.
Halloran, P F; Merino Lopez, M; Barreto Pereira, A
The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell-mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.
Sakajiki, Aminu Muhammad; Naidoo, Sagren; Manga, P; Nazir, M S; Naicker, S
Proteinuria is a marker of poor long-term graft survival and an independent risk factor for total and cardiovascular mortality in the transplant population. We investigated the prevalence of proteinuria and its relationship with graft function and cardiovascular risk factors in kidney transplant recipients (KTRs). Adult KTRs at the Charlotte Maxeke Johannesburg Academic Hospital were recruited. Patients' records were reviewed for information on their posttransplant follow-up. Echocardiography and carotid Doppler were performed for the assessment of cardiac status and carotid intima-media thickness (CIMT), respectively. Proteinuria was analyzed both as a categorical and continuous variable. Graft dysfunction was defined as estimated glomerular filtration rate of <60 mL/min/1.73 m 2 based on the modification of diet in renal disease formula. Framingham's risk score was used to categorize patients' cardiovascular risk. Inferential and modeling statistics were applied as appropriate using Statistical Package for Social Sciences, and P ≤0.05 was considered statistically significant. One hundred KTRs including 63% males were recruited. Proteinuria was present in 51%, the mean ± standard deviation 24 h urinary protein excretion per day was 1.67 ± 2.0 g/day with a range of 0.4-9.4 g/day. Graft dysfunction was found in 52% of patients and 36% had high cardiovascular disease (CVD) risk. Proteinuric KTRs had high CVD risk, P = 0.002. Proteinuria was associated with graft dysfunction, increased left ventricular mass index, increased CIMT, and anemia. Proteinuria is prevalent; it is a marker of graft dysfunction and is associated with markers of atherosclerosis.
Valenzuela, Nicole M; Reed, Elaine F
Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.
Laish, Ido; Braun, Marius; Mor, Eytan; Sulkes, Jaqueline; Harif, Yael; Ben Ari, Ziv
Features of metabolic syndrome are not uncommon in patients after liver transplantation. To examine the prevalence and risk factors of posttransplantation metabolic syndrome (PTMS), the files of 252 transplant recipients (mean age, 54.5 ± 2.8 years, 57.9% male) were reviewed for pretransplant and posttransplant clinical and laboratory parameters (mean follow-up, 6.2 ± 4.4 years). Rates of obesity (body mass index >30 kg/m(2) ), hypertriglyceridemia (>150 mg/dL), high-density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women), hypertension, and diabetes were significantly higher after transplantation than before. Metabolic syndrome was diagnosed in 5.4% of patients before transplantation and 51.9% after. Besides significantly higher rates of the typical metabolic derangements (P < 0.0001), the patients with PTMS were older and heavier than those without PTMS, and they had a higher rate of pretransplant hepatitis C virus infection (P < 0.03) and more posttransplant major vascular and cardiac events (20 events in 15.2% of patients with PTMS versus 6 events in 4.9% of patients without PTMS; P < 0.007). There was no between-group difference in mortality or causes of death (mainly related to recurrent disease, graft failure, and sepsis). Significant independent predictors of PTMS on logistic regression analysis were age (odds ratio [OR] = 1.04), pretransplant nonalcoholic fatty liver disease (OR = 3.4), body mass index (OR = 1.13), diabetes (OR = 5.95), and triglycerides (OR = 1.01). The rate of metabolic syndrome in liver transplant recipients is more than twice that reported for the general population. PTMS is associated with cardiovascular morbidity but not mortality, and it may be predicted by pretransplantation conditions. Prospective studies are required to determine the significance and management of PTMS.
Taber, David J; Hunt, Kelly J; Fominaya, Cory E; Payne, Elizabeth H; Gebregziabher, Mulugeta; Srinivas, Titte R; Baliga, Prabhakar K; Egede, Leonard E
Although outcome inequalities for non-Hispanic black (NHB) kidney transplant recipients are well documented, there is paucity in data assessing the impact of cardiovascular disease (CVD) risk factors on this disparity in kidney transplantation. This was a longitudinal study of a national cohort of veteran kidney recipients transplanted between January 2001 and December 2007. Data included baseline characteristics acquired through the United States Renal Data System linked to detailed clinical follow-up information acquired through the Veterans Affairs electronic health records. Analyses were conducted using sequential multivariable modeling (Cox regression), incorporating blocks of variables into iterative nested models; 3139 patients were included (2095 non-Hispanic whites [66.7%] and 1044 NHBs [33.3%]). NHBs had a higher prevalence of hypertension (100% versus 99%; P<0.01) and post-transplant diabetes mellitus (59% versus 53%; P<0.01) with reduced control of hypertension (blood pressure <140/90 60% versus 69%; P<0.01), diabetes mellitus (A1c <7%, 35% versus 47%; P<0.01), and low-density lipoprotein (<100 mg/dL, 55% versus 61%; P<0.01). Adherence to medications used to manage CVD risk was significantly lower in NHBs. In the fully adjusted models, the independent risk of graft loss in NHBs was substantially reduced (unadjusted hazard ratio, 2.00 versus adjusted hazard ratio, 1.49). CVD risk factors and control reduced the influence of NHB race by 9% to 18%. Similar trends were noted for mortality, and estimates were robust across in sensitivity analyses. These results demonstrate that NHB kidney transplant recipients have significantly higher rates of CVD risk factors and reduced CVD risk control. These issues are likely partly related to medication nonadherence and meaningfully contribute to racial disparities for graft outcomes. © 2016 American Heart Association, Inc.
Carpenter, Myra A; John, Alin; Weir, Matthew R; Smith, Stephen R; Hunsicker, Lawrence; Kasiske, Bertram L; Kusek, John W; Bostom, Andrew; Ivanova, Anastasia; Levey, Andrew S; Solomon, Scott; Pesavento, Todd; Weiner, Daniel E
The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52±9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136±20 mmHg and mean diastolic BP was 79±12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial.
Schena, A; Di Paolo, S; Morrone, L F; Resta, F; Stallone, G; Schena, F P
Hyperlipoproteinemia has been reported to frequently occur in kidney transplanted patients, thus possibly explaining, at least in part, the increased incidence of cardiovascular disease in this population. To evaluate the impact of renal transplantation (Tx), and related immunosuppressive therapy, on plasma lipoprotein and Lp(a) profile, we selected a cohort of kidney transplanted patients (36 M/14 F; age 33.8 + 12.0 yr, range 13-62) lacking significant causes of hyperlipidemia. All patients received a triple immunosuppressive regimen and showed a stable renal function after Tx (plasma creatinine: 1.36 +/- 0.35 mg/dL). One year after Tx, we found a significant increase of total cholesterol (TC), LDL, HDL, ApoB and ApoA-I (p < 0.005), while plasma triglyceride levels remained unmodified. Lp(a) plasma levels after Tx were within the normal range and displayed a significant inverse relationship with apo(a) size. Noteworthy, LDL/HDL ratio and ApoB/ ApoA-I ratio in kidney transplanted patients were almost superimposable with those of normal controls. Specifically, LDL/HDL ratio significantly decreased in 64% of patients after Tx, due to a prevalent increase of HDL, and was associated with a moderate amelioration of plasma TG. In a multiple linear regression model, post-Tx HDL level was significantly related to recipient's age, gender, BMI and cyclosporine (CyA) trough levels (Adj-R2 = 0.35, p = 0.0002), with gender and CyA trough levels being the better predictors of HDL. In conclusion, immunosuppressive regimens, in themselves, do not appear to significantly increase the atherogenic risk related to lipoproteins. Rather, other factors can affect the lipoprotein profile and its vascular effects in renal transplant recipients.
Pisano, Giuseppina; Fracanzani, Anna L; Caccamo, Lucio; Donato, Maria F; Fargion, Silvia
Improved surgical techniques and greater efficacy of new anti-rejection drugs have significantly improved the survival of patients undergoing orthotopic liver transplantation (OLT). This has led to an increased incidence of metabolic disorders as well as cardiovascular and cerebrovascular diseases as causes of morbidity and mortality in OLT patients. In the last decade, several studies have examined which predisposing factors lead to increased cardiovascular risk (i.e., age, ethnicity, diabetes, NASH, atrial fibrillation, and some echocardiographic parameters) as well as which factors after OLT (i.e., weight gain, metabolic syndrome, immunosuppressive therapy, and renal failure) are linked to increased cardiovascular mortality. However, currently, there are no available data that evaluate the development of atherosclerotic damage after OLT. The awareness of high cardiovascular risk after OLT has not only lead to the definition of new but generally not accepted screening of high risk patients before transplantation, but also to the need for careful patient follow up and treatment to control metabolic and cardiovascular pathologies after transplant. Prospective studies are needed to better define the predisposing factors for recurrence and de novo occurrence of metabolic alterations responsible for cardiovascular damage after OLT. Moreover, such studies will help to identify the timing of disease progression and damage, which in turn may help to prevent morbidity and mortality for cardiovascular diseases. Our preliminary results show early occurrence of atherosclerotic damage, which is already present a few weeks following OLT, suggesting that specific, patient-tailored therapies should be started immediately post OLT. PMID:27833378
D'Avola, D; Cuervas-Mons, V; Martí, J; Ortiz de Urbina, J; Lladó, L; Jimenez, C; Otero, E; Suarez, F; Rodrigo, J M; Gómez, M A; Fraga, E; Lopez, P; Serrano, T; Rios, A; Fábrega, E; Herrero, J I
Cardiovascular (CV) diseases are recognized long-term causes of death after liver transplantation (LT). The objective of this multicenter study was to analyse the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 liver transplant recipients along 5 years after LT. The influence of baseline variables on survival, morbidity and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Pre-existing CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of post-transplant diabetes, while cyclosporine increased the risk of arterial hypertension dyslipidemia and metabolic syndrome.
Noureldeen, T; Albekioni, Z; Machado, L; Muddana, N; Marcus, R J; Hussain, S M; Sureshkumar, K K
Induction therapy improves graft outcomes in kidney transplant recipients (KTRs). We aimed to compare the incidences of antibody-mediated rejection (AMR) and acute cellular rejection (ACR) as well as graft and patient outcomes in KTRs who underwent induction with alemtuzumab versus rabbit-antithymocyte globulin (r-ATG). This was a single-center retrospective study involving patients who underwent kidney transplantation between January 2009 and December 2011 after receiving induction therapy with either alemtuzumab or r-ATG. Maintenance immunosuppression included tacrolimus and mycophenolate mofetil with early steroid withdrawal. Acute rejection was diagnosed using allograft biopsy. Among the 108 study patients, 68 received alemtuzumab and 40 got r-ATG. There was a significantly higher incidence of AMR (15% vs 2.5%; P = .008) and similar incidence of ACR (4.4% vs 10%; P = .69) for alemtuzumab versus r-ATG groups. One-year serum creatinine levels (l.68 ± 0.8 mg/dL vs 1.79 ± 1.8 mg/dL; P = .66) as well as graft (91.1 ± 3.5% vs 94.5 ± 3.8%; P = .48) and patient (93.8 ± 3.0% vs 96.4 ± 3.5%; P = .92) survivals were similar for the alemtuzumab versus the r-ATG groups. Our study showed a higher incidence of AMR and similar incidence of ACR in KTRs who underwent induction with alemtuzumab compared with those who received r-ATG and were maintained on tacrolimus and MMF. This was despite a lower HLA mismatch in the alemtuzumab group. One-year graft survival, patient survival, and allograft function were similar. Inadequate B-cell suppression by alemtuzumab as well as altered phenotypic and functional properties of repopulating B cells could be contributing to heightened risk of AMR in these patients. Copyright © 2014 Elsevier Inc. All rights reserved.
Kiberd, Bryce; Panek, Romuald
Background and objectives: Cardiovascular disease is an important cause of morbidity and death in kidney transplant recipients. This study examines the Framingham risk score's ability to predict cardiac and stroke events. Because cyclosporine and tacrolimus have different cardiovascular risk profiles, these agents were also examined. Design, setting, participants, & measurements: A prospective cohort evaluation of 540 patients were followed for a median of 4.7 yr in an outpatient kidney transplant clinic. Baseline Framingham risk scores were calculated and all cardiovascular outcomes were collected. Results: Rates per 100 patient-years were 1.79 for cardiac and 0.78 for stroke events. The ratio of observed-to-predicted cardiac events was 1.64-fold higher [95% confidence interval (CI) 1.19 to 2.94] for the cohort, 2.74-fold higher (95% CI 1.70 to 4.24) in patients age 45 to 60 with prior cardiac disease or diabetes mellitus, but not higher in other age subgroups. Stroke was not increased above predicted. Risk scores for cardiac (c = 0.65, P = 0.003) and stroke (c = 0.71, P = 0.004) events were modest predictors. 10-yr event scores for cardiac (9.3 versus 13.5%, P < 0.001) and stroke (7.1 versus 10.0%, P = 0.002) were lower for tacrolimus compared with cyclosporine-treated patients. However observed cardiac events were higher in tacrolimus recipients (2.50, 95% CI 1.09 to 5.90) in an adjusted Cox model. Conclusions: Although risk scores are only modest predictors, patients with the highest event rates are easily identified. Treating high-risk patients with cardioprotective medications should remain a priority. PMID:18322053
DeFilipp, Zachariah; Duarte, Rafael F; Snowden, John A; Majhail, Navneet S; Greenfield, Diana M; Miranda, José López; Arat, Mutlu; Baker, K Scott; Burns, Linda J; Duncan, Christine N; Gilleece, Maria; Hale, Gregory A; Hamadani, Mehdi; Hamilton, Betty K; Hogan, William J; Hsu, Jack W; Inamoto, Yoshihiro; Kamble, Rammurti T; Lupo-Stanghellini, Maria Teresa; Malone, Adriana K; McCarthy, Philip; Mohty, Mohamad; Norkin, Maxim; Paplham, Pamela; Ramanathan, Muthalagu; Richart, John M; Salooja, Nina; Schouten, Harry C; Schoemans, Helene; Seber, Adriana; Steinberg, Amir; Wirk, Baldeep M; Wood, William A; Battiwalla, Minoo; Flowers, Mary E D; Savani, Bipin N; Shaw, Bronwen E
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all-cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with an estimated prevalence of MetS of 31% to 49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.
DeFilipp, Z; Duarte, R F; Snowden, J A; Majhail, N S; Greenfield, D M; Miranda, J L; Arat, M; Baker, K S; Burns, L J; Duncan, C N; Gilleece, M; Hale, G A; Hamadani, M; Hamilton, B K; Hogan, W J; Hsu, J W; Inamoto, Y; Kamble, R T; Lupo-Stanghellini, M T; Malone, A K; McCarthy, P; Mohty, M; Norkin, M; Paplham, P; Ramanathan, M; Richart, J M; Salooja, N; Schouten, H C; Schoemans, H; Seber, A; Steinberg, A; Wirk, B M; Wood, W A; Battiwalla, M; Flowers, M E D; Savani, B N; Shaw, B E
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.
DeFilipp, Zachariah; Duarte, Rafael F.; Snowden, John A.; Majhail, Navneet S.; Greenfield, Diana M.; Miranda, José López; Arat, Mutlu; Baker, K. Scott; Burns, Linda J.; Duncan, Christine N.; Gilleece, Maria; Hale, Gregory A.; Hamadani, Mehdi; Hamilton, Betty K.; Hogan, William J.; Hsu, Jack W.; Inamoto, Yoshihiro; Kamble, Rammurti T.; Lupo-Stanghellini, Maria Teresa; Malone, Adriana K.; McCarthy, Philip; Mohty, Mohamad; Norkin, Maxim; Paplham, Pamela; Ramanathan, Muthalagu; Richart, John M.; Salooja, Nina; Schouten, Harry C.; Schoemans, Helene; Seber, Adriana; Steinberg, Amir; Wirk, Baldeep M.; Wood, William A.; Battiwalla, Minoo; Flowers, Mary E.D.; Savani, Bipin N.; Shaw, Bronwen E.
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31–49% amongst HCT recipients. While MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. PMID:27184625
Baker, K S; Chow, E; Steinberger, J
Increasing numbers of hematopoietic cell transplantations (HCTs) are being performed annually with a greater number of long-term survivors. There is increasing concern regarding the late complications and long-term effects that are secondary to treatment exposures before HCT as well as during the HCT conditioning therapy. In both the autologous as well as allogeneic transplant setting, transplant survivors experience mortality rates higher than the general population and the risk of premature cardiovascular (CV)-related death is increased 2.3-fold compared with the general population. The etiology of CV-related deaths in HCT survivors is multifactorial; however, increasing evidence suggests that HCT survivors are at higher risk of developing adverse CV risk factors leading to the development of the metabolic syndrome (a constellation high triglyceride levels, low high-density lipoprotein-cholesterol, hypertension, high fasting blood sugars and increased waist circumference), which then predisposes individuals to risk for early CV-related death. Resistance to insulin is the primary underlying pathophysiologic mechanism that contributes to the development of metabolic syndrome and HCT survivors have been shown to be more likely to develop hypertension, hyperlipidemia and to be insulin resistant. However, the relationship between HCT-related treatment exposures (total body irradiation, high dose chemotherapy, calcineurin inhibitors, steroids, etc) and transplant-related complications (such as GVHD) with the development of CV risk factors and insulin resistance is still in the early stages of investigation. Greater knowledge of the concern regarding CV risk in HCT survivors among both patients and care providers will provide the opportunity for appropriate screening as well as interventions for modifiable risk factors.
Tiwari, Saumya; Reddy, Vijaya B.; Bhargava, Rohit; Raman, Jaishankar
Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR) spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients’ biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures. PMID:25932912
Chan, Winnie; Jones, David; Bosch, Jos A; McPhee, Jamie; Crabtree, Nicola; McTernan, Philip G; Kaur, Okdeep; Inston, Nicholas; Moore, Sue; McClean, Andrew; Harper, Lorraine; Phillips, Anna C; Borrows, Richard
Physical fatigue is debilitating and common among kidney transplant recipients (KTRs). This study investigated the mechanistic aetiology of physical fatigue in this setting through examinations of muscle mass, muscular and cardiovascular function, and perceived exertion. The incidence of physical fatigue, its association with quality of life (QoL), and the predictors of perceived exertion, were evaluated. This single-centre observational cross-sectional study enrolled 55 KTRs. Muscle mass was quantified using dual-energy x-ray absorptiometry. Muscular function was assessed by jumping mechanography. Cardiovascular function (maximal oxygen consumption and oxygen pulse) was estimated during submaximal exercise testing, with perceived exertion determined using age-adjusted Borg scale-ratings. Physical fatigue was measured using Multi-Dimensional Fatigue Inventory-20. QoL was assessed using Medical Outcomes Study Short Form-36. Demographic, clinical, nutritional, psychosocial and behavioural predictors of perceived exertion were assessed. Of clinical importance, increased perceived exertion was the only independent predictor of physical fatigue (P = 0.001), with no association found between physical fatigue and muscular or cardiovascular parameters. Physical fatigue occurred in 22% of KTRs, and negatively impacted on QoL (P < 0.001). Predictors of heightened perception included anxiety (P < 0.05) and mental fatigue (P < 0.05). Perception is a key determinant of physical fatigue in KTRs, paving the way for future interventions.
Jashari, R; Goffin, Y; Vanderkelen, A; Van Hoeck, B; du Verger, A; Fan, Y; Holovska, V; Brahy, O
Established in 1989 in Brussels as an international nonprofit association, the European Homograft Bank (EHB) has been collaborating closely with the transplant coordination of the different centers in Belgium and other European countries. Donor selection is made after discussion of exclusion criteria with the transplant coordinator of the procurement center. EHB collaborates with 15 Belgian, 11 German, 10 French, 10 Swiss, 3 Italian, 3 Dutch, and some other procurement and/or implantation centers. Donor ages range from newborn to 65 years. Tissue preparation, morphologic evaluation, and functional testing are performed under Class A laminar flow. After decontamination in a cocktail of 3 antibiotics (lincomycin, vancomycin, and polymixin B) during 20-48 hours, the tissues cryopreserved with liquid nitrogen to -100 degrees C are stored in vapors of liquid nitrogen below -150 degrees C for a maximum of 5 years. Systematic virologic examination of donor blood is performed for HIV, HTLV, hepatitis B/C, and syphilis, as well as for enteroviruses, Q fever, malaria, and West Nile virus by indication. Bacteriologic examination for anaerobic and aerobic contamination is performed at the different steps of processing. Histologic examination for malignant disease and infection is performed systematically. Indications for implantation are discussed with the requesting surgeon. Transport to the implantation center is carried out safely in a dry shipper at -150 degrees C or in dry ice at -76 degrees C. The EHB received 4,511 hearts and 1,169 batches of arteries from January 1989 to December 2008. The 5,133 heart valves (1,974 aortic, 3,106 pulmonary, and 53 mitral) and 2,066 arterial segments have been prepared and stored; 4,600 cryopreserved valvular (2,717 pulmonary, 1,835 aortic, and 48 mitral) and 1,937 arterial allografts have been distributed for implantation in various European Cardiovascular Centers. EHB is not always able to meet the increased demand for heart valves and
Khan, Munasib; Khan, Arif-Ullah; Najeeb-ur-Rehman; Zafar, Muhammad Abdullah; Hazrat, Ali; Gilani, Anwarul-Hassan
Juniperus excelsa Bieb. is used in folk medicine for lowering blood pressure (BP). Its BP-lowering effect, endothelium-dependent and endothelium-independent vasodilator effects, and cardio-modulatory effect are reported here. The crude extract of J. excelsa (Je.Cr) which tested positive for the presence of anthraquinone, flavonoids, saponins, sterols, terpenes, and tannins induced a dose-dependent (10-300 mg/kg) fall in the arterial BP of anesthetized rats. In isolated rabbit aorta, Je.Cr (0.01-5.0 mg/mL) inhibited high K(+) (80 mM)- and phenylephrine (1 μM)-induced contractions, like that caused by verapamil and papaverine. In endothelium-intact rat aortic preparations, N(ω)-nitro-l-arginine methyl ester hydrochloride-sensitive vasodilator activity was noted from Je.Cr, which also relaxed the endothelium-denuded aorta tissues. In guinea pig atria, Je.Cr initially caused mild cardiac stimulation, followed by inhibition, like that exhibited by papaverine. Je.Cr prolonged the R-R interval in electrocardiogram of rats under anesthesia. These results reveal that cardiovascular effects of J. excelsa are mediated possibly through a combination of Ca(++) antagonism, nitric oxide-modulating mechanism, and phosphodiesterase inhibitory mechanism, which explain its medicinal use in hypertension.
Mansell, Holly; Soliman, Mahmoud; Elmoselhi, Hamdi; Shoker, Ahmed
Background The Major Adverse Cardiovascular Events calculator (CRCRTR-MACE) estimates the burden of cardiovascular risk in renal transplant recipients (RTR). Our recent study of 95 RTR reported the 7-year median risk of cardiovascular events (CVE) to be 9.97%, ranging from 1.93 to 84.27%. Nearly a third (28.4%) of the cohort was above 20% risk for a CVE. Since interleukins (ILs) as part of the inflammatory response may play a role in the pathogenesis of cardiovascular disease (CVD), we extended this study to identify which ILs are associated with high cardiovascular risk in this population. Methods Twenty-two ILs were measured by multiplexed fluorescent bead-based immunoassay in 95 RTR and 56 normal controls. Stepwise analysis after multivariate determination of significant demographic and inflammatory variables was performed between the high and low-CVD risk groups (which were arbitrarily set at scores <10% and ≥20%, respectively). Normalized data was presented as mean ± SD and non-normalized data as median (minimum–maximum). Significance was measured at <0.05. Results 27.5% of the low-risk and 31.3% of the high-risk groups had mean IL levels above the 95 percentile of the normal control levels. In the non-parametric analysis IL-6, 9, 16, 17 and 33 were significantly higher in the high-risk group compared to the control. Univariate analysis (UVA) of the high-risk group identified IL-33 as the only IL that remained significantly higher than the control and low-risk groups (p = 0.000). The percentage of patients with IL-33 levels above the 90 percentile of control value in the low and high-risk groups were 15.6% and 52.0%, respectively (p<0.002). UVA of factors significant to high IL-33 levels included estimated glomerular filtration rate (eGFR), while diabetes mellitus, serum phosphorus, microalbuminuria and age also remained significant in the multivariate analysis. Conclusion Circulating IL-33 level is positively associated with high CRCRTR-MACE score
Kaidar, Maital; Berant, Michael; Krauze, Irit; Cleper, Roxana; Mor, Eitan; Bar-Nathan, Nathan; Davidovits, Miriam
Cardiovascular-related mortality is 100-fold higher in pediatric renal transplant recipients than in the age-matched general population. Seventy-seven post-renal transplant children's charts were reviewed for cardiovascular risk factors at two and six months after transplantation (short term) and at two yr after transplantation and the last follow-up visit (mean 7.14 ± 3.5 yr) (long term). Significant reduction was seen in cardiovascular risk factors prevalence from two months after transplantation to last follow-up respectively: Hypertension from 52.1% to 14%, hypercholesterolemia from 48.7% to 33%, hypertriglyceridemia from 50% to 12.5%, anemia from 29.6% to 18.3%, hyperparathyroidism from 32% to 18.3% and hyperglycemia from 11.7% to 10%, and left ventricular hypertrophy from 25.8% at short term to 15%. There was an increase in the prevalence of obesity from 1.5% to 3.9% and of CKD 3-5 from 4.75% to 24%. The need for antihypertensive treatment decreased from 54% to 42%, and the percentage of patients controlled by one medication rose from 26% to 34%, whereas the percentage controlled by 2, 3, and 4 medications decreased from 21.9%, 5.5%, and 1.4% to 6%, 2%, and 0. Children after renal transplantation appear to have high rates of cardiovascular risk factors, mainly on short-term follow-up. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Psaltopoulou, Theodora; Hatzis, George; Papageorgiou, Nikolaos; Androulakis, Emmanuel; Briasoulis, Alexandros; Tousoulis, Dimitris
It is well known that cardiovascular disease is the leading cause of mortality in the western societies. A number of risk factors such as family history, diabetes, hypertension, obesity, diabetes, smoking and physical inactivity are responsible for a significant proportion of the overall cardiovascular risk. Interestingly, recent data suggest there is a gradient in the incidence, morbidity and mortality of cardiovascular disease across the spectrum of socioeconomic status, as this is defined by educational level, occupation or income. Additionally, dietary mediators seem to play significant role in the pathogenesis of cardiovascular disease, mediating some of the discrepancies in atherosclerosis among different socioeconomic layers. Therefore, in the present article, we aim to review the association between socioeconomic status and cardiovascular disease risk factors and the role of different dietary mediators.
Lee, Jung Pyo; Bae, Eunjin; Kang, Eunjeong; Kim, Hack-Lyoung; Kim, Yong-Jin; Oh, Yun Kyu; Kim, Yon Su; Kim, Young Hoon; Lim, Chun Soo
Background Pre-transplant cardiovascular (CV) risk factors affect the development of CV events even after successful kidney transplantation (KT). However, the impact of pre-transplant CV risk factors on allograft failure (GF) has not been reported. Methods and Findings We analyzed the graft outcomes of 2,902 KT recipients who were enrolled in a multi-center cohort from 1997 to 2012. We calculated the pre-transplant CV risk scores based on the Framingham risk model using age, gender, total cholesterol level, smoking status, and history of hypertension. Vascular disease (a composite of ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) was noted in 6.5% of the patients. During the median follow-up of 6.4 years, 286 (9.9%) patients had developed GF. In the multivariable-adjusted Cox proportional hazard model, pre-transplant vascular disease was associated with an increased risk of GF (HR 2.51; 95% CI 1.66–3.80). The HR for GF (comparing the highest with the lowest tertile regarding the pre-transplant CV risk scores) was 1.65 (95% CI 1.22–2.23). In the competing risk model, both pre-transplant vascular disease and CV risk score were independent risk factors for GF. Moreover, the addition of the CV risk score, the pre-transplant vascular disease, or both had a better predictability for GF compared to the traditional GF risk factors. Conclusions In conclusion, both vascular disease and pre-transplant CV risk score were independently associated with GF in this multi-center study. Pre-transplant CV risk assessments could be useful in predicting GF in KT recipients. PMID:27501048
Fleming, Thomas H.; Spranz, David; Schemmer, Peter; Bruckner, Thomas; Uhle, Florian; Martin, Eike O.; Weigand, Markus A.; Hofer, Stefan
Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration. PMID:23766560
Halloran, Philip F; Chang, Jessica; Famulski, Konrad; Hidalgo, Luis G; Salazar, Israel D R; Merino Lopez, Maribel; Matas, Arthur; Picton, Michael; de Freitas, Declan; Bromberg, Jonathan; Serón, Daniel; Sellarés, Joana; Einecke, Gunilla; Reeve, Jeff
The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.
Brandes, Ralf P; Weissmann, Norbert; Schröder, Katrin
The only known function of the Nox family of NADPH oxidases is the production of reactive oxygen species (ROS). Some Nox enzymes show high tissue-specific expression and the ROS locally produced are required for synthesis of hormones or tissue components. In the cardiovascular system, Nox enzymes are low abundant and function as redox-modulators. By reacting with thiols, nitric oxide (NO) or trace metals, Nox-derived ROS elicit a plethora of cellular responses required for physiological growth factor signaling and the induction and adaptation to pathological processes. The interactions of Nox-derived ROS with signaling elements in the cardiovascular system are highly diverse and will be detailed in this article, which is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System".
Dundon, Benjamin K; Torpey, David K; Nelson, Adam J; Wong, Dennis T L; Duncan, Rae F; Meredith, Ian T; Faull, Randall J; Worthley, Stephen G; Worthley, Matthew I
Despite improvements in survival following renal transplantation, high rates of cardiovascular morbidity and mortality remain. Persistence of arterio-venous fistulae (AVF) may contribute to maladaptive cardiovascular remodeling and poor health outcomes in this cohort. Utilizing recent advances in cardiovascular magnetic resonance imaging (CMR), we prospectively evaluated alterations in cardiac and vascular structure and function six months after elective ligation of AVF, following stable, successful renal transplantation. Eighteen subjects underwent CMR evaluation of cardiac structure and function, aortic distensibility and endothelial function prior to AVF ligation and at six months. At follow-up, while left ventricular ejection fraction was unchanged, mean cardiac output decreased by 15.6% (9.6 ± 2.9 L/min vs. 8.1 ± 2.3 L/min, p = 0.004) and left ventricular mass had regressed by 10% (166 ± 56 g vs. 149 ± 51 g, p = 0.0001). Significant improvements were also noted in right ventricular and biatrial structure and function. Aortic distensibility was unchanged at follow-up, but endothelial dependent vasodilatation had improved (2.5 ± 6.5% vs. 8.0 ± 5.9%, p = 0.04). Elective AVF ligation following successful renal transplantation is associated with improvements in left ventricular mass, right ventricular, and biatrial structure and function. Further randomized studies are warranted to determine the potential clinical improvement following AVF ligation in this cohort. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Levine, Matthew H.
Antibody mediated rejection is a significant clinical problem encountered in a subset of renal transplant recipients. This type of rejection has a variable pathogenesis from the presence of donor specific antibodies with no overt disease to immediate hyperacute rejection and many variations between. Antibody mediated rejection is more common in human leukocyte antigen sensitized patients. In general, transplant graft survival after antibody mediated rejection is jeopardized, with less than 50% graft survival 5 years after this diagnosis. A variety of agents have been utilized singly and in combinations to treat antibody mediated rejection with differing results and significant research efforts are being placed on developing new targets for intervention. These same agents have been used in desensitization protocols with some success. In this review, we describe the biology of antibody mediated rejection, review the available agents to treat this form of rejection, and highlight areas of ongoing and future research into this difficult clinical problem. PMID:21940179
Xia, Yu; Zhu, Kai; Lai, Hao; Lang, Meidong; Xiao, Yan; Lian, Sheng
Mesenchymal stem cell (MSC) transplantation by intramyocardial injection has been proposed as a promising therapy strategy for cardiac repair after myocardium infarction. However, low retention and survival of grafted MSCs hinder its further application. In this study, copolymer with N-isopropylacrylamide/acrylic acid/2-hydroxylethyl methacrylate-poly(ɛ-caprolactone) ratio of 88:9.6:2.4 was bioconjugated with type I collagen to construct a novel injectable thermosensitive hydrogel. The injectable and biocompatible hydrogel-mediated MSC transplantation could enhance the grafted cell survival in the myocardium, which contributed to the increased neovascularization, decreased interstitial fibrosis, and ultimately improved heart function to a significantly greater degree than regular MSC transplantation. We suggest that this novel hydrogel has the potential for future stem cell transplantation. PMID:25432986
Xia, Yu; Zhu, Kai; Lai, Hao; Lang, Meidong; Xiao, Yan; Lian, Sheng; Guo, Changfa; Wang, Chunsheng
Mesenchymal stem cell (MSC) transplantation by intramyocardial injection has been proposed as a promising therapy strategy for cardiac repair after myocardium infarction. However, low retention and survival of grafted MSCs hinder its further application. In this study, copolymer with N-isopropylacrylamide/acrylic acid/2-hydroxylethyl methacrylate-poly(ɛ-caprolactone) ratio of 88:9.6:2.4 was bioconjugated with type I collagen to construct a novel injectable thermosensitive hydrogel. The injectable and biocompatible hydrogel-mediated MSC transplantation could enhance the grafted cell survival in the myocardium, which contributed to the increased neovascularization, decreased interstitial fibrosis, and ultimately improved heart function to a significantly greater degree than regular MSC transplantation. We suggest that this novel hydrogel has the potential for future stem cell transplantation.
Park, M; Katz, R; Shlipak, M G; Weiner, D; Tracy, R; Jotwani, V; Hughes-Austin, J; Gabbai, F; Hsu, C Y; Pfeffer, M; Bansal, N; Bostom, A; Gutierrez, O; Sarnak, M; Levey, A; Ix, J H
Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.
Yang, Ying; Wu, Zhenlong; Meininger, Cynthia J; Wu, Guoyao
Reduced availability of nitric oxide (NO) in the vasculature is a major factor contributing to the impaired action of insulin on blood flow and, therefore, insulin resistance in obese and diabetic subjects. Available evidence shows that vascular insulin resistance plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Interestingly, increased concentrations of L-leucine in the plasma occur in obese humans and other animals with vascular dysfunction. Among branched-chain amino acids, L-leucine is unique in inhibiting NO synthesis from L-arginine in endothelial cells and may modulate cardiovascular homeostasis in insulin resistance. Results of recent studies indicate that L-leucine is an activator of glutamine:fructose-6-phosphate aminotransferase (GFAT), which is the first and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, L-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells. We propose that reducing circulating levels of L-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects. Such means may include dietary supplementation with either α-ketoglutarate to enhance the catabolism of L-leucine in the small intestine and other tissues or with N-ethyl-L-glutamine to inhibit GFAT activity in endothelial cells. Preventing leucine-induced activation of GFAT by nutritional supplements or pharmaceutical drugs may contribute to improved cardiovascular function by enhancing vascular NO synthesis.
Matoba, Tetsuya; Koga, Jun-Ichiro; Nakano, Kaku; Egashira, Kensuke; Tsutsui, Hiroyuki
Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of drug delivery systems (DDS) includes micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and crystalline metals. Nano-DDS modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as retard excretion, vascular permeability, and incorporation by mononuclear phagocyte systems, which constitute the 'passive-targeting' property of nano-DDS. These properties of nano-DDS are applicable to inflammatory diseases including atherosclerosis. Atherosclerotic plaque destabilization and rupture account for the majority of acute myocardial infarction, for which inflammatory monocytes and macrophages play critical roles. In our experience, polymeric nanoparticles have been delivered to inflammatory monocytes and macrophages in an atherosclerotic mouse model. Nano-DDS loaded with pioglitazone reduced Ly6C(high) inflammatory monocytes and increased Ly6C(low) non-inflammatory monocytes in the peripheral blood, and induced M2 macrophage-associated genes in the aorta. Pioglitazone-nanoparticles finally stabilized atherosclerotic plaques assessed by a decrease in the number of buried fibrous caps in the plaque. Application of nano-DDS is a unique and promising approach to prevent life-threatening cardiovascular events including acute myocardial infarction by regulating inflammation in the cardiovascular system. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Morozumi, Kunio; Takeda, Asami; Otsuka, Yasuhiro; Horike, Keiji; Gotoh, Norihiko; Narumi, Shunji; Watarai, Yoshihiko; Kobayashi, Takaaki
The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure.
Clinical characteristics and in hospital outcomes of heart transplant recipients with allograft vasculopathy undergoing percutaneous coronary intervention: Insights from the National Cardiovascular Data Registry.
Dasari, Tarun W; Saucedo, Jorge F; Krim, Selim; Alkhouli, Mohamad; Fonarow, Gregg C; Alvarez, Rene; Ibrahim, Homam; Dai, David; Wang, Tracy Y; Costa, Marco; Lindenfeld, JoAnn; Messenger, John C
Cardiac allograft vasculopathy is a major cause of morbidity and mortality following heart transplantation. Large multicenter studies evaluating the clinical characteristics and inhospital outcomes of heart transplant recipients undergoing percutaneous coronary intervention (PCI) are lacking. To evaluate the clinical characteristics, treatment patterns and inhospital outcomes of heart transplant recipients undergoing PCI compared to general population. We analyzed 1,897,328 patients from the National Cardiovascular Data Registry CathPCI registry who underwent PCI of at least 1 native vessel between July 2009 and December 2013 from 1,477 centers, of which 542 patients (0.03%) were heart transplant recipients. Clinical characteristics were evaluated and, after 1:4 propensity matching, inhospital outcomes were compared between 538 heart transplant patients and 2,128 non-transplant patients. Transplant recipients undergoing PCI had a higher prevalence of diabetes, dyslipidemia and peripheral vascular disease; lower prevalence of angina, acute coronary syndrome, abnormal noninvasive functional study, and type C coronary lesions compared to the non-transplant PCI population. After propensity matching, all-cause inhospital mortality was similar between transplant and non-transplant groups (1.3% vs 1.0%; OR, 1.21; 95% CI, 0.54-2.67). This is the largest series to date outlining the characteristics of heart transplant recipients undergoing PCI. Similar inhospital outcomes were noted in heart transplant recipients compared to the general population. Further studies evaluating long-term outcomes are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.
Slopen, Natalie; Chen, Ying; Guida, Jennifer L; Albert, Michelle A; Williams, David R
In 2010, the American Heart Association introduced a new conceptual framework to encourage a focus on primary prevention and provided a definition for "ideal cardiovascular health". In this study we examined the relationship between positive childhood experience and ideal cardiovascular health in mid-life, and the extent to which education, depression, and social support mediate this association. Data are from participants in the Midlife and Aging in the United States study who completed a clinic-based assessment of health (N=1255, aged 34-84years, 2004-2005). We created a positive childhood experiences index based on retrospective report of eight childhood experiences, and calculated a continuous ideal cardiovascular health score for each participant following the American Heart Association's definition of ideal, intermediate and poor cardiovascular health across seven health metrics (analyses conducted in 2015-2016). Positive childhood experiences were associated with ideal cardiovascular health: compared to individuals in the lowest quartile, respondents in the second, third, and fourth quartile of positive childhood experiences scored 0.42 (standard error (SE)=0.18), 0.92 (SE=0.18) and 1.04 (SE=0.18) units higher on ideal cardiovascular health, adjusting for age, sex, and race. Respondent's education, depression status, and social support fully mediated the direct effect of positive childhood experiences on ideal cardiovascular health, with the largest indirect effect for education. These results suggest that positive childhood experiences are associated with ideal cardiovascular health in midlife. Strategies to promote cardiovascular wellbeing may benefit from a focus on social interventions early in life; educational attainment, major depression, and social support may represent key points of intervention.
Mcritchie, R. J.; Vatner, S. F.; Patrick, T. A.; Braunwald, E.; Boettcher, D.; Heyndrickx, G. R.
Experiments were conducted to define the role of the major arterial baroreceptors during moderately severe exercise by comparing the responses of untethered conscious dogs instrumented for the measurement of aortic pressure and cardiac output with those of dogs with total arterial baroreceptor denervation. The reflex heart rate responses to intravenous bolus doses of methoxamine were also examined in intact animals, both at rest and during exercise. Methoxamine is found to cause striking bradycardia at rest, but little bradycardia during exercise. Experimental findings suggest that the arterial baroreceptor reflex is normally inhibited during severe exercise and therefore plays little role in modulating the cardiovascular response to exercise.
Mcritchie, R. J.; Vatner, S. F.; Patrick, T. A.; Braunwald, E.; Boettcher, D.; Heyndrickx, G. R.
Experiments were conducted to define the role of the major arterial baroreceptors during moderately severe exercise by comparing the responses of untethered conscious dogs instrumented for the measurement of aortic pressure and cardiac output with those of dogs with total arterial baroreceptor denervation. The reflex heart rate responses to intravenous bolus doses of methoxamine were also examined in intact animals, both at rest and during exercise. Methoxamine is found to cause striking bradycardia at rest, but little bradycardia during exercise. Experimental findings suggest that the arterial baroreceptor reflex is normally inhibited during severe exercise and therefore plays little role in modulating the cardiovascular response to exercise.
Reddy, Sahadev T; Thai, Ngoc L; Fakhri, Asghar A; Oliva, Jose; Tom, Kusum B; Dishart, Michael K; Doyle, Mark; Yamrozik, June A; Williams, Ronald B; Grant, Saundra B; Poydence, Jacqueline; Shah, Moneal; Singh, Anil; Nathan, Swami; Biederman, Robert W W
Preoperative cardiovascular risk stratification in orthotopic liver transplantation candidates has proven challenging due to limitations of current noninvasive modalities. Additionally, the preoperative workup is logistically cumbersome and expensive given the need for separate cardiac, vascular, and abdominal imaging. We evaluated the feasibility of a "one-stop shop" in a magnetic resonance suite, performing assessment of cardiac structure, function, and viability, along with simultaneous evaluation of thoracoabdominal vasculature and liver anatomy. In this pilot study, patients underwent steady-state free precession sequences and stress cardiac magnetic resonance (CMR), thoracoabdominal magnetic resonance angiography, and abdominal magnetic resonance imaging (MRI) on a standard MRI scanner. Pharmacologic stress was performed using regadenoson, adenosine, or dobutamine. Viability was assessed using late gadolinium enhancement. Over 2 years, 51 of 77 liver transplant candidates (mean age, 56 years; 35% female; mean Model for End-stage Liver Disease score, 10.8; range, 6-40) underwent MRI. All referred patients completed standard dynamic CMR, 98% completed stress CMR, 82% completed late gadolinium enhancement for viability, 94% completed liver MRI, and 88% completed magnetic resonance angiography. The mean duration of the entire study was 72 min, and 45 patients were able to complete the entire examination. Among all 51 patients, 4 required follow-up coronary angiography (3 for evidence of ischemia on perfusion CMR and 1 for postoperative ischemia), and none had flow-limiting coronary disease. Nine proceeded to orthotopic liver transplantation (mean 74 days to transplantation after MRI). There were six ascertained mortalities in the nontransplant group and one death in the transplanted group. Explant pathology confirmed 100% detection/exclusion of hepatocellular carcinoma. No complications during CMR examination were encountered. In this proof-of-concept study, it
Lindsay, Susan L; Riddell, John S; Barnett, Susan C
Damage to the brain and spinal cord leads to permanent functional disability because of the very limited capacity of the central nervous system (CNS) for repair. Transplantation of cells into regions of CNS damage represents one approach to enhancing this repair. At present, the ideal cell type for transplant-mediated repair has not been identified but autologous transplantation would be advantageous. Olfactory tissue, in part because of its capacity for regeneration, has emerged as a promising source of cells and several clinical centers are using olfactory cells or tissues in the treatment of CNS damage. Until now, the olfactory ensheathing cell, a specialized glial cell of the olfactory system has been the main focus of attention. Transplants of this cell have been shown to have a neuroprotective function, support axonal regeneration, and remyelinate demyelinated axons. However, the olfactory mucosa is a heterogeneous tissue, composed of a variety of cells supporting both its normal function and its regenerative capacity. It is therefore possible that it contains several cell types that could participate in CNS repair including putative stem cells as well as glia. Here we review the cellular composition of the olfactory tissue and the evidence that equivalent cell types exist in both rodent and human olfactory mucosa suggesting that it is potentially a rich source of autologous cells for transplant-mediated repair of the CNS.
Wen, Hairuo; Gwathmey, Judith K; Xie, Lai-Hua
Angiotensin II (Ang II), an endogenous peptide hormone, plays critical roles in the pathophysiological modulation of cardiovascular functions. Ang II is the principle effector of the renin-angiotensin system for maintaining homeostasis in the cardiovascular system, as well as a potent stimulator of NAD(P)H oxidase, which is the major source and primary trigger for reactive oxygen species (ROS) generation in various tissues. Recent accumulating evidence has demonstrated the importance of oxidative stress in Ang II-induced heart diseases. Here, we review the recent progress in the study on oxidative stress-mediated effects of Ang II in the cardiovascular system. In particular, the involvement of Ang II-induced ROS generation in arrhythmias, cell death/heart failure, ischemia/reperfusion injury, cardiac hypertrophy and hypertension are discussed. Ca(2+)/calmodulin-dependent protein kinase II is an important molecule linking Ang II, ROS and cardiovascular pathological conditions.
Rao, Sumangala P; Dunbar, Joseph C
The central nervous system (CNS) histaminergic neurons have been shown to regulate feeding behavior and are a target of leptin in the brain. The present study aimed to examine the involvement of the histaminergic system in the leptin-mediated regulation of cardiovascular dynamics. We investigated the cardiovascular responses to the CNS administration of histamine, leptin and alpha-melanocyte stimulating hormone (alpha-MSH) both in the presence and absence of the histamine H1 antagonist, chlorpheniramine. The intracerebroventricular (i.c.v.) administration of histamine resulted in an immediate increase in both mean arterial pressure (MAP) and heart rate (HR) and vasoconstricted the iliac, renal and superior mesenteric vessels. The i.c.v. pretreatment with chlorpheniramine attenuated the histamine-induced increase in MAP, HR and decreased vascular conductance. The i.c.v. administration of leptin increased MAP and HR and decreased vascular conductance. The i.c.v. pretreatment with chlorpheniramine decreased the leptin-induced increase in MAP and the leptin-mediated iliac vasoconstriction. The i.c.v. administration of alpha-MSH also increased MAP, HR and decreased vascular conductance. However, pretreatment with chlorpheniramine did not influence the central alpha-MSH-mediated increase in MAP, HR and decreased vascular conductance. These results indicate that the central histaminergic system mediated by H1 receptors have a role in the central signaling pathway and is involved in leptin's regulation of cardiovascular dynamics. It appears that leptin directly or indirectly stimulates histaminergic neurons that lead to increased cardiovascular activity.
Kim, Miae; Martin, Spencer T; Townsend, Keri R; Gabardi, Steven
Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients.
Jeon, Hee Jung; Kim, Clara Tammy; An, Jung Nam; Lee, Hajeong; Kim, Hyosang; Park, Su-Kil; Joo, Kwon Wook; Lim, Chun Soo; Jung, In Mok; Ahn, Curie; Kim, Yon Su; Kim, Young Hoon; Lee, Jung Pyo
In the general population, proteinuria is associated with progression to kidney failure, cardiovascular disease, and mortality. Here, we analyzed the effects of proteinuria on outcomes in kidney transplant recipients. We performed a retrospective, multi-centre cohort study involving 2047 recipients to evaluate the effects of post-transplant proteinuria on adverse cardiovascular events, graft failure, and mortality. Patients were classified into two groups according to their levels of proteinuria: patients without proteinuria (<150 mg/day, n = 1113) and proteinuric patients (≥ 150 mg/day, n = 934). Multivariate Cox hazard model was conducted with using the maximal proteinuria as time-varying covariate. During a median 55.3-month (range, 0.6-167.1) follow-up, there were 50 cases of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, or coronary revascularization), 115 cases of graft failure, and 52 patient deaths. In multivariate Cox regression with time-varying covariate, proteinuric recipients were significantly associated with major adverse cardiac events (hazard ratio [HR] 8.689, 95% confidence interval [CI] 2.929-25.774, P < 0.001) compared to those without proteinuria. Recipients with proteinuria showed significantly higher incidences of acute rejection (23.1% vs. 9.4%, P < 0.001) and graft failure rate (HR 6.910, 95% CI 3.270-14.601, P < 0.001). In addition, mortality rate was also significantly higher in patients with proteinuria (HR 6.815, 95% CI 2.164-21.467, P = 0.001). Post-transplant proteinuria correlates with adverse cardiovascular events, graft failure, and mortality. Therefore, proteinuria should be evaluated and managed to improve the outcomes of renal recipients. © 2015 Asian Pacific Society of Nephrology.
Al Nasser, Yasser; Moura, Marta C; Mertens, Luc; McCrindle, Brian W; Parekh, Rulan S; Ng, Vicky L; Church, Peter C; Mouzaki, Marialena
CV disease is a major cause of morbidity and mortality following solid organ transplantation in adults. While the prevalence of multiple cardiometabolic risk factors is increased in pediatric solid organ transplant recipients, it is not clear whether they have subclinical CV changes. cIMT, central pWV, and CAC are indicative of subclinical CV disease, and, in adults, predict future CV events. The objective of this systematic review and meta-analysis was to investigate the prevalence of subclinical CV changes, as measured by cIMT, pWV, and CAC among pediatric solid organ transplant recipients. We searched MEDLINE(®) and EMBASE and conducted meta-analysis for studies that evaluated cIMT, central pWV, and CAC among pediatric solid organ transplant recipients (kidney, lung, intestine and liver). The search identified nine eligible studies that included a total of 259 patients and 685 healthy controls. Eight studies reported on kidney transplant recipients and one study on a combined cohort of kidney and liver transplant recipients. The mean cIMT of transplant recipients was significantly higher than that of healthy controls (mean difference = 0.05 mm, 95% CI 0.02-0.07; p < 0.0001) with an estimated pooled prevalence of elevated cIMT of 56.0% (95% CI 17.0-95.0). The one study that assessed pWV showed increased vascular stiffness in transplant recipients compared to healthy controls. No studies assessing for CAC were found. There were limited data regarding subclinical CV disease following pediatric solid organ transplantation. In conclusion, kidney transplantation in childhood is associated with a higher prevalence of subclinical CV changes compared to healthy children. Longitudinal studies are needed to determine whether children have increased CV morbidity and mortality after transplantation.
Sellarés, J; Reeve, J; Loupy, A; Mengel, M; Sis, B; Skene, A; de Freitas, D G; Kreepala, C; Hidalgo, L G; Famulski, K S; Halloran, P F
Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.
Leberkühne, Lynn J; Ebtehaj, Sanam; Dimova, Lidiya G; Dikkers, Arne; Dullaart, Robin P F; Bakker, Stephan J L; Tietge, Uwe J F
Protection of low-density lipoproteins (LDL) against oxidative modification is a key anti-atherosclerotic property of high-density lipoproteins (HDL). This study evaluated the predictive value of the HDL antioxidative function for cardiovascular mortality, all-cause mortality and chronic graft failure in renal transplant recipients (RTR). The capacity of HDL to inhibit native LDL oxidation was determined in vitro in a prospective cohort of renal transplant recipients (RTR, n = 495, median follow-up 7.0 years). The HDL antioxidative functionality was significantly higher in patients experiencing graft failure (57.4 ± 9.7%) than in those without (54.2 ± 11.3%; P = 0.039), while there were no differences for cardiovascular and all-cause mortality. Specifically glomerular filtration rate (P = 0.001) and C-reactive protein levels (P = 0.006) associated independently with antioxidative functionality in multivariate linear regression analyses. Cox regression analysis demonstrated a significant relationship between antioxidative functionality of HDL and graft failure in age-adjusted analyses, but significance was lost following adjustment for baseline kidney function and inflammatory load. No significant association was found between HDL antioxidative functionality and cardiovascular and all-cause mortality. This study demonstrates that the antioxidative function of HDL (i) does not predict cardiovascular or all-cause mortality in RTR, but (ii) conceivably contributes to the development of graft failure, however, not independent of baseline kidney function and inflammatory load. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Overview of Cardiovascular research which addresses risks of space flight, including adaptive changes to the cephalad fluid shift (such as reduced circulating blood volume), potential for heart rhy...
Ozbek, C; Sever, K; Demirhan, O; Mansuroglu, D; Kurtoglu, N; Ugurlucan, M; Sevmis, S; Karakayali, H
- group, whereas the length of follow up was significantly higher in the Tp+ group. The use of inotropic agents was significantly higher in the Tp- group. A logistic regression analysis was made to determine the factors affecting mortality. Revision (p=0.013), blood transfusion (p=0.017), ventilation time (p=0.019), and length of stay in the intensive care unit (p=0.009) were found as predictors of mortality. Survival rates at years 1, 2 and 3 were 86.1%, 81%, 77.5% in the Tp- group, and 96.0%, 96.3%, 90.4% in the Tp+ group. Median survival rate was 41.35±2.02 in the Tp- group, and 49.64±1.59 in the Tp+ group which was significantly higher compared to the Tp- group (p=0.048). Chronic renal failure is among the perioperative risk factors for patients undergoing open heart surgery. Transplantation is still an important health issue due to insufficiency of available transplant organs. Patients with chronic renal failure are well known to have higher risks for coronary artery disease. A radical solution of the cardiovascular system problems prior to kidney transplantation seems to have a significant contribution to the post transplant survival.
Xue, Wenrui; Zhang, Qiang; Xu, Yue; Wang, Wei; Zhang, Xiaodong; Hu, Xiaopeng
The therapeutic success of renal transplantation has been largely attributable to the development of effective and balanced immunosuppressive treatment regimens. This study provides a meta-analysis of a series of randomized controlled trials that compared the effects of tacrolimus and cyclosporine on metabolic syndrome (MetS) and cardiovascular risk factors after renal transplantation. We searched various electronic databases and bibliographies, including MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE, for relevant studies published prior to October 2012. Our meta-analysis included five randomized controlled trials that examined a total of 923 patients. The tacrolimus group and the cyclosporine group exhibited no significant differences in MetS incidence after renal transplantation; risk ratio (RR): 1.06, 95% confidence interval (CI): 0.73-1.55, P = 0.76. Cyclosporine treatment was associated with a higher incidence of hyperlipidemia (RR: 0.50, 95% CI: 0.39-0.64, P < 0.01). Although there were no statistically significant differences, cyclosporine treatment was associated with a higher incidence of hypertension (RR: 0.91, 95% CI: 0.83-1.00, P = 0.06) after renal transplantation compared to tacrolimus treatment, and tacrolimus treatment was associated with a higher incidence of diabetes after renal transplantation (RR: 1.79, 95% CI: 0.98-3.27, P = 0.06) compared to cyclosporine treatment. Compared to tacrolimus treatment, cyclosporine treatment was associated with a higher incidence of hyperlipidemia. Future large-scale studies are expected to be conducted to further confirm our findings.
Pape, Lars; Becker, Jan U; Immenschuh, Stephan; Ahlenstiel, Thurid
Acute antibody-mediated rejection is a diagnostic challenge in renal transplantation medicine. However, it is an important diagnosis to make, since chronic antibody-mediated rejection (CAMR) is the main cause of long-term graft loss. Antibody-mediated rejection is diagnosed by detecting donor-specific antibodies (DSAs) in the blood in combination with observing typical histomorphological signs in kidney biopsy, as described in the Banff classification. Therapy is based on the removal of DSAs by administering intravenous immunoglobulins (IVIGs), plasmapheresis, or immunoadsorption. Reoccurrence of antibodies is diminished by the use of rituximab, increased immunosuppression, and in some cases additional experimental substances. A combination of these techniques has been shown to be successful in the majority of cases of acute and chronic antibody-mediated rejection. Routine DSA monitoring is warranted for early detection of antibody-mediated rejection.
Lee, Charlotte A; Dhawan, Anil; Smith, Richard A; Mitry, Ragai R; Fitzpatrick, Emer
Hepatocyte transplantation (HT) is emerging as a promising alternative to orthotopic liver transplantation (OLT) in patients with certain liver-based metabolic disease and acute liver failure. Hepatocytes are generally infused into the portal venous system, from which they migrate into the liver cell plates of the native organ. One of the major hurdles to the sustained success of this therapy is early cell loss, with up to 70% of hepatocytes lost immediately following infusion. This is largely thought to be due to the instant blood-mediated inflammatory reaction (IBMIR), resulting in the activation of complement and coagulation pathways. Transplanted hepatocytes produce and release tissue factor (TF), which activates the coagulation pathway, leading to the formation of thrombin and fibrin clots. Thrombin can further activate a number of complement proteins, leading to the activation of the membrane attack complex (MAC) and subsequent hepatocyte cell death. Inflammatory cells including granulocytes, monocytes, Kupffer cells, and natural killer (NK) cells have been shown to cluster around transplanted hepatocytes, leading to their rapid clearance shortly after transplantation. Current research aims to improve cell engraftment and prevent early cell loss. This has been proven successful in vitro using pharmacological interventions such as melagatran, low-molecular-weight dextran sulphate, and N-acetylcysteine (NAC). Effective inhibition of IBMIR would significantly improve hepatocyte engraftment, proliferation, and function, providing successful treatment for patients with liver-based metabolic diseases.
Bézie, Séverine; Picarda, Elodie; Ossart, Jason; Tesson, Laurent; Usal, Claire; Renaudin, Karine; Anegon, Ignacio; Guillonneau, Carole
Cytokines and metabolic pathway-controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8+CD45RClo Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8+CD45RClo Tregs and human FOXP3+CD45RCloCD8+ and CD4+ Tregs. IL-34 was involved in the suppressive function of both CD8+ and CD4+ Tregs and markedly inhibited alloreactive immune responses. Additionally, in a rat cardiac allograft model, IL-34 potently induced transplant tolerance that was associated with a total inhibition of alloantibody production. Treatment of rats with IL-34 promoted allograft tolerance that was mediated by induction of CD8+ and CD4+ Tregs. Moreover, these Tregs were capable of serial tolerance induction through modulation of macrophages that migrate early to the graft. Finally, we demonstrated that human macrophages cultured in the presence of IL-34 greatly expanded CD8+ and CD4+ FOXP3+ Tregs, with a superior suppressive potential of antidonor immune responses compared with non-IL-34-expanded Tregs. In conclusion, we reveal that IL-34 serves as a suppressive Treg-specific cytokine and as a tolerogenic cytokine that efficiently inhibits alloreactive immune responses and mediates transplant tolerance.
Khan, Mohammad Afzal
T regulatory cells (Tregs) play a vital role in suppressing heightened immune response, and thereby promote a state of immunological tolerance. Tregs modulate both innate and adaptive immunity, which makes them potential candidates for cell-based immunotherapy in the suppression of uncontrolled activation of graft-specific inflammatory cells and toxic mediators. Graft-specific inflammatory cells (T effector cells) and other inflammatory mediators (immunoglobulins, active complement mediators) are mainly responsible for graft vascular deterioration followed by acute/chronic rejection. Treg-mediated immunotherapy is under investigation to induce allospecific tolerance in various ongoing clinical trials in organ transplant recipients. Treg immunotherapy shows promising results; however, key issues regarding Treg immunotherapy remain unresolved, including the mechanism of action and specific Treg cell phenotypes responsible for a state of tolerance. This review highlights the involvement of various subsets of Tregs during immune suppression, the novelty of Treg functions, effects on angiogenesis, emerging technologies for effective Treg expansion, and plasticity and safety associated with clinical applications. Altogether, this information will assist in designing single/combined Treg-mediated therapies for successful clinical trials in solid organ transplantations. PMID:27878210
Stegall, Mark D; Chedid, Marcio F; Cornell, Lynn D
Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation.
The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation.
Berry, Gerald J; Burke, Margaret M; Andersen, Claus; Bruneval, Patrick; Fedrigo, Marny; Fishbein, Michael C; Goddard, Martin; Hammond, Elizabeth H; Leone, Ornella; Marboe, Charles; Miller, Dylan; Neil, Desley; Rassl, Doris; Revelo, Monica P; Rice, Alexandra; Rene Rodriguez, E; Stewart, Susan; Tan, Carmela D; Winters, Gayle L; West, Lori; Mehra, Mandeep R; Angelini, Annalisa
During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers. Copyright © 2013 International Society for Heart and Lung Transplantation. All rights reserved.
Belin de Chantemèle, Eric J.; Mintz, James D.; Rainey, William E.; Stepp, David W.
Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate (HR), stroke volume, cardiac output and plasma aldosterone levels but not blood pressure (BP). As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin angiotensin aldosterone system (RAAS). Tachyphlyaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. While infusion of leptin in HFD mice had no effect on HR or BP, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature and aldosterone production persists in obesity. BP effects in response to leptin may be limited by a tachyphylactic response in the circulation suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity. PMID:21690486
Fukuda, Daiju; Aikawa, Masanori
Cardiometabolic disease, a global health threat, has been linked to chronic inflammation, in which activated macrophages play a key role. Macrophages are highly heterogeneous hematopoietic cells found in nearly every tissue in the body. Various stimuli recruit monocytes into the cardiovascular system and metabolic organs, where they differentiate to macrophages, and activate these pro-inflammatory phagocytes, leading to the initiation and development of inflammation in these organs. Key regulators of macrophage activation therefore may serve as therapeutic targets for cardiometabolic disease. The Notch signaling pathway, involving 5 ligands and 4 receptors, regulates the differentiation of various cell types during development, and also contributes to the disease processes in adults. We found that the Notch ligand delta-like 4 (Dll4) activates macrophages in vitro as determined by the induction of genes and pathways associated with cardiovascular and metabolic disorders. Our recent study demonstrated in vivo that blockade of Dll4 by a neutralizing antibody attenuates key features typical of cardiovascular and metabolic diseases, such as accumulation of activated macrophages in arteries and fat; chronic atherosclerosis; arterial and valvular calcification; insulin resistance; and fatty liver. These results suggest that Dll4-mediated Notch signaling participates in the shared disease mechanisms for cardiovascular and metabolic disorders. This review summarizes the role of macrophages and Dll4/Notch signaling in the development of inflammation in both the cardiovascular system and metabolic organs.
Fukuda, Daiju; Aikawa, Masanori
Cardiometabolic disease, a global health threat, has been linked to chronic inflammation, in which activated macrophages play a key role. Macrophages are highly heterogeneous hematopoietic cells found in nearly every tissue in the body. Various stimuli recruit monocytes into cardiovascular system and metabolic organs, where they differentiate to macrophages, and activate these pro-inflammatory phagocytes, leading to the initiation and development of inflammation in these organs. Key regulators of macrophage activation therefore may serve as therapeutic targets for the cardiometabolic disease. The Notch signaling pathway, involving five ligands and four receptors, regulates the differentiation of various cell types during development, and also contributes to the disease processes in adults. We found that the Notch ligand delta-like 4 (Dll4) activates macrophages in vitro as determined by the induction of genes and pathways associated with cardiovascular and metabolic disorders. Our recent study demonstrated in vivo that blockade of Dll4 by a neutralizing antibody attenuates key features typical of cardiovascular and metabolic diseases, such as accumulation of activated macrophages in arteries and fat, chronic atherosclerosis, arterial and valvular calcification, insulin resistance, and fatty liver. These results suggest that Dll4-mediated Notch signaling participates in the shared disease mechanisms for cardiovascular and metabolic disorders. This review summarizes the role of macrophages and Dll4/Notch signaling in the development of inflammation in both cardiovascular system and metabolic organs. PMID:24025398
Li, Faith C H; Yen, Jiin-Cherng; Chan, Samuel H H; Chang, Alice Y W
Whereas sudden death, most often associated with cardiovascular collapse, occurs in abusers of the psychostimulant methamphetamine (METH), the underlying mechanism is much less understood. The demonstration that successful resuscitation of an arrested heart depends on maintained functionality of the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of stable blood pressure, suggests that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse. We tested the hypothesis that cessation of brain stem cardiovascular regulation because of a loss of functionality in RVLM mediated by bioenergetics failure and oxidative stress underlies the cardiovascular collapse elicited by lethal doses of METH. Survival rate, cardiovascular responses and biochemical or morphological changes in RVLM induced by intravenous administration of METH in Sprague-Dawley rats were investigated. High doses of METH induced significant mortality within 20 min that paralleled concomitant the collapse of arterial pressure or heart rate and loss of functionality in RVLM. There were concurrent increases in the concentration of METH in serum and ventrolateral medulla, along with tissue anoxia, cessation of microvascular perfusion and necrotic cell death in RVLM. Furthermore, mitochondrial respiratory chain enzyme activity or electron transport capacity and ATP production in RVLM were reduced, and mitochondria-derived superoxide anion level was augmented. All those detrimental physiological and biochemical events were reversed on microinjection into RVLM of a mobile electron carrier in the mitochondrial respiratory chain, coenzyme Q10; a mitochondria-targeted antioxidant and superoxide anion scavenger, Mito-TEMPO; or an oxidative stress-induced necrotic cell death inhibitor, IM-54. We conclude that sustained anoxia and cessation of local blood flow that leads to bioenergetics failure and oxidative stress because of
Li, Faith C. H.; Yen, Jiin-Cherng; Chan, Samuel H. H.; Chang, Alice Y. W.
Background Whereas sudden death, most often associated with cardiovascular collapse, occurs in abusers of the psychostimulant methamphetamine (METH), the underlying mechanism is much less understood. The demonstration that successful resuscitation of an arrested heart depends on maintained functionality of the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of stable blood pressure, suggests that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse. We tested the hypothesis that cessation of brain stem cardiovascular regulation because of a loss of functionality in RVLM mediated by bioenergetics failure and oxidative stress underlies the cardiovascular collapse elicited by lethal doses of METH. Methodology/Principal Findings Survival rate, cardiovascular responses and biochemical or morphological changes in RVLM induced by intravenous administration of METH in Sprague-Dawley rats were investigated. High doses of METH induced significant mortality within 20 min that paralleled concomitant the collapse of arterial pressure or heart rate and loss of functionality in RVLM. There were concurrent increases in the concentration of METH in serum and ventrolateral medulla, along with tissue anoxia, cessation of microvascular perfusion and necrotic cell death in RVLM. Furthermore, mitochondrial respiratory chain enzyme activity or electron transport capacity and ATP production in RVLM were reduced, and mitochondria-derived superoxide anion level was augmented. All those detrimental physiological and biochemical events were reversed on microinjection into RVLM of a mobile electron carrier in the mitochondrial respiratory chain, coenzyme Q10; a mitochondria-targeted antioxidant and superoxide anion scavenger, Mito-TEMPO; or an oxidative stress-induced necrotic cell death inhibitor, IM-54. Conclusion We conclude that sustained anoxia and cessation of local blood flow that leads to
Salcido-Ochoa, Francisco; Hue, Susan Swee-Shan; Peng, Siyu; Fan, Zhaoxiang; Li, Reiko Lixiang; Iqbal, Jabed; Allen, John Carson; Loh, Alwin Hwai Liang
To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes. A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively. In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3(+) regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3(+) regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss. Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.
Tchounwou, Paul B.
MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS-) mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s) of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA-regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS-mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling. PMID:26064773
Chang, Ying-Hua; Ye, Lei; Cai, Wenxuan; Lee, Yoonkyu; Guner, Huseyin; Lee, Youngsook; Kamp, Timothy J.; Zhang, Jianyi; Ge, Ying
Intramyocardial transplantation of cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs) derived from human induced pluripotent stem cells (hiPSCs) has beneficial effects on the post-infarction heart. However, the mechanisms underlying the functional improvements remain undefined. We employed large-scale label-free quantitative proteomics to identify proteins that were differentially regulated following cellular transplantation in a swine model of myocardial infarction (MI). We identified 22 proteins that were significantly up-regulated after trilineage cell transplantation compared to both MI and Sham groups. Among them, 12 proteins, including adenylyl cyclase-associated protein 1 and tropomodulin-1, are associated with positive regulation of muscular contraction whereas 11 proteins, such as desmoplakin and zyxin, are involved in embryonic and muscular development and regeneration. Moreover, we identified 21 proteins up-regulated and another 21 down-regulated in MI, but reversed after trilineage cell transplantation. Proteins up-regulated after MI but reversed by transplantation are related to fibrosis and apoptosis. Conversely, proteins down-regulated in MI but restored after cell therapy are regulators of protein nitrosylation. Our results show that the functionally beneficial effects of trilineage cell therapy are accompanied by differential regulation of protein expression in the recipient myocardium, which may contribute to the improved cardiac function. PMID:26033914
Chang, Ying-Hua; Ye, Lei; Cai, Wenxuan; Lee, Yoonkyu; Guner, Huseyin; Lee, Youngsook; Kamp, Timothy J; Zhang, Jianyi; Ge, Ying
Intramyocardial transplantation of cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs) derived from human induced pluripotent stem cells (hiPSCs) has beneficial effects on the post-infarction heart. However, the mechanisms underlying the functional improvements remain undefined. We employed large-scale label-free quantitative proteomics to identify proteins that were differentially regulated following cellular transplantation in a swine model of myocardial infarction (MI). We identified 22 proteins that were significantly up-regulated after trilineage cell transplantation compared to both MI and Sham groups. Among them, 12 proteins, including adenylyl cyclase-associated protein 1 and tropomodulin-1, are associated with positive regulation of muscular contraction whereas 11 proteins, such as desmoplakin and zyxin, are involved in embryonic and muscular development and regeneration. Moreover, we identified 21 proteins up-regulated and another 21 down-regulated in MI, but reversed after trilineage cell transplantation. Proteins up-regulated after MI but reversed by transplantation are related to fibrosis and apoptosis. Conversely, proteins down-regulated in MI but restored after cell therapy are regulators of protein nitrosylation. Our results show that the functionally beneficial effects of trilineage cell therapy are accompanied by differential regulation of protein expression in the recipient myocardium, which may contribute to the improved cardiac function.
Haarala, A; Kähönen, M; Lehtimäki, T; Aittoniemi, J; Jylhävä, J; Hutri-Kähönen, N; Taittonen, L; Laitinen, T; Juonala, M; Viikari, J; Raitakari, O T; Hurme, M
Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flow-mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24-39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P < 0·001) and systolic (P = 0·053) and diastolic (P = 0·002) blood pressure elevation, and associated inversely with flow-mediated dilation (P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0·029) and diastolic (P = 0·004) blood pressure elevation and flow-mediated dilation (P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.
Zhao, Mengxin; Xue, Kai; Wang, Feng; Liu, Shanshan; Bai, Shijie; Sun, Bo; Zhou, Jizhong; Yang, Yunfeng
Despite microbes' key roles in driving biogeochemical cycles, the mechanism of microbe-mediated feedbacks to global changes remains elusive. Recently, soil transplant has been successfully established as a proxy to simulate climate changes, as the current trend of global warming coherently causes range shifts toward higher latitudes. Four years after southward soil transplant over large transects in China, we found that microbial functional diversity was increased, in addition to concurrent changes in microbial biomass, soil nutrient content and functional processes involved in the nitrogen cycle. However, soil transplant effects could be overridden by maize cropping, which was attributed to a negative interaction. Strikingly, abundances of nitrogen and carbon cycle genes were increased by these field experiments simulating global change, coinciding with higher soil nitrification potential and carbon dioxide (CO2) efflux. Further investigation revealed strong correlations between carbon cycle genes and CO2 efflux in bare soil but not cropped soil, and between nitrogen cycle genes and nitrification. These findings suggest that changes of soil carbon and nitrogen cycles by soil transplant and cropping were predictable by measuring microbial functional potentials, contributing to a better mechanistic understanding of these soil functional processes and suggesting a potential to incorporate microbial communities in greenhouse gas emission modeling. PMID:24694714
Tassoni, Alessia; Gutteridge, Alex; Barber, Amanda C; Osborne, Andrew; Martin, Keith R
A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long-term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM-MSCs) to help identify factors able to modulate graft-induced reactive gliosis. We found in vivo that intravitreal BM-MSC transplantation is associated with gliosis-mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin-2 (Lcn-2) was identified as a potential new indicator of graft-induced reactive gliosis. Pharmacological inhibition of STAT3 in BM-MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM-MSC retinal engraftment. Inhibition of stem cell-induced reactive gliosis is critical for successful transplantation-based strategies for neuroprotection, replacement, and regeneration of the optic nerve.
Zhao, Mengxin; Xue, Kai; Wang, Feng; Liu, Shanshan; Bai, Shijie; Sun, Bo; Zhou, Jizhong; Yang, Yunfeng
Despite microbes' key roles in driving biogeochemical cycles, the mechanism of microbe-mediated feedbacks to global changes remains elusive. Recently, soil transplant has been successfully established as a proxy to simulate climate changes, as the current trend of global warming coherently causes range shifts toward higher latitudes. Four years after southward soil transplant over large transects in China, we found that microbial functional diversity was increased, in addition to concurrent changes in microbial biomass, soil nutrient content and functional processes involved in the nitrogen cycle. However, soil transplant effects could be overridden by maize cropping, which was attributed to a negative interaction. Strikingly, abundances of nitrogen and carbon cycle genes were increased by these field experiments simulating global change, coinciding with higher soil nitrification potential and carbon dioxide (CO2) efflux. Further investigation revealed strong correlations between carbon cycle genes and CO2 efflux in bare soil but not cropped soil, and between nitrogen cycle genes and nitrification. These findings suggest that changes of soil carbon and nitrogen cycles by soil transplant and cropping were predictable by measuring microbial functional potentials, contributing to a better mechanistic understanding of these soil functional processes and suggesting a potential to incorporate microbial communities in greenhouse gas emission modeling.
Khan, Saif A; Al-Riyami, Dawood; Al-Mula Abed, Yasser W; Mohammed, Saja; Al-Riyami, Marwa; Al-Lawati, Nabil M
Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 µmol/L which continued to rise, necessitating haemodialysis. A biopsy indicated ABMR with acute cellular rejection. No improvement was observed following standard ABMR treatment and she continued to require dialysis. Five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. The patient became dialysis-free with serum Cr levels of 119 µmol/L within four months. This case report indicates that eculizumab is a promising agent in the treatment of ABMR.
Stevenson, Sarah; Mallett, Andrew; Oliver, Kimberley; Hyland, Valentine; Hawley, Carmel; Malmanche, Theo; Isbel, Nicole
We present a case of an unsensitized patient with end-stage kidney disease secondary to atypical haemolytic uremic syndrome (aHUS) with mutations in CD46/MCP and CFH who developed severe, intractable antibody-mediated rejection (ABMR) unresponsive to therapy post kidney transplantation. There were no haematological features of thrombotic microangiopathy. The patient received standard induction therapy and after an initial fall in serum creatinine, severe ABMR developed in the setting of urosepsis. Despite maximal therapy with thymoglobulin, plasma exchange and methylprednisolone, rapid graft loss resulted and transplant nephrectomy was performed. Luminex at 4 weeks showed a new DSA and when repeated after nephrectomy showed antibodies to each of the 5 mismatched antigens with high MFI. The rate of recurrence of disease in patients with aHUS referred for transplantation is 50% and is associated with a high rate of graft loss. It is dependent in part on the nature of the mutation with circulating factors CFH and CFI more likely to cause recurrent disease than MCP which is highly expressed in the kidney. There is increasing interest in the role of complement in the development and propagation of ABMR via terminal complement activation. This case suggesting that dysregulation of the alternative complement pathway within the transplant kidney may have contributed to the severe AMR. Very little is known about the impact of complement dysregulation and the development of anti HLA antibodies however the strength of HLA antibody formation was prominent in this case.
Chehade, Hassib; Rotman, Samuel; Matter, Maurice; Girardin, Eric; Aubert, Vincent; Pascual, Manuel
We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15, 16, and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.
Chin, Nicholas; Westall, Glen; Paraskeva, Miranda; Ciciulla, John; Cantwell, Linda; Snell, Greg
A bilateral sequential lung transplant was performed on a young female with cystic fibrosis-related bronchiectasis. She had negative prospective T- and B-cell crossmatch, and no known donor-specific antibodies. Post-transplantation, she developed bilateral pulmonary infiltrates of uncertain etiology, compounded by persistent tachycardia and questionable medication adherence. Despite aggressive intervention for suspected cellular rejection with high-dose intravenous corticosteroid, immunoglobulin, and anti-thymocyte globulin, her condition deteriorated to ultimately require ventilatory support. The eventual discovery of eplet donor-recipient mismatches on related DQB1 alleles raised the diagnosis of antibody-mediated rejection. Before plasmapheresis could be instituted, the patient rapidly succumbed to respiratory failure. Postmortem examination confirmed features of atypical allograft rejection, without evidence of classic acute cellular rejection. This is an unconventional case of antibody-mediated lung allograft rejection – an entity that is currently a difficult diagnostic and therapeutic challenge. Prevention of donor-specific antibodies by correct donor-recipient matching, and optimizing adherence post-transplantation are most important. PMID:25802749
Cardiovascular diseases (CVDs), including atherosclerosis, stroke, and myocardial infarction, is a major cause of death worldwide. In aspects of cell therapy against CVD, it is generally accepted that endothelial progenitor cells (EPCs) are potent neovascular modulators in ischemic tissues. In response to ischemic injury signals, EPCs located in a bone marrow niche migrate to injury sites and form new vessels by secreting various vasculogenic factors including VEGF, SDF-1, and FGF, as well as by directly differentiating into endothelial cells. Nonetheless, in ischemic tissues, most of engrafted EPCs do not survive under harsh ischemic conditions and nutrient depletion. Therefore, an understanding of diverse EPC-related cytoprotective mediators underlying EPC homeostasis in ischemic tissues may help to overcome current obstacles for EPC-mediated cell therapy for CVDs. Additionally, to enhance EPC's functional capacity at ischemic sites, multiple strategies for cell survival should be considered, that is, preconditioning of EPCs with function-targeting drugs including natural compounds and hormones, virus mediated genetic modification, combined therapy with other stem/progenitor cells, and conglomeration with biomaterials. In this review, we discuss multiple cytoprotective mediators of EPC-based cardiovascular repair and propose promising therapeutic strategies for the treatment of CVDs. PMID:28090210
Ng, Yolanda W; Singh, Manpreet; Sarwal, Minnie M
Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR.
Adam, Oliver; Laufs, Ulrich
HMG-CoA reductase inhibitors (statins) lower serum cholesterol concentrations and are beneficial in the primary and secondary prevention of coronary heart disease. The positive clinical effects have only partially been reproduced with other lipid-lowering interventions suggesting potential statin effects in addition to cholesterol lowering. In experimental models, direct beneficial cardiovascular effects that are mediated by the inhibition of isoprenoids have been documented, which serve as lipid attachments for intracellular signaling molecules such as small Rho guanosine triphosphate-binding proteins, whose membrane localization and function are dependent on isoprenylation. Rac1 GTPase is an established master regulator of cell motility through the cortical actin reorganization and of reactive oxygen species generation through the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Observations in cells, animals, and humans have implicated the activation of Rac1 GTPase as a key component of cardiovascular pathologies, including the endothelial dysfunction, cardiac hypertrophy and fibrosis, atrial fibrillation, stroke, hypertension, and chronic kidney disease. However, the underlying signal transduction remains incompletely understood. Based on the recent advance made in Rac1 research in the cardiovascular system by using mouse models with transgenic overexpression of activated Rac1 or conditional knockout, as well as Rac1-specific small molecule inhibitor NSC 23766, the improved understanding of the Rac1-mediated effects statins may help to identify novel therapeutic targets and strategies.
Hering, Dagmara; Lachowska, Kamila; Schlaich, Markus
A high incidence of acute cardiovascular events and sudden cardiac death following unexpected acute emotional stress or a natural catastrophic disaster has been well-documented over the past decades. Chronic psychosocial factors have been shown to be directly linked to the development of hypertension, cardiovascular disease and stroke. Activation of various neurogenic pathways is an important mediator of acute and chronic stress-induced hypertension and heart disease. Heightened sympathetic activation has been shown to be a critical contributor linking psychogenic effects on cardiovascular regulation to serious and often fatal CV outcomes. Accordingly, several therapeutic approaches that attenuate autonomic imbalance via modulation of increased sympathetic outflow by either non-pharmacological or interventional means have been shown to alleviate clinical symptoms. Likewise stress reduction per se achieved with transcendental medicine has been linked to improved patient outcomes. Therapies that oppose adrenergic activity and/or have the potential to attenuate negative emotions are likely to reduce cardiovascular risk and its adverse consequences attributable to chronic mental stress.
Roux-Lombard, P; Pagano, S; Montecucco, F; Satta, N; Vuilleumier, N
During the last 15 years, a growing body of evidence supported the fact that auto-antibodies represent not only emergent markers but also active mediators of cardiovascular disease (CVD), clinically represented mostly by acute coronary syndrome (ACS) and stroke. There is a contrasted relationship between auto-antibodies and CVD, some being protective, while others acting as potential risk factors. Therefore, we performed a review of the literature on the respective cardiovascular prognostic value of the most relevant auto-antibodies in ACS and stroke, and their putative pathophysiological properties in atherogenesis. This review highlights auto-antibodies as active modulators of the innate immune system in atherogenesis (either toward a pro- or anti-inflammatory response), or by affecting basal heart rate regulation (anti-apoA-1 IgG). Given their apparent prognostic independency towards traditional cardiovascular risk factors, the data available in the literature indicates that some of those auto-antibodies could be of valuable help for cardiovascular risk stratification in the future, especially because their deleterious effects have been shown to be potentially abrogated in vivo and in vitro by existing therapeutic modalities. Although evidence in humans is currently lacking, these studies may open innovative therapeutic perspectives for CVD in the future.
van den Berg, Else; Pasch, Andreas; Westendorp, Welmoet H; Navis, Gerjan; Brink, Elizabeth J; Gans, Reinold O B; van Goor, Harry; Bakker, Stephan J L
In post-transplant conditions, sulfur may be protective by intermediate conversion to hydrogen sulfide and thiosulfate. However, sulfate, the end product of sulfur-containing amino acids (SAAs), contributes to metabolic acid load and may adversely influence acid-base homeostasis. We investigated the association of urinary sulfur metabolites with cardiometabolic parameters in renal transplant recipients (RTRs) and analyzed their predictive capacity for mortality. We studied urinary sulfate and thiosulfate excretion in 24-hour urine samples from 707 RTRs at a median 5.4 years (interquartile range, 1.9 to 12.2) after transplantation as well as from 110 controls. Diet was assessed for SAA content and various risk factors were measured. Urinary sulfate was similar, whereas thiosulfate was higher in RTRs versus controls. SAA intake was lower in RTRs compared with controls and correlated with sulfate but not thiosulfate excretion. Sulfate beneficially associated with eGFR, net acid excretion, systolic BP, high-sensitivity C-reactive protein, N-terminal probrain natriuretic peptide, and proteinuria (all P≤0.01). Thiosulfate beneficially associated with eGFR, serum acidity, high-sensitivity C-reactive protein, and N-terminal probrain natriuretic peptide (all P≤0.001). During a median 27 months (interquartile range, 22-36) of follow-up, 47 RTRs died. After adjustment for age, sex, and eGFR, hazard ratios for mortality were 0.87 (95% confidence interval, 0.82 to 0.92; P<0.001) for urinary sulfate and 0.60 (95% confidence interval, 0.41 to 0.59; P=0.01) for thiosulfate. Thus, despite the association of urinary sulfate with metabolic acid load, urinary sulfate and thiosulfate beneficially associated with survival in RTRs, possibly by influencing cardiovascular parameters. Intervention studies with exogenous sulfur are warranted to elucidate mechanisms underlying these promising associations in RTRs. Copyright © 2014 by the American Society of Nephrology.
Anastasopoulos, Nikolaos-Andreas; Dounousi, Evangelia; Papachristou, Evangelos; Pappas, Charalampos; Leontaridou, Eleni; Savvidaki, Eirini; Goumenos, Dimitrios; Mitsis, Michael
AIM To investigate the incidence and the determinants of cardiovascular morbidity in Greek renal transplant recipients (RTRs) expressed as major advance cardiac event (MACE) rate. METHODS Two hundred and forty-two adult patients with a functioning graft for at least three months and available data that were followed up on the August 31, 2015 at two transplant centers of Western Greece were included in this study. Baseline recipients’ data elements included demographics, clinical characteristics, history of comorbid conditions and laboratory parameters. Follow-up data regarding MACE occurrence were collected retrospectively from the patients’ records and MACE risk score was calculated for each patient. RESULTS The mean age was 53 years (63.6% males) and 47 patients (19.4%) had a pre-existing cardiovascular disease (CVD) before transplantation. The mean estimated glomerular filtration rate was 52 ± 17 mL/min per 1.73 m2. During follow-up 36 patients (14.9%) suffered a MACE with a median time to MACE 5 years (interquartile range: 2.2-10 years). Recipients with a MACE compared to recipients without a MACE had a significantly higher mean age (59 years vs 52 years, P < 0.001) and a higher prevalence of pre-existing CVD (44.4% vs 15%, P < 0.001). The 7-year predicted mean risk for MACE was 14.6% ± 12.5% overall. In RTRs who experienced a MACE, the predicted risk was 22.3% ± 17.1% and was significantly higher than in RTRs without an event 13.3% ± 11.1% (P = 0.003). The discrimination ability of the model in the Greek database of RTRs was good with an area under the receiver operating characteristics curve of 0.68 (95%CI: 0.58-0.78). CONCLUSION In this Greek cohort of RTRs, MACE occurred in 14.9% of the patients, pre-existing CVD was the main risk factor, while MACE risk model was proved a dependable utility in predicting CVD post RT. PMID:28280695
Kim, Eun Jung; Chang, Suyon; Kim, So Yeon; Huh, Kyu Ha; Kang, Soojeong; Choi, Yong Seon
Patients with end-stage renal disease (ESRD) show characteristic abnormalities in cardiac structure and function. We evaluated the influence of these abnormalities on adverse cardiopulmonary outcomes after living donor kidney transplantation in patients with valid preoperative transthoracic echocardiographic evaluation. We then observed any development of major postoperative cardiovascular complications and pulmonary edema until hospital discharge. In-hospital major cardiovascular complications were defined as acute myocardial infarction, ventricular fibrillation/tachycardia, cardiogenic shock, newly-onset atrial fibrillation, clinical pulmonary edema requiring endotracheal intubation or dialysis. Among the 242 ESRD study patients, 9 patients (4%) developed major cardiovascular complications, and 39 patients (16%) developed pulmonary edema. Diabetes, ischemia-reperfusion time, left ventricular end-diastolic diameter (LVEDd), left ventricular mass index (LVMI), right ventricular systolic pressure (RVSP), left atrium volume index (LAVI), and high E/E' ratios were risk factors of major cardiovascular complications, while age, LVEDd, LVMI, LAVI, and high E/E' ratios were risk factors of pulmonary edema. The optimal E/E' cut-off value for predicting major cardiovascular complications was 13.0, showing 77.8% sensitivity and 78.5% specificity. Thus, the patient's E/E' ratio is useful for predicting in-hospital major cardiovascular complications after kidney transplantation. We recommend that goal-directed therapy employing E/E' ratio be enacted in kidney recipients with baseline diastolic dysfunction to avert postoperative morbidity. (http://Clinical Trials.gov number: NCT02322567) PMID:27499694
Romo-Nava, Francisco; Buijs, Frederik N; Valdés-Tovar, Marcela; Benítez-King, Gloria; Basualdo, MariCarmen; Perusquía, Mercedes; Heinze, Gerhard; Escobar, Carolina; Buijs, Ruud M
Second generation antipsychotics (SGA) are associated with adverse cardiometabolic side effects contributing to premature mortality in patients. While mechanisms mediating these cardiometabolic side effects remain poorly understood, three independent studies recently demonstrated that melatonin was protective against cardiometabolic risk in SGA-treated patients. As one of the main target areas of circulating melatonin in the brain is the suprachiasmatic nucleus (SCN), we hypothesized that the SCN is involved in SGA-induced early cardiovascular effects in Wistar rats. We evaluated the acute effects of olanzapine and melatonin in the biological clock, paraventricular nucleus and autonomic nervous system using immunohistochemistry, invasive cardiovascular measurements, and Western blot. Olanzapine induced c-Fos immunoreactivity in the SCN followed by the paraventricular nucleus and dorsal motor nucleus of the vagus indicating a potent induction of parasympathetic tone. The involvement of a SCN-parasympathetic neuronal pathway after olanzapine administration was further documented using cholera toxin-B retrograde tracing and vasoactive intestinal peptide immunohistochemistry. Olanzapine-induced decrease in blood pressure and heart rate confirmed this. Melatonin abolished olanzapine-induced SCN c-Fos immunoreactivity, including the parasympathetic pathway and cardiovascular effects while brain areas associated with olanzapine beneficial effects including the striatum, ventral tegmental area, and nucleus accumbens remained activated. In the SCN, olanzapine phosphorylated the GSK-3β, a regulator of clock activity, which melatonin prevented. Bilateral lesions of the SCN prevented the effects of olanzapine on parasympathetic activity. Collectively, results demonstrate the SCN as a key region mediating the early effects of olanzapine on cardiovascular function and show melatonin has opposing and potentially protective effects warranting additional investigation.
Maréchal, Céline; Schlieper, Georg; Nguyen, Pauline; Krüger, Thilo; Coche, Emmanuel; Robert, Annie; Floege, Jorgen; Goffin, Eric; Jadoul, Michel
Summary Background and objectives Vascular calcifications predict cardiovascular disease, the major cause of death in renal transplant recipients (RTRs). We studied the determinants of fetuin-A, a potent circulating calcification inhibitor encoded by the AHSG gene, and tested its association with vascular calcifications and long-term survival and cardiovascular events (CVEs) in RTRs. Design, setting, participants, & measurements Two hundred seventy-seven prevalent RTRs from a single center were included. CVEs and deaths were prospectively recorded during a 5-year follow-up. Results Independent determinants of lower serum fetuin-A levels were lower plasma cholesterol, the AHSG rs4918 G allele, and history of smoking. Low serum fetuin-A level was a determinant of aortic calcifications (assessed using spiral CT). Low fetuin-A levels (≤0.47 g/L, first quintile) were independently associated with CVEs and deaths (hazard ratio = 1.83; 95% confidence interval, 1.07 to 3.04). The association was confirmed for all-cause mortality, and the major adverse cardiovascular endpoints were analyzed separately. Patients with low fetuin-A and high high-sensitivity C-reactive protein (>4.36 mg/L, fourth quintile) levels had a 3.5-fold increased risk of all-cause mortality and CVEs. In the presence of inflammation, CVE-free survival was influenced by common variants in the AHSG gene. Conclusions These data show that low fetuin-A levels are independently associated with aortic calcifications and a higher risk of CVEs and mortality. They support fetuin-A as a circulating biomarker able to identify RTRs at risk for vascular calcifications and CVEs. PMID:21527649
Gordts, Philip L.; Ellinwood, N. Matthew; Schwartz, Philip H.; Dickson, Patricia I.; Esko, Jeffrey D.; Wang, Raymond Y.
Background Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease. Methods Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry. Results Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice. Conclusions Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for
Godfrey, V L; Rouse, B T; Wilkinson, J E
The X-linked mutation, scurfy (sf), causes a fatal lymphoreticular disease characterized by runting, lymphadenopathy, splenomegaly, hypergammaglobulinemia, exfoliative dermatitis, Coombs'-positive anemia, and death by 24 days of age. T lymphocytes are required to mediate this syndrome as shown by a total absence of disease in mice bred to be scurfy and nude (sf/Y; nu/nu). The scurfy phenotype is not transmitted by sf/Y bone marrow transplants, though cells of scurfy origin do reconstitute all lymphoid organs in the recipient mouse. These data suggest that scurfy disease results from an abnormal T cell development process and not from an intrinsic stem cell defect. We therefore tested the ability of transplanted scurfy thymuses to transmit scurfy disease to congenic euthymic mice, to athymic (nude) mice, and to severe combined immunodeficiency (SCID) mice. Euthymic recipients of sf/Y thymic grafts remained clinically normal as did all SCID and nude recipients of normal thymus transplants. Morphological lesions similar to those found in scurfy mice occurred in all H-2-compatible nude and SCID recipients of sf/Y thymic grafts. Intraperitoneal injections of scurfy thymocytes, splenocytes, and lymph node cells also transmitted the scurfy phenotype to H-2-compatible nude mice and SCID mice. Our findings indicate that scurfy disease can be transmitted to T cell-deficient mice by engraftment of scurfy T cells, but that pathogenic scurfy T cell activities can be inhibited (or prevented) in immunocompetent recipient mice.
Tassoni, Alessia; Gutteridge, Alex; Barber, Amanda C.; Osborne, Andrew
abstract A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long‐term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM‐MSCs) to help identify factors able to modulate graft‐induced reactive gliosis. We found in vivo that intravitreal BM‐MSC transplantation is associated with gliosis‐mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin‐2 (Lcn‐2) was identified as a potential new indicator of graft‐induced reactive gliosis. Pharmacological inhibition of STAT3 in BM‐MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM‐MSC retinal engraftment. Inhibition of stem cell‐induced reactive gliosis is critical for successful transplantation‐based strategies for neuroprotection, replacement, and regeneration of the optic nerve. Stem Cells 2015;33:3006–3016 PMID:26175331
Mainra, R; Xu, Q; Chibbar, R; Hassan, A; Shoker, A
Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female.
Wu, Grace W.; Kobashigawa, Jon A.; Fishbein, Michael C.; Patel, Jignesh K.; Kittleson, Michelle M.; Reed, Elaine F.; Kiyosaki, Krista K.; Ardehali, Abbas
Background Antibody-mediated rejection (AMR) has been associated with poor outcome after heart transplantation. The diagnosis of AMR usually includes endomyocardial biopsy findings of endothelial cell swelling, intravascular macrophages, C4d+ staining, and associated left ventricular dysfunction. The significance of AMR findings in biopsy specimens of asymptomatic heart transplant patients (normal cardiac function and no symptoms of heart failure) is unclear. Methods Between July 1997 and September 2001, AMR was found in the biopsy specimens of 43 patients. Patients were divided into 2 groups: asymptomatic AMR (AsAMR, n = 21) and treated AMR (TxAMR with associated left ventricular dysfunction, n = 22). For comparison, a control group of 86 contemporaneous patients, without AMR, was matched for age, gender, and time from transplant. Outcomes included 5-year actuarial survival and development of cardiac allograft vasculopathy (CAV). Patients were considered to have AMR if they had ≥ 1 endomyocardial biopsy specimen positive for AMR. Results The 5-year actuarial survival for the AsAMR (86%), TxAMR (68%), and control groups (79%) was not significantly different (p = 0.41). Five-year freedom from CAV (≥ 30% stenosis in any vessel) was AsAMR, 52%; TxAMR, 68%; and control, 79%. Individually, freedom from CAV was significantly lower in the AsAMR group compared with the control group (p = 0.02). There was no significant difference between AsAMR vs TxAMR and TxAMR vs control for CAV. Conclusions Despite comparable 5-year survival with controls after heart transplantation, AsAMR rejection is associated with a greater risk of CAV. Trials to treat AsAMR to alter outcome are warranted. PMID:19416767
Wu, Grace W; Kobashigawa, Jon A; Fishbein, Michael C; Patel, Jignesh K; Kittleson, Michelle M; Reed, Elaine F; Kiyosaki, Krista K; Ardehali, Abbas
Antibody-mediated rejection (AMR) has been associated with poor outcome after heart transplantation. The diagnosis of AMR usually includes endomyocardial biopsy findings of endothelial cell swelling, intravascular macrophages, C4d+ staining, and associated left ventricular dysfunction. The significance of AMR findings in biopsy specimens of asymptomatic heart transplant patients (normal cardiac function and no symptoms of heart failure) is unclear. Between July 1997 and September 2001, AMR was found in the biopsy specimens of 43 patients. Patients were divided into 2 groups: asymptomatic AMR (AsAMR, n = 21) and treated AMR (TxAMR with associated left ventricular dysfunction, n = 22). For comparison, a control group of 86 contemporaneous patients, without AMR, was matched for age, gender, and time from transplant. Outcomes included 5-year actuarial survival and development of cardiac allograft vasculopathy (CAV). Patients were considered to have AMR if they had > or = 1 endomyocardial biopsy specimen positive for AMR. The 5-year actuarial survival for the AsAMR (86%), TxAMR (68%), and control groups (79%) was not significantly different (p = 0.41). Five-year freedom from CAV (> or = 30% stenosis in any vessel) was AsAMR, 52%; TxAMR, 68%; and control, 79%. Individually, freedom from CAV was significantly lower in the AsAMR group compared with the control group (p = 0.02). There was no significant difference between AsAMR vs TxAMR and TxAMR vs control for CAV. Despite comparable 5-year survival with controls after heart transplantation, AsAMR rejection is associated with a greater risk of CAV. Trials to treat AsAMR to alter outcome are warranted.
Kobashigawa, Jon; Crespo-Leiro, Maria G; Ensminger, Stephan M; Reichenspurner, Hermann; Angelini, Annalisa; Berry, Gerald; Burke, Margaret; Czer, Lawrence; Hiemann, Nicola; Kfoury, Abdallah G; Mancini, Donna; Mohacsi, Paul; Patel, Jignesh; Pereira, Naveen; Platt, Jeffrey L; Reed, Elaine F; Reinsmoen, Nancy; Rodriguez, E Rene; Rose, Marlene L; Russell, Stuart D; Starling, Randy; Suciu-Foca, Nicole; Tallaj, Jose; Taylor, David O; Van Bakel, Adrian; West, Lori; Zeevi, Adriana; Zuckermann, Andreas
The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues. Copyright © 2011 International Society for Heart and Lung Transplantation. All rights reserved.
Purroy, Carolina; Fairchild, Robert L; Tanaka, Toshiaki; Baldwin, William M; Manrique, Joaquin; Madsen, Joren C; Colvin, Robert B; Alessandrini, Alessandro; Blazar, Bruce R; Fribourg, Miguel; Donadei, Chiara; Maggiore, Umberto; Heeger, Peter S; Cravedi, Paolo
Although spontaneous kidney transplant acceptance/tolerance occurs in mice and occasionally in humans, mechanisms remain unclear. Herein we test the hypothesis that EPO, a hormone predominantly produced by the adult kidney, has immunomodulating properties that are required for spontaneous kidney graft acceptance. In vitro, in a manner dependent on the EPO receptor and CD131 on antigen-presenting cells, EPO induced the secretion of active TGFβ by antigen-presenting cells, which in turn converted naïve CD4(+) T cells into functional Foxp3(+) regulatory T cells (Treg). In murine transplant models, pharmacologic downregulation of kidney-derived EPO prevented spontaneous Treg generation. In a controlled, prospective cohort clinical study, EPO administration at doses used to correct anemia augmented the frequency of peripheral CD4(+)CD25(+)CD127(lo) T cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferation in vitro via tyrosine phosphatase SHP-1-dependent uncoupling of IL-2Rβ signaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2Rγ signaling and maintaining constitutively quenched IL-2Rβ signaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGFβ mRNA and abrogated kidney allograft acceptance. Together, our findings delineate the protolerogenic properties of EPO in inhibiting conventional T cells while simultaneously promoting Treg induction, and suggest that manipulating the EPO/EPO receptor signaling axis could be exploited to prevent and/or treat T cell-mediated pathologies, including transplant rejection. Copyright © 2017 by the American Society of Nephrology.
Doke, Tomohito; Sato, Waichi; Takahashi, Kazuo; Hayashi, Hiroki; Koide, Sigehisa; Sasaki, Hitomi; Kusaka, Mamoru; Shiroki, Ryoichi; Hoshinaga, Kiyotaka; Takeda, Asami; Yuzawa, Yukio; Hasegawa, Midori
A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.
Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik; Koefoed-Nielsen, Pernille; Bistrup, Claus
ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime.
Fernández-Gutiérrez, Benjamín; Perrotti, Pedro P; Gisbert, Javier P; Domènech, Eugeni; Fernández-Nebro, Antonio; Cañete, Juan D; Ferrándiz, Carlos; Tornero, Jesús; García-Sánchez, Valle; Panés, Julián; Fonseca, Eduardo; Blanco, Francisco; Rodríguez-Moreno, Jesús; Carreira, Patricia; Julià, Antonio; Marsal, Sara; Rodriguez-Rodriguez, Luis
To analyze in several immune-mediated inflammatory diseases (IMIDs) the influence of demographic and clinical-related variables on the prevalence of cardiovascular disease (CVD), and compare their standardized prevalences.Cross-sectional study, including consecutive patients diagnosed with rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn disease, or ulcerative colitis, from rheumatology, gastroenterology, and dermatology tertiary care outpatient clinics located throughout Spain, between 2007 and 2010. Our main outcome was defined as previous diagnosis of angina, myocardial infarction, peripheral vascular disease, and/or stroke. Bivariate and multivariate logistic and mixed-effects logistic regression models were performed for each condition and the overall cohort, respectively. Standardized prevalences (in subjects per 100 patients, with 95% confidence intervals) were calculated using marginal analysis.We included 9951 patients. For each IMID, traditional cardiovascular risk factors had a different contribution to CVD. Overall, older age, longer disease duration, presence of traditional cardiovascular risk factors, and male sex were independently associated with a higher CVD prevalence. After adjusting for demographic and traditional cardiovascular risk factors, systemic lupus erythematosus exhibited the highest CVD standardized prevalence, followed by rheumatoid arthritis, psoriasis, Crohn disease, psoriatic arthritis, and ulcerative colitis (4.5 [95% confidence interval (CI): 2.2, 6.8], 1.3 [95% CI: 0.8, 1.8], 0.9 [95% CI: 0.5, 1.2], 0.8 [95% CI: 0.2, 1.3], 0.6 [95% CI: 0.2, 1.0], and 0.5 [95% CI: 0.1, 0.8], respectively).Systemic lupus erythematosus, rheumatoid arthritis, and psoriasis are associated with higher prevalence of CVD compared with other IMIDs. Specific prevention programs should be established in subjects affected with these conditions to prevent CVD.
Dare, Anna J; Plank, Lindsay D; Phillips, Anthony R J; Gane, Edward J; Harrison, Barry; Orr, David; Jiang, Yannan; Bartlett, Adam S J R
The effects of pretransplant obesity, diabetes mellitus (DM), coronary artery disease (CAD), and hypertension (HTN) on outcomes after liver transplantation (LT) are controversial. Questions have also been raised about the appropriateness of the body mass index (BMI) for assessing obesity in patients with end-stage liver disease. Both issues have implications for organ allocation in LT. To address these questions, we undertook a cohort study of 202 consecutive patients (2000-2010) undergoing LT at a national center in New Zealand. BMI and body fat percentage (%BF) values (dual-energy X-ray absorptiometry) were measured before transplantation, and the methods were compared. The influence of pretransplant risk variables (including obesity, DM, CAD, and HTN) on the 30-day postoperative event rate, length of hospital stay, and survival were analyzed. There was agreement between the calculated BMI and the measured %BF for 86.0% of the study population (κ coefficient = 0.73, 95% confidence interval = 0.61-0.85), and this was maintained across increasing Model for End-Stage Liver Disease scores. Obesity was an independent risk factor for the postoperative event rate [count ratio (CR) = 1.03, P < 0.001], as was DM (CR = 1.4, P < 0.001). Obesity with concomitant DM was the strongest predictor of the postoperative event rate (CR = 1.75, P < 0.001) and a longer hospital stay (5.81 days, P < 0.01). Independent metabolic risk factors had no effect on 30-day, 1-year, or 5-year patient survival. In conclusion, BMI is an adequate tool for assessing obesity-associated risk in LT. Early post-LT morbidity is highest for patients with concomitant obesity and DM, although these factors do not appear to influence recipient survival. © 2014 American Association for the Study of Liver Diseases.
Cruzado, Josep M; Pascual, Julio; Sánchez-Fructuoso, Ana; Serón, Daniel; Díaz, Joan M; Rengel, Manuel; Oppenheimer, Federico; Hernández, Domingo; Paravisini, Alexandra; Saval, Núria; Morales, José M
Left ventricular hypertrophy (LVH) regression after kidney transplantation may be influenced by immunosuppression. In a 24-month open-label, multicenter, phase-IV study, 71 kidney allograft recipients without previous acute rejection, showing eGFR >40 ml/min and proteinuria <500 mg/day and between 6 months and 3 years post-transplantation, were randomized to receive everolimus (EVR) + mycophenolic acid (MPA) or were maintained on tacrolimus (TAC) + MPA. The aim was to assess whether the conversion to EVR could reduce left ventricular mass index (LVMi) at month-24. LVMi at month-24 decreased without differences between groups (TAC: 54.0 vs. 48.2 g/m(2.7) ; EVR: 53.4 vs. 49.4 g/m(2.7) ). The LVH prevalence at baseline and month-24 was 59.4% and 40.6% in TAC group and 57.1% and 50.0% in EVR group. EVR conversion was associated with nearly disappearance of concentric LVH and concentric remodeling pattern. The procollagen type I N-terminal propeptide at month-24 showed greater reduction in EVR group (51.6 vs. 58.2 mg/l; P = 0.004). Conversion from TAC to EVR was associated with a significant improvement of eGFR (P = 0.0315, ancova). Adverse events were similar between groups without rejection episode or graft loss. Conversion from TAC to EVR did not further reduce LVMi after 24 months, although its effect on concentric LVH deserves further investigation (NCT01169701). © 2016 Steunstichting ESOT.
Miller, Christopher A; Naish, Josephine H; Shaw, Steven M; Yonan, Nizar; Williams, Simon G; Clark, David; Bishop, Paul W; Ainslie, Mark P; Borg, Alex; Coutts, Glyn; Parker, Geoffrey J M; Ray, Simon G; Schmitt, Matthias
Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR
Barn, Kulpreet; Laftavi, Mark; Pierce, Drew; Ying, Chin; Boden, William E; Pankewycz, Oleh
Long-term kidney transplant graft and patient survival is often limited by cardiovascular (CV) disease. Risk factors for CV disease such as diabetes, hypertension and elevated low-density lipoprotein levels are well documented; however, the impact of low levels of high-density lipoprotein (HDL) has not been defined. We performed a retrospective chart review of 324 consecutive renal transplant recipients from 2001 to 2007 to correlate baseline HDL levels with major adverse cardiovascular events (MACEs) defined as a composite of new onset CV illness, cerebral vascular events and peripheral vascular disease. A total of 92 MACEs occurred over a total of 1913 patient years of follow-up. Low HDL cholesterol levels were noted in 58.3% of patients. Compared with those with normal HDL levels, a greater percentage of patients with low HDL levels had post-transplant MACEs (20% vs. 60% respectively) and experienced an increased rate of all cause mortality. Sixty-two percent of all MACEs occurred in patients with low HDL levels. In the low HDL group, the odds ratio for experiencing a MACE was 1.92. Therefore, HDL cholesterol may provide an important new therapeutic target to prevent vascular morbidity and mortality following renal transplantation.
Coutance, Guillaume; Ouldamar, Salima; Rouvier, Philippe; Saheb, Samir; Suberbielle, Caroline; Bréchot, Nicolas; Hariri, Sarah; Lebreton, Guillaume; Leprince, Pascal; Varnous, Shaida
Late antibody-mediated rejection (AMR) after heart transplantation is suspected to be associated with a poor short-term prognosis. A retrospective single-center observational study was performed. Late AMR was defined as AMR occurring at least 1 year after heart transplantation. The study included all consecutive patients with proven and treated late acute AMR at the authors' institution between November 2006 and February 2013. The aim was to analyze the prognosis after late AMR, including mortality, recurrence of AMR, left ventricular ejection fraction, and cardiac allograft vasculopathy (CAV). Selected endomyocardial biopsy specimens obtained before AMR were also blindly reviewed to identify early histologic signs of AMR. The study included 20 patients treated for late AMR. Despite aggressive immunosuppressive therapies (100% of patients received intravenous methylprednisolone, 90% received intravenous immunoglobulin [IVIg],85% received plasmapheresis, 45% received rituximab), the prognosis remained poor. Survival after late AMR was 80% at 1 month, 60% at 3 months, and 50% at 1 year. All early deaths (<3 months, n = 8) were directly attributable to graft dysfunction or to complication of the intense immunosuppressive regimen. Among survivors at 3 months (n = 12), histologic persistence or recurrence of AMR, persistent left ventricular dysfunction, and fulminant CAV were common (33%, 33%, and 17% of patients). Microvascular inflammation was detected in at least 1 biopsy specimen obtained before AMR in 13 patients (65%). Prognosis after late AMR is poor despite aggressive immunosuppressive therapies. Fulminant CAV is a common condition in these patients. Microvascular inflammation is frequent in endomyocardial biopsy specimens before manifestation of symptomatic AMR. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Kobashigawa, Jon; Crespo-Leiro, Maria G.; Ensminger, Stephan M.; Reichenspurner, Hermann; Angelini, Annalisa; Berry, Gerald; Burke, Margaret; Czer, Lawrence; Hiemann, Nicola; Kfoury, Abdallah G.; Mancini, Donna; Mohacsi, Paul; Patel, Jignesh; Pereira, Naveen; Platt, Jeffrey L.; Reed, Elaine F.; Reinsmoen, Nancy; Rodriguez, E. Rene; Rose, Marlene L.; Russell, Stuart D.; Starling, Randy; Suciu-Foca, Nicole; Tallaj, Jose; Taylor, David O.; Van Bakel, Adrian; West, Lori; Zeevi, Adriana; Zuckermann, Andreas
BACKGROUND The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. METHODS The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. RESULTS A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. CONCLUSIONS The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues. PMID:21300295
Morita, Miwa; Joyce, Daniel; Miller, Charles; Fung, John J.; Lu, Lina; Qian, Shiguang
Liver tolerance was initially recognized by the spontaneous acceptance of liver allograft in many species. The underlying mechanisms are not completely understood. We have been inspired by an unexpected phenomenon that the liver transplant tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigate the rejection of liver allografts deficient in IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effectors (Tef) cell-derived IFN-γ to drive the expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in liver transplant tolerance. Comparable elevations of T regulatory cells and myeloid-derived suppressor cells are seen in both rejection and tolerance groups, and are not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, as spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. MMCI may represent an important homeostatic mechanism that supports peripheral tolerance, and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is actively participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers. PMID:25998530
Rascio, Federica; Pontrelli, Paola; Accetturo, Matteo; Oranger, Annarita; Gigante, Margherita; Castellano, Giuseppe; Gigante, Maddalena; Zito, Anna; Zaza, Gianluigi; Lupo, Antonio; Ranieri, Elena; Stallone, Giovanni; Gesualdo, Loreto; Grandaliano, Giuseppe
Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control
Möckel, Martin; Mueller, Eda; Bocksch, Wolfgang; Babel, Nina; Schindler, Ralf; Reinke, Petra
Background. Benefits of cardiac screening in kidney transplant candidates (KTC) will be dependent on the availability of effective interventions. We retrospectively evaluated characteristics and outcome of percutaneous coronary interventions (PCI) in KTC selected for revascularization by a cardiac screening approach. Methods. In 267 patients evaluated 2003 to 2006, screening tests performed were reviewed and PCI characteristics correlated with major adverse cardiovascular events (MACE) during a follow-up of 55 months. Results. Stress tests in 154 patients showed ischemia in 28 patients (89% high risk). Of 58 patients with coronary angiography, 38 had significant stenoses and 18 cardiac interventions (6.7% of all). 29 coronary lesions in 17/18 patients were treated by PCI. Angiographic success rate was 93.1%, but procedural success rate was only 86.2%. Long lesions (P = 0.029) and diffuse disease (P = 0.043) were associated with MACE. In high risk patients, cardiac screening did not improve outcome as 21.7% of patients with versus 15.5% of patients without properly performed cardiac screening had MACE (P = 0.319). Conclusion. The moderate procedural success of PCI and poor outcome in long and diffuse coronary lesions underscore the need to define appropriate revascularization strategies in KTC, which will be a prerequisite for cardiac screening to improve outcome in these high-risk patients. PMID:25045528
Wang, Shuo; Wang, Jina; Yang, Cheng; Xu, Ming
Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR. PMID:28255564
Kimball, Pamela M; Gupta, Gaurav; McDougan, Felecia
Presence of antibody [Ab] against angiotensin receptor [AT1R] indicates heightened risk for antibody mediated rejection [AMR] after transplantation but is insufficient as a marker. We speculated AT1R might be released systemically because of AMR and might be a useful biomarker. AT1R was measured in blood from 73 Normals and 72 renal patients pre- and post-transplantation. Patients were stratified as AMR-free [Gp1], AMR<1yr [Gp2] and AMR>1yr [Gp3]. AT1R was higher [13±26vs.367±537, p<0.01)] and more prevalent [20% vs. 92%, p<0.01] among renal patients than Normals. Pretransplant levels were similar [p=ns] between groups. One-year posttransplant levels approached [p<0.01] normalcy for Gps1+3 but spiked during AMR and remained elevated [155±58, p<0.01] for 50% Gp2 patients. One-year AT1R levels were higher among subsequent graft failures than surviving grafts [171±267vs. 38±50, p<0.01]. Pretransplant AT1R was abnormally elevated: possibly indicating ongoing tissue injury. Pretransplant AT1R didn't predict risk for AMR. However, AT1R spiked during early AMR and sustained elevations were associated with poorer outcomes. Copyright © 2017. Published by Elsevier Inc.
Wang, Shuo; Zhang, Chao; Wang, Jina; Yang, Cheng; Xu, Ming; Rong, Ruiming; Zhu, Tongyu; Zhu, Dong
Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR.
Lindblom, Susanne; Hong, Jaan; Nilsson, Bo; Korsgren, Olle; Ronquist, Gunnar
Aims Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. Methods Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. Results Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. Conclusion A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions. PMID:25322825
Liu, Jun-Yan; Li, Ning; Yang, Jun; Li, Nan; Qiu, Hong; Ai, Ding; Chiamvimonvat, Nipavan; Zhu, Yi; Hammock, Bruce D.
Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX-mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE's degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib. PMID:20837537
de Chantemèle, Eric J. Belin; Muta, Kenjiro; Mintz, James; Tremblay, Michel L.; Marrero, Mario B.; Fulton, David; Stepp, David W.
Background Obesity causes hypertension and sympathoactivation, a process proposed to be mediated by leptin. Protein tyrosine phosphatase 1B (PTP1B), a major new pharmaceutical target to treat obesity and type II diabetes, constrains leptin’s metabolic actions, but the extent to which PTP1B regulates leptin’s cardiovascular effects is unclear. This study examined the hypothesis that PTP1B is a negative regulator of the cardiovascular effects of leptin. Methods and Results PTP1B KO mice had lower body fat but higher mean arterial pressure (MAP: 116±5 vs. 105±5 mmHg, p<0.05) than controls. Leptin infusion produced a greater anorexic effect in PTP1B KO mice and a marked increase in MAP (135±5 mmHg) in PTP1B KO mice only. Decreased MAP to ganglionic blockade was higher in PTP1B KO mice (−38±3% vs. −29±3%, p<0.05) suggesting increased sympathetic tone. PTP1B deletion blunted MAP responses to phenylephrine (PE) injection (55±10% vs. 93±7%, p<0.05). PE-induced aortic contraction was reduced in PTP1B KO mice (57.7±9 vs. 96.3±12% of KCl, p<0.05), consistent with desensitization to chronically elevated sympathetic tone. Furthermore, PTP1B deletion significantly reduced gene expression of three alpha-1 adrenergic receptor sub-types, consistent with blunted constriction to PE. Conclusion these data indicate that PTP1B is a key regulator of the cardiovascular effects of leptin and that reduced vascular adrenergic reactivity provides a compensatory limit to leptin’s effects on MAP. PMID:19687357
Recent studies suggest that apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is another inorganic gaseous mediator in the cardiovascular system. H2S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionin gamma--lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B6) as a cofactor. CBS is the main H2S-producing enzyme in the brain and CSE is involved in H2S formation in the cardiovascular system. H2S induces hypotension in vivo and vasodilation vitro by opening KATP channels in vascular smooth muscle cells. Chronic administration of CSE inhibitor induces arterial hypertension in the rat. In addition, decreased H2S generation has been demonstrated in the vasculature of spontaneously hypertensive rat, in experimental hypertension induced by NO synthase blockade, and in hypoxia-induced pulmonary hypertension, and administration of exogenous H2S donor has significant therapeutic effects in these models. Deficiency of H2S may contribute to atherogenesis in some patients with hyperhomocysteinemia, in whom the metabolism of homocysteine to cysteine and H2S is compromised by vitamin B6 deficiency. Reduced H2S production in the brain was observed in patients with Alzheimer's disease. On the other hand, excess of H2S may lead to mental retardation in patients with Down's syndrome and may be involved in the pathogenesis of hypotension associated with septic shock.
Okafor, Osita N; Gorog, Diana A
Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation.
Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Rus-Machan, Jutta; Kienreich, Katharina; Verheyen, Nicolas; Gaksch, Martin; Grübler, Martin; Fahrleitner-Pammer, Astrid; Mrak, Peter; Toplak, Hermann; Kraigher-Krainer, Elisabeth; März, Winfried; Pilz, Stefan
Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. © 2013.
Atlantis, Evan; Shi, Zumin; Penninx, Brenda J W H; Wittert, Gary A; Taylor, Anne; Almeida, Osvaldo P
To determine whether chronic medical conditions mediate the association between depression and cardiovascular disease (CVD) mortality. Data analyzed were from 6,394 subjects aged 25-74 years who participated in extensive health examinations in the NHEFS conducted between 1971 and 1975 and follow-up studies to 1992. CVD mortality was the endpoint. Depression predictors were clinically significant depressive symptoms at baseline by the GWB-D, and/or at 1982-1984 by the CES-D ('baseline', 'new', or 'twice' depression). Chronic conditions were prevalent/incident high blood pressure, diabetes, and non-fatal CVD by examination and/or self-report. Mediation effects were assessed by stepwise adjustments of covariates and additive interactions in competing risks regression models (accounting for other mortality causes) and logit models. Baseline, new, and twice depression were significant predictors of CVD mortality in competing-risks models adjusted for demographics (HRs 1.3, 1.4, and 2.0), but effects were progressively weakened and became non-significant after adjustment for lifestyle factors, prevalent and incident medical conditions, respectively. CVD mortality risk was 80% higher for depression plus incident non-fatal CVD than without (HR 4.0 vs. 3.2, additive interaction), and mediation effects of depression via chronic medical conditions (particularly via incident non-fatal CVD) increased the risk by 2-11% in logit models, independent of all covariates. Several levels of evidence suggest that the association between depression and CVD mortality is partially mediated by prevalent/incident chronic medical conditions, as well as unhealthy lifestyle behaviors. Patients presenting with clinically significant depressive symptoms, particularly if persistent, should be assessed for both chronic conditions and lifestyle risk factors.
Beal, Sarah J.; Hillman, Jennifer; Dorn, Lorah D.; Out, Dorothée; Pabst, Stephanie
This longitudinal study examines links among adolescent internalizing and externalizing symptoms, the prenatal environment (e.g., nicotine exposure) and pre/perinatal maternal health, and cardiovascular risk factors. Girls (N=262) ages 11–17 reported internalizing and externalizing behaviors and mothers reported about the prenatal environment and maternal health during and 3 months post-pregnancy. Adolescent cardiovascular risk included adiposity, smoking, blood pressure, and salivary C-reactive protein. Internalizing symptoms mediated relations between prenatal exposures/maternal health and adiposity; externalizing symptoms mediated relations between prenatal exposures and adolescent smoking. Healthcare providers who attend to internalizing and externalizing symptoms in girls may ultimately influence cardiovascular health, especially among those with pre/perinatal risk factors. PMID:25750471
Costa Ferrer, Raquel; Serrano Rosa, Miguel Ángel; Zornoza Abad, Ana; Salvador Fernández-Montejo, Alicia
The cardiovascular (CV) response to social challenge and stress is associated with the etiology of cardiovascular diseases. New ways of communication, time pressure and different types of information are common in our society. In this study, the cardiovascular response to two different tasks (open vs. closed information) was examined employing different communication channels (computer-mediated vs. face-to-face) and with different pace control (self vs. external). Our results indicate that there was a higher CV response in the computer-mediated condition, on the closed information task and in the externally paced condition. These role of these factors should be considered when studying the consequences of social stress and their underlying mechanisms.
Merhi, Basma; Shireman, Theresa; Carpenter, Myra A; Kusek, John W; Jacques, Paul; Pfeffer, Marc; Rao, Madhumathi; Foster, Meredith C; Kim, S Joseph; Pesavento, Todd E; Smith, Stephen R; Kew, Clifton E; House, Andrew A; Gohh, Reginald; Weiner, Daniel E; Levey, Andrew S; Ix, Joachim H; Bostom, Andrew
Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. Cohort study. The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus
Background: Elderly individuals are considered to be more susceptible to particulate matter (PM) related cardiovascular (CV) health effects. In this study we investigated UfCP mediated CV effects on aged SHRs and compared the findings to that of adult SHRs to identify age related...
Background: Elderly individuals are considered to be more susceptible to particulate matter (PM) related cardiovascular (CV) health effects. In this study we investigated UfCP mediated CV effects on aged SHRs and compared the findings to that of adult SHRs to identify age related...
Taner, Timucin; Heimbach, Julie K; Rosen, Charles B; Nyberg, Scott L; Park, Walter D; Stegall, Mark D
In simultaneous liver-kidney transplantation (SLK), the liver can protect the kidney from hyperacute rejection and may also decrease acute cellular rejection rates. Whether the liver protects against chronic injury is unknown. To answer this we studied renal allograft surveillance biopsies in 68 consecutive SLK recipients (14 with donor-specific alloantibodies at transplantation [DSA+], 54 with low or no DSA, [DSA-]). These were compared with biopsies of a matched cohort of kidney transplant alone (KTA) recipients (28 DSA+, 108 DSA-). Overall 5-year patient and graft survival was not different: 93.8% and 91.2% in SLK, and 91.9% and 77.1% in KTA. In DSA+ recipients, KTA had a significantly higher incidence of acute antibody-mediated rejection (46.4% vs. 7.1%) and chronic transplant glomerulopathy (53.6% vs. 0%). In DSA- recipients at 5 years, KTA had a significantly higher cumulative incidence of T cell-mediated rejection (clinical plus subclinical, 30.6% vs. 7.4%). By 5 years, DSA+ KTA had a 44% decline in mean GFR while DSA+SLK had stable GFR. In DSA- KTA, the incidence of a combined endpoint of renal allograft loss or over a 50% decline in GFR was significantly higher (20.4% vs. 7.4%). Simultaneously transplanted liver allograft was the most predictive factor for a significantly lower incidence of cellular (odds ratio 0.13, 95% confidence interval 0.06-0.27) and antibody-mediated injury (odds ratio 0.11, confidence interval 0.03-0.32), as well as graft functional decline (odds ratio 0.22, confidence interval 0.06-0.59). Thus, SLK is associated with reduced chronic cellular and antibody-mediated alloimmune injury in the kidney allograft.
Halloran, P F; Pereira, A B; Chang, J; Matas, A; Picton, M; De Freitas, D; Bromberg, J; Serón, D; Sellarés, J; Einecke, G; Reeve, J
In a reference set of 403 kidney transplant biopsies, we recently developed a microarray-based test that diagnoses antibody-mediated rejection (ABMR) by assigning an ABMR score. To validate the ABMR score and assess its potential impact on practice, we performed the present prospective INTERCOM study (clinicaltrials.gov NCT01299168) in 300 new biopsies (264 patients) from six centers: Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis. We assigned ABMR scores using the classifier created in the reference set and compared it to conventional assessment as documented in the pathology reports. INTERCOM documented uncertainty in conventional assessment: In 41% of biopsies where ABMR features were noted, the recorded diagnoses did not mention ABMR. The ABMR score correlated with ABMR histologic lesions and donor-specific antibodies, but not with T cell-mediated rejection lesions. The agreement between ABMR scores and conventional assessment was identical to that in the reference set (accuracy 85%). The ABMR score was more strongly associated with failure than conventional assessment, and when the ABMR score and conventional assessment disagreed, only the ABMR score was associated with early progression to failure. INTERCOM confirms the need to reduce uncertainty in the diagnosis of ABMR, and demonstrates the potential of the ABMR score to impact practice.
VanWagner, Lisa B; Ning, Hongyan; Whitsett, Maureen; Levitsky, Josh; Uttal, Sarah; Wilkins, John T; Abecassis, Michael M; Ladner, Daniela P; Skaro, Anton I; Lloyd-Jones, Donald M
Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk assessment tool that allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point-based prediction model (risk score) for CVD complications after OLT, the CAR-OLT risk score, among a cohort of 1024 consecutive patients aged 18-75 years who underwent first OLT in a tertiary-care teaching hospital (2002-2011). The main outcome measures were major 1-year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias-corrected 95% confidence intervals for the regression coefficients of the final model.Among 1024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included pre-operative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the CAR-OLT point-based score (C statistic=0.78, bias-corrected C statistic=0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer-Lemeshow p=0.33). The point-based CAR-OLT risk score can identify patients at risk for CVD complications after OLT surgery (available at: www.carolt.us). This score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.
Samuelson, Clare; O'Toole, Laurence; Boland, Elaine; Greenfield, Diana; Ezaydi, Yousef; Ahmedzai, Sam H; Snowden, John A
Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors. We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation. Thirty-two patients with a median duration of 6 years (range 2-12) from original diagnosis of myeloma and three lines (range 2-6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common. Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age. This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients.
Samuelson, Clare; O'Toole, Laurence; Boland, Elaine; Greenfield, Diana; Ezaydi, Yousef; Ahmedzai, Sam H.; Snowden, John A.
Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors. Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation. Results: Thirty-two patients with a median duration of 6 years (range 2–12) from original diagnosis of myeloma and three lines (range 2–6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common. Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age. Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients. PMID:27077780
A. Hyperlipidaemia risk profiles should be identified by regular screening (at least once a year) for cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride blood levels in renal transplant patients. B. In renal transplant patients, hyperlipidaemia must be treated in order to keep the cholesterol/lipid levels within recommended limits according to the number of risk factors. C. Management of hyperlipidaemia after renal transplantation should be the same as for the dialysis population, with, in addition, modification of the immunosuppressive protocol when appropriate. D. Patients should be carefully monitored for adverse effects of lipid-lowering agents or interactions with immunosuppressive drugs.
Prasad, Kailash; Tiwari, Shuchita
Advanced glycation end products (AGEs) are heterogeneous group of molecules formed from non-enzymatic reaction of reducing sugars with amino group of proteins, lipids, and nucleic acid. Interaction of AGEs with its cell-bound receptor (RAGE) results in generation of oxygen radicals, nuclear factor kappa-β, pro-inflammatory cytokines and cell adhesion molecules, and is involved in the pathophysiology of cardiovascular diseases (CVD). Circulating soluble forms of RAGE (sRAGE) and endo-secretory RAGE (esRAGE) compete with RAGE for ligand binding and function as a decoy. This paper describes the endogenous and exogenous (high dietary AGEs, cooking food under high dry heat, elevated pH, and long period) sources of AGEs. AGE-RAGE-mediated CVD includes atherosclerosis, coronary artery disease, carotid artery disease, hypertension, peripheral vascular diseases, heart failure, cardiomyopathy, and microangiopathy. The therapeutic intervention with reduction in AGEs and RAGE, and elevation in sRAGE has been reported for the treatment of AGE-RAGE-mediated CVD. Reduction in levels of AGEs can be achieved by reduction in consumption of food containing low amount of AGEs, cooking food at low temperature, moist heat, and shorter duration. AGE formation can be reduced with drugs, vitamins and stoppage of cigarette smoking. Statins, telmisartan, and curcumin have been used for suppression of RAGE. Statins, ACE-inhibitors, Rosiglitazone and vitamin D have been used to increase levels of sRAGE. Finally exogenous administration of sRAGE can be helpful in amelioration of CVD. In conclusion, AGE-RAGE-mediated CVD could be attenuated with reduction in consumption of AGEs, suppression of RAGE and elevation of sRAGE.
Kajikawa, Masato; Maruhashi, Tatsuya; Hida, Eisuke; Iwamoto, Yumiko; Matsumoto, Takeshi; Iwamoto, Akimichi; Oda, Nozomu; Kishimoto, Shinji; Matsui, Shogo; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Aibara, Yoshiki; Nakashima, Ayumu; Noma, Kensuke; Higashi, Yukihito
Measurement of nitroglycerine-induced vasodilation has been performed to differentiate endothelium-dependent vasodilation from endothelium-independent vasodilation as a control test for flow-mediated vasodilation (FMD). Recently, nitroglycerine-induced vasodilation per se has been reported to be a useful marker of the grade of atherosclerosis. The present study aimed to evaluate the prognostic value of FMD combined with nitroglycerine-induced vasodilation for future cardiovascular events. We measured FMD and nitroglycerine-induced vasodilation in 402 subjects, including patients with cardiovascular diseases. During a median follow-up period of 32.3 months, 38 first major cardiovascular events (death from cardiovascular causes, acute myocardial infarction, stroke, and coronary revascularization) occurred. Receiver-operator characteristic curve analysis revealed that FMD alone and nitroglycerine-induced vasodilation alone can predict cardiovascular events with areas under the curve of 0.671 (cutoff 3.3%) and 0.692 (cutoff 11.6%), respectively. FMD combined with nitroglycerine-induced vasodilation predicts cardiovascular events with an area under the curve of 0.701. After adjustment for age, sex, and cardiovascular risk factors, above cutoff FMD (≥3.3%) and below cutoff nitroglycerine-induced vasodilation (<11.6%; hazard ratio, 5.55; 95% confidence interval, 1.61-25.46;P=0.006) and below cutoff FMD (<3.3%) and below cutoff nitroglycerine-induced vasodilation (<11.6%; hazard ratio, 7.20; 95% confidence interval, 2.37-31.36;P<0.001) remained strong independent indicator of cardiovascular events. These findings suggest that the combination of FMD and nitroglycerine-induced vasodilation measurements can more accurately predict cardiovascular events compared with FMD alone. URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000001167. © 2016 American Heart Association, Inc.
Irure, J; López-Hoyos, M; Rodrigo, E; Gómez-Román, J; Ruiz, J C; Arias, M; San Segundo, D
The definition of antibody-mediated rejection (AMR) is based on serologic (presence and/or development of donor-specific anti-HLA antibodies [DSAs]) and histologic (C4d deposition and endothelial damage) criteria. However, several cases of AMR have been described without C4d deposition, and other cases of histologic AMR without DSAs, which could be driven by other non-HLA alloantibodies such as anti-MICA or anti-angiotensin II type I receptor (AT1R). Here we studied clinical and histologic humoral rejection in kidney transplant recipients without evidence of anti-HLA antibodies. Fifteen kidney transplant recipients with AMR defined as C4d(+) and/or histologic g+ptc without anti-HLA antibodies in screening test were studied. Sera at the moment of biopsy and 2 months earlier were studied for anti-HLA antibodies by Luminex, in neat, diluted 1/160, and sera after treatment with dithiothreitol (DTT) and confirmed by single-antigen test. The anti-AT1R was measured by enzyme-linked immunosorbent assay. A lack of anti-HLA and MICA antibodies was confirmed after anti-HLA screening test in all conditions (neat, diluted, and DTT-treated) and de novo development of AT1R antibodies was ruled out. Nevertheless, after single-antigen test, 3 patients were identified with a weak reaction against class I antigen and another 4 patients against class II antigen. Due to the lack of locus-C typing in the donors, the DSA assignment cannot be confirmed, whereas anti-HLA class II antigens were DSA. A low sensitivity in the screening of anti-HLA antibody testing was observed. Our results suggest performing single-antigen test in seronegative patients with clinical humoral rejection after screening to confirm the presence of DSA. Copyright Â© 2016 Elsevier Inc. All rights reserved.
Morita, Miwa; Joyce, Daniel; Miller, Charles; Fung, John J; Lu, Lina; Qian, Shiguang
Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers. © 2015 by the American Association for the Study of Liver Diseases.
Wijndaele, Katrien; Brage, Søren; Besson, Hervé; Khaw, Kay-Tee; Sharp, Stephen J.; Luben, Robert; Bhaniani, Amit; Wareham, Nicholas J.; Ekelund, Ulf
Background Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal) cardiovascular disease (CVD), non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables. Methodology/Principal Findings A population-based cohort of 12,608 men and women (aged 61.4±9.0), free from stroke, myocardial infarction and cancer at baseline in 1998–2000 were followed up until 2007 (6.9±1.9 years). Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA1c) were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95%CI = 1.03–1.08; 2,620 cases), non-fatal CVD (HR = 1.06, 95%CI = 1.03–1.09; 2,134 cases), and coronary heart disease (HR = 1.08, 95%CI = 1.03–1.13; 940 cases), independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA1c and the clustered metabolic risk score only partially mediated these associations. Conclusions These results indicate that the most prevalent leisure time (sedentary) behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered. PMID
de Mendonça-Filho, Hugo Tannus Furtado; Pereira, Kelly Cristina; Fontes, Mariane; Vieira, Daniel Augusto de Souza Aranha; de Mendonça, Maria Lucia A Furtado; Campos, Luiz Antonio de Almeida; Castro-Faria-Neto, Hugo Caire
Introduction Cardiovascular surgery with cardiopulmonary bypass (CPB) has improved in past decades, but inflammatory activation in this setting is still unpredictable and is associated with several postoperative complications. Perioperative levels of macrophage migration inhibitory factor (MIF) and other inflammatory mediators could be implicated in adverse outcomes in cardiac surgery. Methods Serum levels of MIF, monocyte chemoattractant protein (MCP)-1, soluble CD40 ligand, IL-6 and IL-10 from 93 patients subjected to CPB were measured by enzyme-linked immunosorbent assay and compared with specific and global postoperative organ dysfunctions through multiple organ dysfunction score (MODS) and sequential organ failure assessment (SOFA). Results Most of the cytokines measured had a peak of production between 3 and 6 hours after CPB, but maximum levels of MIF occurred earlier, at the cessation of CPB. Among specific organ dysfunctions, the most frequent was hematological, occurring in 82% of the patients. Circulatory impairment was observed in 73.1% of the patients, and 51% of these needed inotropics or vasopressors within the first 24 hours after surgery. The third most frequent dysfunction was pulmonary, occurring in 48.4% of the patients. Preoperative levels of MIF showed a relevant direct correlation with the intensity of global organ dysfunction measured by SOFA (ρ = 0.46, p < 0.001) and MODS (ρ = 0.50, p < 0.001) on the third day after surgery. MCP-1 production was associated with postoperative thrombocytopenia, and MIF was related to the use of a high dose of vasopressors in patients with cardiovascular impairment and also to lower values of the ratio of partial arterial oxygen tension (PaO2) to fraction of inspired oxygen (FiO2) registered in the first 24 hours after CPB. Conclusion Despite the multifactorial nature of specific or multiple organ dysfunctions, MIF should be explored as a predicting factor of organ dysfunction, or even as a potential
Couzi, Lionel; Manook, Miriam; Perera, Ranmith; Shaw, Olivia; Ahmed, Zubir; Kessaris, Nicos; Dorling, Anthony; Mamode, Nizam
Graft survival seems to be worse in positive cross-match (HLAi) than in ABO-incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty-nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody-mediated rejection (AMR) were different. Five-year death-censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti-A/B and anti-HLA antibodies.
Holley, J.L.; Fenton, R.A.; Arthur, R.S. )
This study assessed the usefulness of thallium stress testing as a predictor of perioperative cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation. Demographic factors influencing the exercise performance in these patients were also examined. The medical records of 189 consecutive patients with diabetic nephropathy who were evaluated for cadaveric renal transplantation were reviewed. Thallium stress testing was the initial examination of cardiovascular status in 141 patients. An adequate examination was one in which at least 70% of maximum heart rate was achieved. A thallium stress test was normal if there were no ST segment depressions on the electrocardiogram and no perfusion abnormalities on the thallium scan. Forty-four patients underwent cardiac catheterization as the initial evaluation (Group C) and four patients underwent transplantation without a formal cardiovascular evaluation (Group D). Sixty-four of the 141 patients undergoing thallium stress testing had an adequate and normal examination (Group A). The incidence of perioperative cardiac events in this group was 2%. Seventy-seven patients (Group B) had an abnormal (n = 41) or an inadequate (n = 36) thallium stress test and most (n = 61) then underwent coronary angiography. The use of beta-blockers was the only predictor of an abnormal or inadequate thallium stress test. Forty-three percent of patients with inadequate or abnormal thallium stress tests had significant coronary artery disease on cardiac catheterization. The perioperative risk of cardiac events was not different in Group A versus Groups B, C, and D combined. Survival of Group A and B patients was not different but was significantly longer than that of Group C patients.
Wang, Ying; Chung, Sang-Jin; McCullough, Marjorie L; Song, Won O; Fernandez, Maria Luz; Koo, Sung I; Chun, Ock K
Hyperlipidemia and elevated circulating C-reactive protein (CRP) and total homocysteine (tHcy) concentrations are cardiovascular disease (CVD) risk factors. Previous studies indicated that higher serum carotenoid concentrations were inversely associated with some of these biomarkers. However, whether dietary carotenoid intake is inversely associated with these CVD risk biomarkers is not well known. We assessed the associations between individual dietary carotenoid intake and CVD risk biomarkers and tested whether the serum carotenoid concentrations explain (mediate) or influence the strength of (moderate) the associations, if any association exists. Dietary data collected from 2 24-h dietary recalls and serum measurements in adult men (n = 1312) and women (n = 1544) from the NHANES 2003-2006 were used. Regression models designed for survey analysis were used to examine the associations between individual dietary carotenoids and log-transformed blood cholesterol, CRP, and tHcy. The corresponding individual serum carotenoid concentration was considered as mediator (and moderator if applicable). After adjustment for covariates, significant inverse associations with LDL cholesterol were observed for dietary β-carotene (P < 0.05) and lutein + zeaxanthin (P < 0.001), and with tHcy for dietary β-carotene (P < 0.05), lycopene (P < 0.05), and total carotenoids (P < 0.05). Dietary lutein + zeaxanthin intake was also positively associated with HDL cholesterol concentrations (P < 0.01). Most of these associations were null after additional adjustment for corresponding serum carotenoid concentrations, indicating the complete mediation effects of serum carotenoids. Serum β-carotene significantly moderated the associations between dietary β-carotene and CRP (P-interaction < 0.05), and quartile 4 of dietary β-carotene was associated with lower CRP concentrations only among participants with serum β-carotene > 0.43 μmol/L. In this population-based cross-sectional study
Lee, Wen-Shin; Erdelyi, Katalin; Matyas, Csaba; Mukhopadhyay, Partha; Varga, Zoltan V; Liaudet, Lucas; Hask’, György; ’iháková, Daniela; Mechoulam, Raphael; Pacher, Pal
Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell–mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell–mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation. PMID:26772776
Lee, Wen-Shin; Erdelyi, Katalin; Matyas, Csaba; Mukhopadhyay, Partha; Varga, Zoltan V; Liaudet, Lucas; Haskó, György; Čiháková, Daniela; Mechoulam, Raphael; Pacher, Pal
Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a non-psychoactive constituent of Marijuana which exerts antiinflammatory effects independent from classical cannabinoid receptors. Recently 80 clinical trials have been reported investigating the effects of CBD in various diseases from inflammatory bowel disease to graft-versus-host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received FDA approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T cell-infiltration, profound inflammatory response, fibrosis (measured by qRT-PCR, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation.
Halloran, P F; Famulski, K S; Chang, J
Histologic diagnosis of antibody-mediated rejection (ABMR) in kidney transplant biopsies uses lesion score cutoffs such as 0 versus >0 rather than actual scores and requires donor-specific antibody (DSA); however, cutoffs lose information, and DSA is not always reliable. Using microarray-derived molecular ABMR scores as a histology-independent estimate of ABMR in 703 biopsies, we reassessed criteria for ABMR to determine relative importance of various lesions, the utility of equations using actual scores rather than cutoffs, and the potential for diagnosing ABMR when DSA is unknown or negative. We confirmed that the important features for ABMR diagnosis were peritubular capillaritis (ptc), glomerulitis (g), glomerular double contours, DSA and C4d staining, but we questioned some features: arterial fibrosis, vasculitis, acute tubular injury, and sum of ptc+g scores. Regression equations using lesion scores predicted molecular ABMR more accurately than score cutoffs (area under the curve 0.85-0.86 vs. 0.75). DSA positivity improved accuracy, but regression equations predicted ABMR with moderate accuracy when DSA was unknown. Some biopsies without detectable DSA had high probability of ABMR by regression, although most had HLA antibody. We concluded that regression equations using lesion scores plus DSA maximized diagnostic accuracy and can estimate probable ABMR when DSA is unknown or undetectable.
Remport, Adam; Ivanyi, Bela; Mathe, Zoltan; Tinckam, Kathryn; Mucsi, Istvan; Molnar, Miklos Z
Transplant glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibody-mediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR.
De Nardin, E
Epidemiological studies have implicated periodontitis (PD) as a risk factor for development of cardiovascular disease (CVD). Persistent infections such as periodontitis induce inflammatory and immune responses which may contribute to coronary atherogenesis, and, in conjunction with other risk factors, may lead to coronary heart disease (CHD). In this review, mechanisms are described that may help explain the association between periodontal infections and CHD. Periodontal diseases are bacterial infections associated with bacteremia, inflammation, and a strong immune response, all of which may represent significant risk factors for the development of atherogenesis, CHD, and myocardial infarction (MI). Several mechanisms may participate in this association, including those induced by oral organisms, and those associated with host response factors. This review will focus on host factors. Oral pathogens and inflammatory mediators (such as interleukin [IL]-1 and tumor necrosis factor [TNF]-alpha) from periodontal lesions intermittently reach the bloodstream inducing systemic inflammatory reactants such as acute-phase proteins, and immune effectors including systemic antibodies to periodontal bacteria. This review will describe the potential role of various inflammatory as well as immunologic factors that may play a role in periodontitis as a possible risk factor for CHD.
Demarzo, Marcelo M. P.; Montero-Marin, Jesús; Stein, Phyllis K.; Cebolla, Ausiàs; Provinciale, Jaime G.; García-Campayo, Javier
The psychological construct of mindfulness refers to an awareness that emerges by intentionally paying attention to the present experience in a non-judgmental or evaluative way. This particular quality of awareness has been associated to several indicators of physical and psychological health, and can be developed using mindfulness-based interventions (MBIs), and therefore MBIs have been successfully applied as preventive and complementary interventions and therapies in medicine and psychology. Together with quiet sitting and lying meditation practices, mindful physical exercises such as “mindful walking” and “mindful movement” are key elements in MBIs and couple muscular activity with an internally directed focus, improving interoceptive attention to bodily sensations. In addition, MBIs seem to share similar mechanisms with physical fitness (PF) by which they may influence cardiovascular responses to stress. Based on these facts, it is feasible to raise the question of whether physical training itself may induce the development of that particular quality of awareness associated with mindfulness, or if one's dispositional mindfulness (DM) (the tendency to be more mindful in daily life) could moderate the effects of exercise on cardiovascular response to stress. The role of mindfulness as a mediator or moderator of the effect of exercise training on cardiovascular responses to stress has barely been studied. In this study, we have hypothesized pathways (moderation and mediation) by which mindfulness could significantly influence the effects of PF on cardiovascular responses to stress and discussed potential practical ways to test these hypotheses. PMID:24723891
Kim, Byung G.; Dai, Hai-Ning; Lynskey, James V.; Mcatee, Marietta; Bregman, Barbara S.
Transplantation of growth-permissive cells or tissues was used to bridge a lesion cavity and induce axonal growth in experimental spinal cord injury (SCI). Axonal interactions between host and transplant may be affected by upregulation of inhibitory chondroitin sulfate proteoglycans (CSPGs) following various transplantation strategies. The extent of axonal growth and functional recovery after transplantation of embryonic spinal cord tissue decreases in adult compared to neonatal host. We hypothesized that CSPGs contribute to the decrease in the extent to which transplant supports axonal remodeling and functional recovery. Expression of CSPGs increased after overhemisection SCI in adult rats but not in neonates. Embryonic spinal cord transplant was surrounded by CSPGs deposited in host cord, and the interface between host and transplant seemed to contain a large amount of CSPGs. Intrathecally delivered chondroitinase ABC (C'ase) improved recovery of distal forelimb usage and skilled motor behavior after C4 overhemisection injury and transplantation in adults. This behavioral recovery was accompanied by an increased amount of raphespinal axons growing into the transplant, and raphespinal innervation to the cervical motor region was promoted by C'ase plus transplant. Moreover, C'ase increased the number of transplanted neurons that grew axons to the host cervical enlargement, suggesting that degradation of CSPGs supports remodeling not only of host axons but also axons from transplanted neurons. Our results suggest that CSPGs constitute an inhibitory barrier to prevent axonal interactions between host and transplant in adults, and degradation of the inhibitory barrier can potentiate transplant-mediated axonal remodeling and functional recovery after SCI. PMID:16705682
Jirasiritham, S; Khunprakant, R; Techawathanawanna, N; Jirasiritham, Si; Mavichak, V
This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/microL to 50/microL remaining in the 50 to 220/microL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.
Feingold, Brian; Salgado, Cláudia M; Reyes-Múgica, Miguel; Drant, Stacey E; Miller, Susan A; Kennedy, Mark; Kellman, Peter; Schelbert, Erik B; Wong, Timothy C
Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Levine, Deborah J; Glanville, Allan R; Aboyoun, Christina; Belperio, John; Benden, Christian; Berry, Gerald J; Hachem, Ramsey; Hayes, Don; Neil, Desley; Reinsmoen, Nancy L; Snyder, Laurie D; Sweet, Stuart; Tyan, Dolly; Verleden, Geert; Westall, Glen; Yusen, Roger D; Zamora, Martin; Zeevi, Adriana
Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Aubert, O; Bories, M-C; Suberbielle, C; Snanoudj, R; Anglicheau, D; Rabant, M; Martinez, F; Scemla, A; Legendre, C; Sberro-Soussan, R
Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation.
Guida, Bruna; Maresca, Immacolata Daniela; Germanò, Roberta; Trio, Rossella; Nastasi, Anna Maria; Federico, Stefano; Memoli, Andrea; Apicella, Luca; Memoli, Bruno; Sabbatini, Massimo
We evaluated dietary intake and nutritional-inflammation status in ninety-six renal transplant recipients, 7.2 ± 5.0 years after transplantation. Patients were classified as normoweight (NW), overweight (OW), and obese (OB), if their body mass index was between 18.5 and 24.9, 25.0 and 29.9, and ≥30 kg/m2, respectively. Food composition tables were used to estimate nutrient intakes. The values obtained were compared with those recommended in current nutritional guidelines. 52% of the patients were NW, 29% were OW, and 19% were OB. Total energy, fat, and dietary n-6 PUFAs intake was higher in OB than in NW. IL-6 and hs-CRP were higher in OB than in NW. The prevalence of multidrug regimen was higher in OB. In all patients, total energy, protein, saturated fatty acids, and sodium intake were higher than guideline recommendations. On the contrary, the intake of unsaturated and n-6 and n-3 polyunsaturated fatty acids and fiber was lower than recommended. In conclusion, the prevalence of obesity was high in our patients, and it was associated with inflammation and the assumption of multiple cardiovascular and antidiabetic drugs. Dietary intake did not meet nutritional recommendations in all patients, especially in obese ones, highlighting the need of a long-term nutritional support in renal transplant recipients. PMID:23984354
Ishida, Hideki; Kondo, Tsunenori; Shimizu, Tomokazu; Nozaki, Taiji; Tanabe, Kazunari
The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies.
Orandi, B J; Alachkar, N; Kraus, E S; Naqvi, F; Lonze, B E; Lees, L; Van Arendonk, K J; Wickliffe, C; Bagnasco, S M; Zachary, A A; Segev, D L; Montgomery, R A
The updated Banff classification allows for the diagnosis of antibody-mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d-negative AMR (n = 51) compared with C4d-positive AMR patients (n = 156) and matched control subjects without AMR. All first-year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor-specific antibody (DSA). C4d-negative AMR patients were not different from C4d-positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ABO-incompatibility). C4d-positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8-32] days vs. 46 [interquartile range 20-191], p < 0.001) and were three times more common (7.8% vs 2.5%). One- and 2-year post-AMR-defining biopsy graft survival in C4d-negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d-positive AMR patients, respectively (p = 0.4). C4d-negative AMR was associated with a 2.56-fold (95% confidence interval, 1.08-6.05, p = 0.033) increased risk of graft loss compared with AMR-free matched controls. No clinical characteristics were identified that reliably distinguished C4d-negative from C4d-positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.
Tian, Ch; Liu, Y-G; Yan, J-K; Liu, S-D; Zhao, S-T; Wang, H-W
The objective of this study was to investigate the roles of B- and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) in acute and chronic transplant rejection and immune tolerance. The expression patterns of BTLA/HVEM, interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-γ were analyzed among patients presenting with acute rejection episodes versus those maintaining stable renal function during therapy with mycophenolate mofetil (MMF), cyclosporine, or tacrolimus (FK506) plus prednisolone. The expressions of BTLA/HVEM in the rejection group were obviously increased compared with the stable group (P < .05), followed by the elevation of serum levels of IL-2 and IFN-γ. The expression levels of BTLA/HVEM can be considered to be early indicators of an acute rejection episode following kidney transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.
Kourtzelis, Ioannis; Kotlabova, Klara; Lim, Jong-Hyung; Mitroulis, Ioannis; Ferreira, Anaisa; Chen, Lan-Sun; Gercken, Bettina; Steffen, Anja; Kemter, Elisabeth; Ameln, Anne Klotzsche-von; Waskow, Claudia; Hosur, Kavita; Chatzigeorgiou, Antonios; Ludwig, Barbara; Wolf, Eckhard; Hajishengallis, George; Chavakis, Triantafyllos
Summary Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood–islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation. PMID:26676803
Kourtzelis, Ioannis; Kotlabova, Klara; Lim, Jong-Hyung; Mitroulis, Ioannis; Ferreira, Anaisa; Chen, Lan-Sun; Gercken, Bettina; Steffen, Anja; Kemter, Elisabeth; Klotzsche-von Ameln, Anne; Waskow, Claudia; Hosur, Kavita; Chatzigeorgiou, Antonios; Ludwig, Barbara; Wolf, Eckhard; Hajishengallis, George; Chavakis, Triantafyllos
Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood-islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.
European Association of Cardiovascular Imaging/Cardiovascular Imaging Department of the Brazilian Society of Cardiology recommendations for the use of cardiac imaging to assess and follow patients after heart transplantation.
Badano, Luigi P; Miglioranza, Marcelo H; Edvardsen, Thor; Colafranceschi, Alexandre Siciliano; Muraru, Denisa; Bacal, Fernando; Nieman, Koen; Zoppellaro, Giacomo; Marcondes Braga, Fabiana G; Binder, Thomas; Habib, Gilbert; Lancellotti, Patrizio
The cohort of long-term survivors of heart transplant is expanding, and the assessment of these patients requires specific knowledge of the surgical techniques employed to implant the donor heart, the physiology of the transplanted heart, complications of invasive tests routinely performed to detect graft rejection (GR), and the specific pathologies that may affect the transplanted heart. A joint EACVI/Brazilian cardiovascular imaging writing group committee has prepared these recommendations to provide a practical guide to echocardiographers involved in the follow-up of heart transplant patients and a framework for standardized and efficient use of cardiovascular imaging after heart transplant. Since the transplanted heart is smaller than the recipient's dilated heart, the former is usually located more medially in the mediastinum and tends to be rotated clockwise. Therefore, standard views with conventional two-dimensional (2D) echocardiography are often difficult to obtain generating a large variability from patient to patient. Therefore, in echocardiography laboratories equipped with three-dimensional echocardiography (3DE) scanners and specific expertise with the technique, 3DE may be a suitable alternative to conventional 2D echocardiography to assess the size and the function of cardiac chambers. 3DE measurement of left (LV) and right ventricular (RV) size and function are more accurate and reproducible than conventional 2D calculations. However, clinicians should be aware that cardiac chamber volumes obtained with 3DE cannot be compared with those obtained with 2D echocardiography. To assess cardiac chamber morphology and function during follow-up studies, it is recommended to obtain a comprehensive echocardiographic study at 6 months from the cardiac transplantation as a baseline and make a careful quantitation of cardiac chamber size, RV systolic function, both systolic and diastolic parameters of LV function, and pulmonary artery pressure. Subsequent
Restrepo, Diana Patricia; Tamayo, Alejandra
The onset of affective and psychotic in liver transplant patients symptoms, raises the need to explore the possible etiologies of mental symptoms. Case report and literature review. Four clinical cases of patients undergoing orthotopic liver transplantation, who in the early post transplant showed affective symptoms, delusions and psychomotor agitation for which they needed psychiatric hospitalization and treatment with psychotropic drugs are presented. Three of the patients had clinical improvement and one patient died by suicide. The development of mental symptoms in the post-transplant period opens the possibility of considering the secondary organic mental disorder a basic condition. The adverse drug reaction may explain affective mental disorders in these four cases were reported. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
Choy, Jonathan C.; Kerjner, Alexandra; Wong, Brian W.; McManus, Bruce M.; Granville, David J.
T cell-induced endothelial injury is an important event in the development of transplant vascular disease (TVD), the leading expression of chronic rejection of vascularized organ transplants. However, the precise contribution of perforin to vascular damage in allografts and resultant TVD has not been addressed in vivo. Minor histocompatability antigen mismatched mouse heterotopic cardiac transplants were performed from 129J donors into C57Bl/6 (wild-type (WT)) or perforin knockout (PKO) recipients. Perforin was abundant in immune infiltrates in the myocardium and vasculature of transplanted hearts in WT mice. Allograft coronary arteries in both WT and PKO mice had considerable vasculitis. There was also marked endothelial disruption, as well as TUNEL-positivity in the endothelial region, in coronary arteries of hearts transplanted into WT mice that was not evident in PKO recipients (P = 0.05). At 30 days post-transplantation, intimal thickening was assessed on elastic Van Gieson-stained ventricular sections. There was an average of 54.2 ± 6.7% luminal narrowing of coronary arteries in allografts from WT mice as compared to 13.4 ± 5.1% luminal narrowing in PKO counterparts (P < 0.00002). In summary, perforin plays a primary role in endothelial damage and the resultant onset and progression of TVD. PMID:15215168
Gesundheit, Benjamin; Shapira, Michael Y; Resnick, Igor B; Amar, Avraham; Kristt, Don; Dray, Lilianne; Budowski, Einat; Or, Reuven
Acute myeloid leukemia (AML) is an extremely aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). We report the successful outcome of cell-mediated cytokine-activated immunotherapy in a high-risk pediatric AML patient who relapsed shortly after allogeneic HSCT. Donor lymphocyte infusion along with interferon induced a graft-versus-leukemia effect, presenting as a reversible episode of graft-versus-host disease, which led to stable complete donor chimerism and total eradication of AML for over 24 months, at the time of this report. The curative potential of immunotherapy in hematological malignancies is discussed.
Exposure to air pollution increases risk of cardiovascular morbidity and mortality, especially in individuals with underlying cardiopulmonary disease. While the mechanisms accounting for these effects are unclear, several epidemiological studies have reported decreases in oxygen ...
Exposure to air pollution increases risk of cardiovascular morbidity and mortality, especially in individuals with underlying cardiopulmonary disease. While the mechanisms accounting for these effects are unclear, several epidemiological studies have reported decreases in oxygen ...
Background: Previous studies provided compelling evidences for particulate matter (PM) associated cardiovascular health effects. Elderly individuals, particularly those with preexisting conditions like hypertension are regarded to be vulnerable. Experimental data are warranted to...
Background: Previous studies provided compelling evidences for particulate matter (PM) associated cardiovascular health effects. Elderly individuals, particularly those with preexisting conditions like hypertension are regarded to be vulnerable. Experimental data are warranted to...
Graft Failure; Death; Acute Rejection of Renal Transplant; Infections; Bone Disease; Post Transplant Diabetes Mellitus; Quality of Life; HLA Antibody Production; Cardiovascular Risk Factors; Non-HLA Antibody Production
da Silva, Alexandre A; Spradley, Frank T; Granger, Joey P; Hall, John E; do Carmo, Jussara M
We previously demonstrated that leptin has powerful central nervous system (CNS)-mediated antidiabetic actions. In this study we tested the importance of melanocortin-4 receptors (MC4Rs) for leptin's ability to suppress food intake, increase blood pressure (BP) and heart rate (HR), and normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R-KO) and control wild-type (WT) rats were implanted with intracerebroventricular (ICV) cannula and BP and HR were measured 24 h/day by telemetry. After 5-day control period, an injection of streptozotocin (50 mg/kg, ip) was used to induce diabetes. Eight days after injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 μg/day) for 7 days. At baseline, MC4R-KO rats were hyperphagic and 40% heavier than WT rats. Despite obesity, BP was similar (112 ± 2 vs. 111 ± 2 mmHg) and HR was lower in MC4R-KO rats (320 ± 6 vs. 347 ± 5 beats/min). Induction of diabetes increased food intake (30%) and reduced BP (∼17 mmHg) and HR (∼61 beats/min) in WT rats, while food intake, BP, and HR were reduced by ∼10%, 7 mmHg, and 33 beats/min, respectively, in MC4R-KO rats. Leptin treatment normalized blood glucose (437 ± 10 to 136 ± 18 mg/dl), reduced food intake (40%), and increased HR (+60 beats/min) and BP (+9 mmHg) in WT rats. Only modest changes in blood glucose (367 ± 16 to 326 ± 23 mg/dl), food intake (5%), HR (+16 beats/min) and BP (+4 mmHg) were observed in MC4R-KO rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic antidiabetic, anorexic, and cardiovascular actions. Copyright © 2015 the American Physiological Society.
Slepian, Marvin J; Sheriff, Jawaad; Hutchinson, Marcus; Tran, Phat; Bajaj, Naing; Garcia, Joe G N; Scott Saavedra, S; Bluestein, Danny
Shear-mediated platelet activation (SMPA) is central in thrombosis of implantable cardiovascular therapeutic devices. Despite the morbidity and mortality associated with thrombosis of these devices, our understanding of mechanisms operative in SMPA, particularly in free flowing blood, remains limited. Herein we present and discuss a range of emerging mechanisms for consideration for "free flow" activation under supraphysiologic shear. Further definition and manipulation of these mechanisms will afford opportunities for novel pharmacologic and mechanical strategies to limit SMPA and enhance overall implant device safety.
Burton, Hannah; Douthwaite, Sam; Newsholme, William; Horsfield, Catherine
Hepatitis B virus (HBV) presents a risk to patients and staff in renal units. To minimise viral transmission, there are international and UK guidelines recommending HBV immunisation for patients commencing renal replacement therapy (RRT) and HBV surveillance in kidney transplant recipients. We report the case of a 56-year-old male who was immunised against HBV before starting haemodialysis. He received a deceased donor kidney transplant three years later, at which time there was no evidence of HBV infection. After a further six years he developed an acute kidney injury; allograft biopsy revealed an acute thrombotic microangiopathy (TMA) with glomerulitis, peritubular capillaritis, and C4d staining. Due to a “full house” immunoprofile, tests including virological screening were undertaken, which revealed acute HBV infection. Entecavir treatment resulted in an improvement in viral load and kidney function. HBV genotyping demonstrated a vaccine escape mutant, suggesting “past resolved” infection that reactivated with immunosuppression, though posttransplant acquisition cannot be excluded. This is the first reported case of acute HBV infection associated with immune complex mediated glomerulonephritis and TMA. Furthermore, it highlights the importance of HBV surveillance in kidney transplant recipients, which although addressed by UK guidelines is not currently practiced in all UK units. PMID:27800206
Salter, Tracey; Burton, Hannah; Douthwaite, Sam; Newsholme, William; Horsfield, Catherine; Hilton, Rachel
Hepatitis B virus (HBV) presents a risk to patients and staff in renal units. To minimise viral transmission, there are international and UK guidelines recommending HBV immunisation for patients commencing renal replacement therapy (RRT) and HBV surveillance in kidney transplant recipients. We report the case of a 56-year-old male who was immunised against HBV before starting haemodialysis. He received a deceased donor kidney transplant three years later, at which time there was no evidence of HBV infection. After a further six years he developed an acute kidney injury; allograft biopsy revealed an acute thrombotic microangiopathy (TMA) with glomerulitis, peritubular capillaritis, and C4d staining. Due to a "full house" immunoprofile, tests including virological screening were undertaken, which revealed acute HBV infection. Entecavir treatment resulted in an improvement in viral load and kidney function. HBV genotyping demonstrated a vaccine escape mutant, suggesting "past resolved" infection that reactivated with immunosuppression, though posttransplant acquisition cannot be excluded. This is the first reported case of acute HBV infection associated with immune complex mediated glomerulonephritis and TMA. Furthermore, it highlights the importance of HBV surveillance in kidney transplant recipients, which although addressed by UK guidelines is not currently practiced in all UK units.
Halloran, Philip F; Reeve, Jeff P; Pereira, Andre B; Hidalgo, Luis G; Famulski, Konrad S
Prospective studies of unselected indication biopsies from kidney transplants, combining conventional assessment with molecular analysis, have created a new understanding of transplant disease states and their outcomes. A large-scale Genome Canada grant permitted us to use conventional and molecular phenotypes to create a new disease classification. T cell-mediated rejection (TCMR), characterized histologically or molecularly, has little effect on outcomes. Antibody-mediated rejection (ABMR) manifests as microcirculation lesions and transcript changes reflecting endothelial injury, interferon-γ effects, and natural killer cells. ABMR is frequently C4d negative and has been greatly underestimated by conventional criteria. Indeed, ABMR, triggered in some cases by non-adherence, is the major disease causing failure. Progressive dysfunction is usually attributable to specific diseases, and pure calcineurin inhibitor toxicity rarely explains failure. The importance of ABMR argues against immunosuppressive drug minimization and stands as a barrier to tolerance induction. Microarrays also defined the transcripts induced by acute kidney injury (AKI), which correlate with reduced function, whereas histologic changes of acute tubular injury do not. AKI transcripts are induced in kidneys with late dysfunction, and are better predictors of failure than fibrosis and inflammation. Thus progression reflects ongoing parenchymal injury, usually from identifiable diseases such as ABMR, not destructive fibrosis.
Sellarés, J; de Freitas, D G; Mengel, M; Reeve, J; Einecke, G; Sis, B; Hidalgo, L G; Famulski, K; Matas, A; Halloran, P F
We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence.
Vogt, Daniel; Wu, Pei-Rung; Sorrells, Shawn F.; Arnold, Christine; Alvarez-Buylla, Arturo; Rubenstein, John L. R.
GABAergic cortical interneurons, derived from the embryonic medial and caudal ganglionic eminences (MGE and CGE), are functionally and morphologically diverse. Inroads have been made in understanding the roles of distinct cortical interneuron subgroups, however, there are still many mechanisms to be worked out that may contribute to the development and maturation of different types of GABAergic cells. Moreover, altered GABAergic signaling may contribute to phenotypes of autism, schizophrenia and epilepsy. Specific Cre-driver lines have begun to parcel out the functions of unique interneuron subgroups. Despite the advances in mouse models, it is often difficult to efficiently study GABAergic cortical interneuron progenitors with molecular approaches in vivo. One important technique used to study the cell autonomous programming of these cells is transplantation of MGE cells into host cortices. These transplanted cells migrate extensively, differentiate, and functionally integrate. In addition, MGE cells can be efficiently transduced with lentivirus immediately prior to transplantation, allowing for a multitude of molecular approaches. Here we detail a protocol to efficiently transduce MGE cells before transplantation for in vivo analysis, using available Cre-driver lines and Cre-dependent expression vectors. This approach is advantageous because it combines precise genetic manipulation with the ability of these cells to disperse after transplantation, permitting greater cell-type specific resolution in vivo. PMID:25938985
Wikström Shemer, Elisabeth A; Stephansson, Olof; Thuresson, Marcus; Thorsell, Malin; Ludvigsson, Jonas F; Marschall, Hanns-Ulrich
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. It is associated with hepatobiliary diseases that might predispose to cancer and also with gestational diabetes and preeclampsia. In this study, we examined associations between ICP and cancer, and immune-mediated and cardiovascular diseases. By linking the Swedish Medical Birth Register and the Swedish Patient Register, we identified 11,388 women with ICP and 113,893 matched women without ICP who gave birth between 1973 and 2009. Diagnoses of cancer and immune-mediated and cardiovascular diseases both before and after delivery were obtained from the Patient Register. The main outcome measures were hazard ratios (HRs), calculated through Cox regression, for the indicated diseases after delivery. ICP was not associated with later overall cancer (HR 1.07, 95% confidence interval [CI] 0.94-1.21), but it was associated with later liver and biliary tree cancer (HR 3.61, 95% CI 1.68-7.77, and 2.62, 95% CI 1.26-5.46, respectively). ICP was also associated with later immune-mediated diseases (HR 1.28, 95% CI 1.19-1.38), and specifically diabetes mellitus (HR 1.47, 95% CI 1.26-1.72), thyroid disease (HR 1.30, 95% CI 1.14-1.47), psoriasis (HR 1.27, 95% CI 1.07-1.51), inflammatory polyarthropathies (HR 1.32, 95% CI 1.11-1.58) and Crohn's disease (HR 1.55, 95% CI 1.14-2.10), but not ulcerative colitis (HR 1.21, 95% CI 0.93-1.58). Women with ICP also had a small increased risk of later cardiovascular disease (HR 1.12, 95% CI 1.06-1.19). Women with ICP have increased risk of later hepatobiliary cancer and immune-mediated and cardiovascular diseases. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Perna, Laura; Mons, Ute; Schöttker, Ben; Brenner, Hermann
Several studies reported an association between concentrations of serum uric acid and cognitive function, but the evidence is contradictory. It is known that uric acid is associated with cardiovascular diseases, especially among women. Stratifying by sex and history of cardiovascular disease may clarify whether uric acid is an independent risk factor for cognitive dysfunction. A population-based study was conducted in the German State of Saarland. A subgroup of participants aged ≥70years underwent a comprehensive assessment of cognitive function. Linear regression models and restricted cubic spline functions were used to assess association of uric acid with cognitive performance in 1144 study participants. High levels of uric acid were associated with worse cognitive performance among women (-0.57; 95% CI: -1.10 to -0.04) but not among men (-0.12; 95% CI: -0.64 to 0.39). The association was much stronger among the subgroup of women with cardiovascular diseases (-1.91; 95% CI: -3.15 to -0.67) and also revealed a dose-response relationship in this subgroup. Serum uric acid showed an inverse association with cognitive function among women and the association was amplified by the presence of cardiovascular disease. These results highlight the importance of stratifying by sex and cardiovascular disease in future studies on uric acid and cognition. Copyright © 2015 Elsevier Inc. All rights reserved.
Huang, G; Wilson, N A; Reese, S R; Jacobson, L M; Zhong, W; Djamali, A
Animal models of antibody-mediated rejection (ABMR) may provide important evidence supporting proof of concept. We elicited donor-specific antibodies (DSA) by transfusion of donor blood (Brown Norway RT1(n) ) into a complete mismatch recipient (Lewis RT1(l) ) 3 weeks prior to kidney transplantation. Sensitized recipients had increased anti-donor splenocyte IgG1, IgG2b and IgG2c DSA 1 week after transplantation. Histopathology was consistent with ABMR characterized by diffuse peritubular capillary C4d and moderate microvascular inflammation with peritubular capillaritis + glomerulitis > 2. Immunofluorescence studies of kidney allograft tissue demonstrated a greater CD68/CD3 ratio in sensitized animals, primarily of the M1 (pro-inflammatory) phenotype, consistent with cytokine gene analyses that demonstrated a predominant T helper (TH )1 (interferon-γ, IL-2) profile. Immunoblot analyses confirmed the activation of the M1 macrophage phenotype as interferon regulatory factor 5, inducible nitric oxide synthase and phagocytic NADPH oxidase 2 were significantly up-regulated. Clinical biopsy samples in sensitized patients with acute ABMR confirmed the dominance of M1 macrophage phenotype in humans. Despite the absence of tubulitis, we were unable to exclude the effects of T cell-mediated rejection. These studies suggest that M1 macrophages and TH 1 cytokines play an important role in the pathogenesis of acute mixed rejection in sensitized allograft recipients.
Venner, J M; Hidalgo, L G; Famulski, K S; Chang, J; Halloran, P F
The recent recognition that antibody-mediated rejection (ABMR) is the major cause of kidney transplant loss creates strong interest in its pathogenesis. We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set. In the Combined Set of 703 biopsies, 2603 transcripts were significantly changed (FDR < 0.05) in ABMR versus all other biopsies. In cultured cells, the transcripts strongly associated with ABMR were expressed in endothelial cells, e.g. cadherins CDH5 and CDH13; IFNG-treated endothelial cells, e.g. phospholipase PLA1A and chemokine CXCL11; or NK cells, e.g. cytotoxicity molecules granulysin (GNLY) and FGFBP2. Other ABMR transcripts were expressed in normal kidney but not cell lines, either increased e.g. Duffy chemokine receptor (DARC) or decreased e.g. sclerostin (SOST). Pathway analysis of ABMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors; leukocyte-endothelial interactions; and NK signaling, including evidence for CD16a Fc receptor signaling elements shared with T cells. These data support a model of ABMR involving injury-repair in the microcirculation induced by cognate recognition involving antibody and CD16a, triggering IFNG release and antibody-dependent NK cell-mediated cytotoxicity.
Frazer, Nicole L; Larkin, Kevin T; Goodie, Jeffrey L
To examine whether differences in behavioral responses to stress mediated or moderated the relation between cardiovascular response to stress and parental history of hypertension, 64 healthy undergraduates-16 men with hypertensive parents (PH+), 16 men without hypertensive parents (PH-), 16 PH+ women, and 16 PH- women-participated in a mental arithmetic task, mirror tracing task, and 2 interpersonal role plays. PH+ participants exhibited higher resting heart rates than PH- participants and higher resting systolic blood pressures (SBPs) than PH- women. PH+ participants exhibited greater SBP responses to tasks and engaged in more negative verbal and nonverbal behavior across tasks than PH- counterparts. Differences in behavioral responding neither mediated nor moderated the observed relation between parental history status and SBP response to stress.
Bożek-Pająk, D; Ziaja, J; Kowalik, A; Farnik, M; Kolonko, A; Kujawa-Szewieczek, A; Kamińska, D; Kuriata-Kordek, M; Król, R; Więcek, A; Klinger, M; Cierpka, L
The beneficial influence of kidney (KTx) or simultaneous pancreas and kidney transplantation (SPK) on quality of life (QOL) in patients with end-stage kidney disease caused by type 1 diabetes mellitus was confirmed in many studies. The aim of this study was to identify factors that influence QOL of patients in long-term follow-up after SPK or KTx. Twenty-seven SPK and 26 KTx patients with good function of transplanted organs at least 1 year after transplantation were enrolled into the analysis. To estimate QOL of the recipients the Kidney Disease and Quality of Life Short Form was applied. Within the whole analyzed group, the necessity of exogenous insulin administration correlated (P < .05) with symptom/problem list (γ = -0.35), effects of kidney disease (-0.38), cognitive function (-0.47), sleep (-0.42), overall health (-0.47), physical functioning (-0.61), role-physical (-0.32), pain (-0.50), general health (-0.32), emotional well-being (-0.31), role-emotional (-0.36), social function (-0.33), energy/fatigue (-0.44), and the SF-12 physical composite (-0.44). History of cardiovascular episode correlated (P < .05) with symptom/problem list (γ = -0.59), effects of kidney disease (-0.46), burden of kidney disease (-0.56), sleep (-0.54), social support (-0.51), physical functioning (-0.55), role-physical (-0.70), pain (-0.60), general health (-0.57), emotional well-being (-0.45), role-emotional (-0.95), social function (-0.58), energy/fatigue (-0.59), SF-12 physical composite (-0.45), and SF-12 mental composite (-0.83). Exogenous insulin administration and history of cardiovascular episode are the most important factors influencing QOL in patients after SPK or KTx, particularly worsening its physical components. Copyright © 2016 Elsevier Inc. All rights reserved.
Zhang, Yanling; Gao, Yongxin; Speth, Robert C; Jiang, Nan; Mao, Yingying; Sumners, Colin; Li, Hongwei
Viral vectors have been utilized extensively to introduce genetic material into the central nervous system. In order to investigate gene functions in cardiovascular control regions of rat brain, we applied WPRE (woodchuck hepatitis virus post-transcriptional regulatory element) enhanced-adenoviral (Ad) and adeno-assoicated virus (AAV) type 2 vectors to mediate neuronal gene delivery to the paraventricular nucleus of the hypothalamus, the nucleus tractus solitarius and the rostral ventrolateral medulla, three important cardiovascular control regions known to express renin-angiotensin system (RAS) genes. Ad or AAV2 harboring an enhanced green fluorescent protein (EGFP) reporter gene or the angiotensin type 2 receptor gene were microinjected into these brain regions in adult rats. Our results demonstrated that both AAV2 and Ad vectors elicited long-term neuronal transduction in these regions. Interestingly, we found that the WPRE caused expression of GFP driven by the synapsin1 promoter in pure glial cultures or co-cultures of neurons and glia derived from rat hypothalamus and brainstem. However, in rat paraventricular nucleus WPRE did not cause expression of GFP in glia. This demonstrates the potential use of these vectors in studies of physiological functions of certain genes in the cardiovascular control regions of the brain.
Clark, Vernessa R; Cobb, Renia E B; Hopkins, Reginald; Smith, Christine E
The purpose of the present study was to examine the ability of Black racial identity to mediate cardiovascular reactivity to racism. The Multidimensional Model of Racial Identity (MMRI), which consists of four dimensions, salience, centrality, regard, and ideology was used to define Black racial identity. The subdimensions of ideology are oppressed minority, nationalist, humanist, and assimilationist racial identities. Heart rate, cardiac output, stroke volume, and blood pressure were measured in 72 African-American men as they viewed a videotaped scene depicting racial profiling and a neutral scene. We hypothesized that individuals with high levels of Black-oriented identities (centrality, public regard, private regard, oppressed minority, and nationalist) would be less stressed by the racial profiling scenes than those low in these identities. In addition, we predicted that individuals with high levels of non-Black-oriented identities (assimilationist, humanist) would be more stressed by the racial profiling scenes than those with low levels of these identities. Private regard, humanist, and assimilationist racial identities were significantly associated with increased cardiovascular reactivity to the scenes. Specifically, private regard significantly predicted cardiac output and stroke volume responses to the scenes. In addition, assimilationist and humanist racial identities were associated with greater blood output and faster heart rates in response to the scenes. Although private regard (Black oriented) and assimilationist and humanist (non- Black oriented) racial identities showed elevated cardiovascular reactivity to the scenes, the underlying mechanisms of these associations may differ.
Qian, Zhiping; Lee, Chih-Yuan; Murata, Kazunori; Liu, Jinhuan; Fox-Talbot, Karen; Wasowska, Barbara A; Baldwin, William M
Many patients on the waiting list for transplants are sensitized from previous blood transfusions, pregnancy, or transplants. We investigated the role of complement in acute and chronic pathology in hearts transplanted to sensitized rats. Blood was transfused from allogeneic PVG.R8 rats or control isogeneic PVG.1U rats to C6-sufficient and -deficient PVG.1U rats. Three weeks later hearts were transplanted from PVG.R8 donors and low-dose cyclosporin A was initiated. Allogeneic but not isogeneic blood transfusion elicited strong immunoglobulin (Ig) M, IgG1 and IgG2b alloantibody responses. Sensitization caused accelerated acute rejection of cardiac allografts by C6-sufficient recipients (4 days). In contrast, allografts functioned over 40 days in all C6-deficient recipients, but sensitization caused increased interstitial fibrosis and chronic vasculopathy. Circulating alloantibodies were associated with deposits of C4d on the vascular endothelium together with pericapillary accumulation of neutrophils and macrophages in the grafts. In contrast, T cells accumulated in periarterial lymphatics that did not have C4d deposits. Presensitization by allogeneic blood transfusion causes accelerated acute graft rejection in the presence of the complete complement cascade. In the absence of C6, macrophages colocalized with deposits of C4d and T cells accumulated in the periarterial lymphatics.
Shimizu, Hiroaki; Kataoka, Masaaki; Ohtsuka, Masayuki; Ito, Hiroshi; Kimura, Fumio; Togawa, Akira; Yoshidome, Hiroyuki; Kato, Atsushi; Miyazaki, Masaru
The precise mechanisms of pulmonary injury after liver transplantation, especially those associated with cold ischemia time, are not yet clear. We histologically evaluated the number of accumulated polymorphonuclear neutrophils (PMNs) in lungs, and pulmonary injury after liver transplantation with varying periods of cold ischemia (1, 6 and 24h in University of Wisconsin solution at 4 degrees C). Pulmonary expression of cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) mRNA were investigated by quantitative reverse-transcription polymerase chain reaction. The levels of tumor necrosis factor-alpha (TNFalpha), which stimulates these chemokine productions, were also monitored after liver transplantation. The accumulated PMN number, and lung edema, quantified by wet to dry weight ratio, significantly increased in the 24-hr cold-ischemia group after 3h of reperfusion, compared with the 1-hr and 6-hr cold-ischemia groups. Both pulmonary MIP-2 and CINC mRNA expression in the 24-hr group were remarkably upregulated at this time. According to the histological examination, pulmonary injury in the 24-hr group was prominent, characterized by interstitial edema, and alveolar hemorrhage. Furthermore, TNF in the hepatic vein was detected only in the 24-hr group. Cold ischemia time prolongation upregulates pulmonary MIP-2 and CINC expression via hepatic-derived TNFalpha, and promotes PMN accumulation, resulting in increased pulmonary injury after liver transplantation.
Rubach, M P; Pavlisko, E N; Perfect, J R
We describe a case of pericarditis and large pericardial effusion in a 63-year-old African-American man undergoing autologous hematopoietic stem cell transplant for multiple myeloma. Pericardial tissue biopsy demonstrated fibrinous pericarditis, and immunohistochemistry stains were positive for respiratory syncytial virus. The patient improved with oral ribavirin and intravenous immune globulin infusions. © 2013 John Wiley & Sons A/S.
Aspirin Use and Incident Cardiovascular Disease, Kidney Failure, and Death in Stable Kidney Transplant Recipients: A Post Hoc Analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial
Dad, Taimur; Tighiouart, Hocine; Joseph, Alin; Bostom, Andrew; Carpenter, Myra; Hunsicker, Lawrence; Kusek, John W.; Pfeffer, Marc; Levey, Andrew S.; Weiner, Daniel E.
Background Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain. Study Design Post hoc cohort analysis of FAVORIT, a randomized trial examining the effect of homocysteine-lowering vitamins on CVD in kidney transplant recipients. Setting & Participants Prevalent adult kidney transplant recipients with hyperhomocysteinemia and stable kidney function from the United States, Canada, and Brazil participating in FAVORIT, with no known history of CVD. Predictor Aspirin use, with aspirin users matched to nonusers using a propensity score. Outcomes Incident CVD events, kidney failure, all-cause mortality, a composite of CVD events or mortality, and a composite of kidney failure or mortality. Cox proportional hazards models with a robust variance to account for the correlation in outcomes within matched pairs were sequentially adjusted for demographic, clinical, and laboratory characteristics to assess the association between aspirin use and events. Results 981 aspirin users were matched to 981 nonusers. During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92–1.58], 0.92 [95% CI, 0.69–1.23], 1.19 [95% CI, 0.81–1.74], 1.03 [0.82–1.31], and 1.11 [95% CI, 0.88–1.38], respectively). Limitations We did not examine dose or continued use of aspirin after randomization. CVD history is dependent on participant report at baseline. Aspirin use was non–randomly assigned. Conclusions Aspirin use is not associated with reduced risk for incident CVD, all
Zhang, Zhi-Hua; Felder, Robert B.
Systemic administration of tumour necrosis factor - alpha (TNF-α) induces the release of norepinephrine (NE) in the paraventricular nucleus (PVN) of hypothalamus and an increase in expression of corticotrophin-releasing-factor (CRF) and CRF type 1 receptors. We explored the hypothesis that CRF and NE in PVN mediate the cardiovascular and sympathetic responses to acute systemic administration of TNF-α. In anaesthetised rats, the increases in arterial pressure and heart rate induced by intracarotid artery injection of TNF-α were attenuated by intracerebroventricular (ICV) injection of either the α1-adrenergic antagonist prazosin or the CRF antagonist α-helical CRF. Prazosin blocked the TNF-α-induced increase in renal sympathetic nerve activity (RSNA), while α-helical CRF substantially reduced the RSNA response. Conversely, CRF and the α1-adrenergic agonist phenylephrine (PE), administered ICV, both elicited increases in PVN neuronal activity, RSNA, arterial pressure and heart rate. Microinjection of CRF and PE directly into PVN evoked smaller responses. These results are consistent with the hypothesis that NE and CRF in the PVN mediate the cardiovascular and sympathetic responses to acute systemic administration of TNF-α. PMID:18777604
Shih, C-D; Chuang, Y-C
The present study investigated the cardiovascular effects of orexin (OX)-A and OX-B in the nucleus tractus solitarii (NTS) and delineated the engagement of nitric oxide (NO) and GABA in OX-induced cardiovascular responses. In adult male Sprague-Dawley rats maintained under propofol anesthesia, microinjection bilaterally into the NTS of OX-A or OX-B evoked bi-directional cardiovascular effects in a dose-dependent manner. At a lower dose (5 pmol), OX-A or OX-B decreased systemic arterial pressure (SAP), heart rate (HR), and power density of the vasomotor components of SAP signals, our experimental index for sympathetic neurogenic vasomotor tone. At higher doses (>20 pmol), these two compounds elicited cardiovascular excitatory responses. These bi-directional cardiovascular effects of OX were abolished by co-injection of an OX(1) receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride (SB-334867, 0.75 nmol) or the OX(2) receptor antiserum (1:20). In addition, the vasodepressor effects of low dose (5 pmol) OX-A or OX-B in the NTS were attenuated by a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME, 5 nmol), a neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (2.5 pmol) or the soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (250 pmol). The vasopressor effects of high dose (200 pmol) OX were reversed by co-administration with GABA(A) or GABA(B) receptor antagonist, bicuculline methiodine (10 pmol) or 2-hydroxy saclofen (100 pmol), or l-NAME (5 nmol). Our results indicate that OX-A or OX-B elicited bi-directional cardiovascular effects via OX receptor-dependent mechanisms. The vasodepressor effects of OX were induced by the nNOS-derived NO and activation of sGC-associated signaling pathway, whereas the vasopressor effects were mediated by interaction with GABAergic or nitrergic neurotransmission in the NTS.
Kizilbash, Sarah; Claes, Donna; Ashoor, Isa; Chen, Ashton; Jandeska, Sara; Matar, Raed Bou; Misurac, Jason; Sherbotie, Joseph; Twombley, Katherine; Verghese, Priya
Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection.
Khankan, Rana R; Griffis, Khris G; Haggerty-Skeans, James R; Zhong, Hui; Roy, Roland R; Edgerton, V Reggie; Phelps, Patricia E
Multiple neural and peripheral cell types rapidly respond to tissue damage after spinal cord injury to form a structurally and chemically inhibitory scar that limits axon regeneration. Astrocytes form an astroglial scar and produce chondroitin sulfate proteoglycans (CSPGs), activate microglia, and recruit blood-derived immune cells to the lesion for debris removal. One beneficial therapy, olfactory ensheathing cell (OEC) transplantation, results in functional improvements and promotes axon regeneration after spinal cord injury. The lack of an OEC-specific marker, however, has limited the investigation of mechanisms underlying their proregenerative effects. We compared the effects of enhanced green fluorescent protein-labeled fibroblast (FB) and OEC transplants acutely after a complete low-thoracic spinal cord transection in adult rats. We assessed the preservation of neurons and serotonergic axons, the levels of inhibitory CSPGs and myelin debris, and the extent of immune cell activation between 1 and 8 weeks postinjury. Our findings indicate that OECs survive longer than FBs post-transplantation, preserve axons and neurons, and reduce inhibitory molecules in the lesion core. Additionally, we show that OECs limit immune-cell activation and infiltration, whereas FBs alter astroglial scar formation and increase immune-cell infiltration and concomitant secondary tissue damage. Administration of cyclosporine-A to enhance graft survival demonstrated that immune suppression can augment OEC contact-mediated protection of axons and neurons during the first 2 weeks postinjury. Collectively, these data suggest that OECs have neuroprotective and immunomodulatory mechanisms that create a supportive environment for neuronal survival and axon regeneration after spinal cord injury. Spinal cord injury creates physical and chemical barriers to axon regeneration. We used a complete spinal cord transection model and olfactory ensheathing cell (OEC) or fibroblast (FB; control
Khankan, Rana R.; Griffis, Khris G.; Haggerty-Skeans, James R.; Zhong, Hui; Roy, Roland R.; Edgerton, V. Reggie
Multiple neural and peripheral cell types rapidly respond to tissue damage after spinal cord injury to form a structurally and chemically inhibitory scar that limits axon regeneration. Astrocytes form an astroglial scar and produce chondroitin sulfate proteoglycans (CSPGs), activate microglia, and recruit blood-derived immune cells to the lesion for debris removal. One beneficial therapy, olfactory ensheathing cell (OEC) transplantation, results in functional improvements and promotes axon regeneration after spinal cord injury. The lack of an OEC-specific marker, however, has limited the investigation of mechanisms underlying their proregenerative effects. We compared the effects of enhanced green fluorescent protein-labeled fibroblast (FB) and OEC transplants acutely after a complete low-thoracic spinal cord transection in adult rats. We assessed the preservation of neurons and serotonergic axons, the levels of inhibitory CSPGs and myelin debris, and the extent of immune cell activation between 1 and 8 weeks postinjury. Our findings indicate that OECs survive longer than FBs post-transplantation, preserve axons and neurons, and reduce inhibitory molecules in the lesion core. Additionally, we show that OECs limit immune-cell activation and infiltration, whereas FBs alter astroglial scar formation and increase immune-cell infiltration and concomitant secondary tissue damage. Administration of cyclosporine-A to enhance graft survival demonstrated that immune suppression can augment OEC contact-mediated protection of axons and neurons during the first 2 weeks postinjury. Collectively, these data suggest that OECs have neuroprotective and immunomodulatory mechanisms that create a supportive environment for neuronal survival and axon regeneration after spinal cord injury. SIGNIFICANCE STATEMENT Spinal cord injury creates physical and chemical barriers to axon regeneration. We used a complete spinal cord transection model and olfactory ensheathing cell (OEC) or
Del Bello, Arnaud; Danjoux, Marie; Congy-Jolivet, Nicolas; Lavayssière, Laurence; Esposito, Laure; Muscari, Fabrice; Kamar, Nassim
Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Tourneur, Emilie; Ben Mkaddem, Sanae; Chassin, Cécilia; Bens, Marcelle; Goujon, Jean-Michel; Charles, Nicolas; Pellefigues, Christophe; Aloulou, Meryem; Hertig, Alexandre; Monteiro, Renato C.; Girardin, Stephen E.; Philpott, Dana J.; Rondeau, Eric
Acute pyelonephritis (APN), which is mainly caused by uropathogenic Escherichia coli (UPEC), is the most common bacterial complication in renal transplant recipients receiving immunosuppressive treatment. However, it remains unclear how immunosuppressive drugs, such as the calcineurin inhibitor cyclosporine A (CsA), decrease renal resistance to UPEC. Here, we investigated the effects of CsA in host defense against UPEC in an experimental model of APN. We show that CsA-treated mice exhibit impaired production of the chemoattractant chemokines CXCL2 and CXCL1, decreased intrarenal recruitment of neutrophils, and greater susceptibility to UPEC than vehicle-treated mice. Strikingly, renal expression of Toll-like receptor 4 (Tlr4) and nucleotide-binding oligomerization domain 1 (Nod1), neutrophil migration capacity, and phagocytic killing of E. coli were significantly reduced in CsA-treated mice. CsA inhibited lipopolysaccharide (LPS)-induced, Tlr4-mediated production of CXCL2 by epithelial collecting duct cells. In addition, CsA markedly inhibited Nod1 expression in neutrophils, macrophages, and renal dendritic cells. CsA, acting through inhibition of the nuclear factor of activated T-cells (NFATs), also markedly downregulated Nod1 in neutrophils and macrophages. Silencing the NFATc1 isoform mRNA, similar to CsA, downregulated Nod1 expression in macrophages, and administration of the 11R-VIVIT peptide inhibitor of NFATs to mice also reduced neutrophil bacterial phagocytosis and renal resistance to UPEC. Conversely, synthetic Nod1 stimulating agonists given to CsA-treated mice significantly increased renal resistance to UPEC. Renal transplant recipients receiving CsA exhibited similar decrease in NOD1 expression and neutrophil phagocytosis of E. coli. The findings suggest that such mechanism of NFATc1-dependent inhibition of Nod1-mediated innate immune response together with the decrease in Tlr4-mediated production of chemoattractant chemokines caused by CsA may
Kanbay, Mehmet; Bayram, Yeter; Solak, Yalcin; Sanders, Paul W.
Potassium and sodium share a yin/yang relationship in the regulation of blood pressure (BP). BP is directly associated with the total body sodium and negatively correlated with the total body potassium. Epidemiologic, experimental, and clinical studies have demonstrated that potassium is a significant regulator of BP and further improves cardiovascular outcomes. Hypertensive cardiovascular damage, stroke and stroke-related death are accelerated by salt intake but could be prevented by increased dietary potassium intake. The antihypertensive effect of potassium supplementation appears to occur through several mechanisms that include regulation of vascular sensitivity to catecholamines, promotion of natriuresis, limiting plasma renin activity, and improving endothelial function. In the absence of chronic kidney disease, the combined evidence supports a diet high in potassium content serves a vasculoprotective function, especially in the setting of salt-sensitive hypertension and prehypertension. PMID:23735420
Kanbay, Mehmet; Bayram, Yeter; Solak, Yalcin; Sanders, Paul W
Potassium and sodium share a yin/yang relationship in the regulation of blood pressure (BP). BP is directly associated with the total body sodium and negatively correlated with the total body potassium. Epidemiologic, experimental, and clinical studies have shown that potassium is a significant regulator of BP and further improves cardiovascular outcomes. Hypertensive cardiovascular damage, stroke, and stroke-related death are accelerated by salt intake but might be curbed by increasing dietary potassium intake. The antihypertensive effect of potassium supplementation appears to occur through several mechanisms that include regulation of vascular sensitivity to catecholamines, promotion of natriuresis, limiting plasma renin activity, and improving endothelial function. In the absence of chronic kidney disease, the combined evidence suggests that a diet rich in potassium content serves a vasculoprotective function, particularly in the setting of salt-sensitive hypertension and prehypertension.
Huebsch, Nathaniel; Lippens, Evi; Lee, Kangwon; Mehta, Manav; Koshy, Sandeep T.; Darnell, Max C.; Desai, Rajiv M.; Madl, Christopher M.; Xu, Maria; Zhao, Xuanhe; Chaudhuri, Ovijit; Verbeke, Catia; Kim, Woo Seob; Alim, Karen; Mammoto, Akiko; Ingber, Donald E.; Duda, Georg N.; Mooney, David J.
The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype. Stem cell behaviour can also be controlled in vitro by manipulating the elasticity of both porous and non-porous materials, yet translation to therapeutic processes in vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying, respectively, the hydrogel’s elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel’s elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direct therapeutic stem cell behaviours in situ.
Hegazy, S K; Adam, A G; Hamdy, N A; Khalafallah, N M
Infections downregulate cytochrome-P activities and thus may alter drug disposition, especially for drugs with a narrow therapeutic index. Cyclosporine (CyA), still used for the prevention of allograft rejection in renal transplant recipients in Egypt, seems to be affected by these infectious changes, based on random clinical observations. In the present study, the effects of bacterial and fungal infection on CyA metabolism were studied in renal transplant patients and subsequent nephrotoxicity was monitored. Twenty renal transplant patients, diagnosed with fungal or bacterial infection, were recruited from the renal transplantation outpatient clinic in Alexandria University Hospitals. No dose adjustment in CyA was performed at least 1 week before the onset of infection. Exclusion criteria were patients with acute or chronic unstable liver disease, elderly patients, and patients on concomitant drugs affecting CyA metabolism. CyA trough levels and serum creatinine (SCR) concentrations were measured by fluorescence polarization immunoassay and enzymatic assay, respectively, pre-infection, during infection and in many cases, post infection. CyA trough levels and SCR concentrations increased significantly during the infection (P < 0.001, P = 0.002) respectively. Of the patients, 87% experienced a concomitant rise in CyA trough level and SCR concentrations. No significant difference between pre-infection and post-infection levels of CyA trough and SCR was found. CyA trough and SCR levels increased during bacterial and fungal infections and returned to pre-infection levels once the infection was resolved. The data generated stress the importance of monitoring CyA levels during episodes of infection. Our recommendations concerning CyA dose adjustment differ according to severity and duration of infection. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Whangbo, J; Ritz, J; Bhatt, A
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota. PMID:27526283
Salguero, Gustavo; Daenthanasanmak, Anusara; Münz, Christian; Raykova, Ana; Guzmán, Carlos A; Riese, Peggy; Figueiredo, Constanca; Länger, Florian; Schneider, Andreas; Macke, Laura; Sundarasetty, Bala Sai; Witte, Torsten; Ganser, Arnold; Stripecke, Renata
De novo regeneration of immunity is a major problem after allogeneic hematopoietic stem cell transplantation (HCT). HCT modeling in severely compromised immune-deficient animals transplanted with human stem cells is currently limited because of incomplete maturation of lymphocytes and scarce adaptive responses. Dendritic cells (DC) are pivotal for the organization of lymph nodes and activation of naive T and B cells. Human DC function after HCT could be augmented with adoptively transferred donor-derived DC. In this study, we demonstrate that adoptive transfer of long-lived human DC coexpressing high levels of human IFN-α, human GM-CSF, and a clinically relevant Ag (CMV pp65 protein) promoted human lymphatic remodeling in immune-deficient NOD.Rag1(-/-).IL-2rγ(-/-) mice transplanted with human CD34(+) cells. After immunization, draining lymph nodes became replenished with terminally differentiated human follicular Th cells, plasma B cells, and memory helper and cytotoxic T cells. Human Igs against pp65 were detectable in plasma, demonstrating IgG class-switch recombination. Human T cells recovered from mice showed functional reactivity against pp65. Adoptive immunotherapy with engineered DC provides a novel strategy for de novo immune reconstitution after human HCT and a practical and effective tool for studying human lymphatic regeneration in vivo in immune deficient xenograft hosts.
da Silva, L G; Menezes, R C A; Villela, D C; Fontes, M A P
Neurons in the region of dorsomedial hypothalamus are involved in the organization of the physiological responses to emotional stress. We have recently shown that the cardiovascular response evoked by activation of dorsomedial hypothalamus neurons is largely dependent on a synaptic relay with the lateral/dorsolateral periaqueductal gray region. In this study, we aimed to investigate whether excitatory amino acid receptors at the lateral/dorsolateral periaqueductal gray region are involved in mediating the response evoked by activation of dorsomedial hypothalamus neurons. In conscious rats, the cardiovascular effects produced by microinjection of GABA(A) receptor antagonist, bicuculline methiodide into the dorsomedial hypothalamus were evaluated before and after injection of different excitatory amino acid antagonists into lateral/dorsolateral periaqueductal gray region. Pretreatment of lateral/dorsolateral periaqueductal gray region with the non-selective ionotropic excitatory amino acid receptor antagonist kynurenic acid or with the N-methyl-D-aspartate receptor-selective antagonist, MK-801, largely reduced the tachycardic and pressor effects evoked by activation of dorsomedial hypothalamus neurons by bicuculline methiodide microinjection (heart rate 90 and 74%; blood pressure 81 and 84%, respectively). The non-N-methyl-D-aspartate receptor-selective antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, did not alter the cardiovascular response evoked by dorsomedial hypothalamus activation. In an additional series of experiments, microinjection of the N-methyl-D-aspartate receptor agonist, N-methyl-D-aspartate, into the lateral/dorsolateral periaqueductal gray region, evoked an increase in heart rate and a pressor response that was accompanied by an increase in locomotor activity. These effects were not altered by pretreatment of lateral/dorsolateral periaqueductal gray region neurons with 6-cyano-7-nitroquinoxaline-2,3-dione but were completely abolished by MK-801
Dhoke, Neha R; Geesala, Ramasatyaveni; Das, Amitava
Stem cells exposed to pathological levels of reactive oxygen species (ROS) at wound sites fail to regenerate tissue. The molecular mechanism underlying differential levels of ROS-mediated regulation of stem cells remains elusive. This study elucidates the mechanistic role of catalase at 10 μM H2O2-induced proliferation of mouse bone marrow stromal (BMSC) and hematopoietic (HSPC) stem/progenitor cells. BMSCs and HSPCs depicted an increased growth rate and colony formation, in the presence of 10 μM but not 100 μM concentration of H2O2, an effect that was perturbed by Vit. C. Mechanistically, JNK activation-FOXO3a nuclear translocation and binding of FOXO3a to catalase promoter at 10 μM H2O2 led to an increased expression and activity of anti-oxidant gene, catalase. This was followed by an increased proliferative phenotype via the AKT-dependent pathway that was perturbed in the presence of catalase-inhibitor, 3-aminotriazole due to an increased ROS-mediated inactivation of AKT. Preclinically, 10 μM H2O2-mediated preconditioning of BMSCs/HSPCs transplantation accelerated wound closure, enhanced catalase expression, and decreased ROS levels at the wound site. Transplantation of male donor cells into female recipient mice or GFP-labeled BMSCs or HSPCs depicted an increased engraftment and proliferation in preconditioned cell transplanted groups as compared with the wound control. Wound healing occurred via keratinocyte generation and vascularization in preconditioned BMSCs, whereas only neo-vascularization occurred in the preconditioned HSPCs transplanted groups. Innovation and Conclusion: Our study suggests a distinct role of catalase that protects BMSCs and HSPCs from low ROS and promotes proliferation. Transplantation of preconditioned stem cells enhanced wound tissue regeneration with a better antioxidant defense mechanism-as a therapeutic approach in stem cell transplantation-mediated tissue regeneration. Antioxid. Redox Signal. 00, 000-000.
Van, Nguyen Dinh; Falk, Christine S; Sandmann, Lisa; Vondran, Florian W R; Helfritz, Fabian; Wedemeyer, Heiner; Manns, Michael P; Ciesek, Sandra; von Hahn, Thomas
Objective In HCV infected individuals graft infection occurs shortly after orthotopic liver transplantation (OLT). We aimed to describe the composition of the inflammatory response at this time, how it affects the HCV replication cycle and identify novel proviral and antiviral factors. Design We used a Luminex assay to quantify 50 inflammatory mediators in sera before and shortly after OLT. In vitro grown HCV based on the JFH-1 isolate were used to characterise the effects of patient sera and individual mediators on HCV. Results Although the mediator composition is highly variable between individuals, sera drawn immediately post-OLT significantly enhance HCV infectivity compared with control sera from before OLT in about half of the cases. Among 27 non-interferon inflammatory mediators fibroblast growth factor (FGF)-2 stood out as it enhanced HCV RNA replication and release of infectious particles. The effect was concentration-dependent and detectable in dividing and non-dividing cells. Moreover, pharmacological inhibition of FGF-2 receptor signalling abrogated the enhancing effect of FGF-2 and inhibited HCV replication in the absence of serum FGF-2 suggesting that HCV replication is dependent on basal activation of the FGF-2 triggered signalling pathway. Finally, in individuals with chronic HCV infection with high viral load, serum FGF-2 was significantly higher compared with those with low viral load. Conclusions Although no single mediator may account for this effect, serum shortly post-OLT enhances HCV infection. FGF-2 is a novel endogenous driver of HCV replication and a potential therapeutic target. PMID:25800783
Yelken, B; Arpalı, E; Görcin, S; Kocak, B; Karatas, C; Demiralp, E; Turkmen, A
Antibody-mediated rejection (AMR) is responsible for up to 20%-30% of acute rejection episodes after kidney transplantation. In several cases, conventional therapies including plasmapheresis, intravenous immunoglobulin, and anti-CD20 therapy can resolve AMR successfully. But in some cases the load of immunoglobulins that can activate complement cascade may submerge the routine desensitization therapy and result in the formation of membrane attack complexes. Eculizumab, a monoclonal antibody against C5, was reported to be an option in cases with severe AMR that are resistant to conventional therapy. Here, we present 8 cases that were resistant to conventional therapy and in which eculizumab was given as a salvage treatment. Given the bad prognosis for renal transplants displaying acute injury progressing rapidly to cortical necrosis on the biopsy, the prompt use of eculizumab could have the advantage of immediate effects by stopping cellular injury. This can provide a therapeutic window to allow conventional treatment modalities to be effective and prevent early graft loss.
Miskin, Ruth; Abramovitz, Rene
Plasminogen activator inhibitor-1 (PAI-1) is a major physiological regulator of the fibrinolytic system and is thought to promote vascular diseases. Recently, we have reported that PAI-1 gene expression was markedly enhanced locally in cardiovascular cells immediately after injecting (i.p.) mice with kainate, an analog of glutamate, which is the principal excitatory neurotransmitter in the central nervous system. Here we investigated whether the induction of PAI-1 mRNA by kainate could be mediated through sympathetic versus parasympathetic efferent neurons. To this end, we used a group of drugs known to interfere with the aforementioned pathways. PAI-1 gene expression was monitored in the heart via in situ hybridization using (35)S-labeled PAI-1-specific riboprobes. We have found that the elevation of PAI-1 mRNA levels, as detected 3 h after systemic administration of kainate, was reduced by mecamylamine, guanethidine and phentolamine, but not by propranolol or atropine. In addition, the adrenergic agonists phenylephrine and adrenaline themselves, but not clonidine, induced PAI-1 with a spatial distribution similar to that of kainate (i.e. in coronary arteries throughout the heart, and in cardiocytes in the left ventricular and atrial myocardium). Collectively, these results show that kainate activated the PAI-1 gene in cardiovascular cells primarily through the sympathetic nervous system (SNS), via the alpha1-adrenergic receptor. Hence, the results suggest that PAI-1 is likely to be increased during enhanced sympathetic efferent neuronal activity, such as occurring in heart failure or cardiac hypertrophy. The results also reinforce the previously reported linkage of PAI-1 to physiological stress. Furthermore, to our knowledge, this is the first demonstration that glutamate can enhance gene expression in a peripheral tissue. Thus, these findings raise the possibility that glutamate, acting via the SNS, can affect cardiovascular homeostasis and pathology by
Topuz, Bora B; Altinbas, Burcin; Ilhan, Tuncay; Yilmaz, Mustafa S; Erdost, Hatice; Saha, Sikha; Savci, Vahide; Yalcin, Murat
The present study was designed to determine the involvement of central prostaglandin synthesis on the pressor and bradycardic effect of cytidine 5'-diphosphocholine (CDP-choline). Intracerebroventricular (i.c.v.) administration of CDP-choline was made and blood pressure and heart rate were recorded in male Sprague Dawley rats throughout this study. Microdialysis and immunohistochemical studies were performed to measure extracellular total prostaglandin concentration and to show cyclooxygenase-1 and -2 (COX-1 and -2) immunoreactivities, respectively, in the posterior hypothalamic area. Moreover, rats were pretreated (i.c.v) with mepacrine [a phospholipase A2 (PLA2) inhibitor], ibuprofen [a nonselective COX inhibitor], neomycine [a phospholipase C (PLC) inhibitor] or furegrelate [a thromboxane A2 (TXA2) synthesis inhibitor] 5 min prior to the injection of CDP-choline to determine the effects of these inhibitors on cardiovascular responses to CDP-choline. Control rats were pretreated (i.c.v) with saline. CDP-choline caused a dose- and time-dependent increase in blood pressure and decrease in heart rate. Immunohistochemical studies showed that CDP-choline increased COX-1 and -2 immunoreactivities in the posterior hypothalamic area. CDP-choline also elevated hypothalamic extracellular total prostaglandin concentration by 62%, as shown in microdialysis studies. Mepacrine or ibuprofen pretreatments almost completely blocked the pressor and bradycardic responses to CDP-choline while neomycine or furegrelate partially attenuated the drug-induced cardiovascular effects. The results suggest that CDP-choline may stimulate prostaglandin synthesis through the activation of PLA2, cyclooxygenases (COX-1 and -2) and prostaglandins and at least TXA2, may mediate the drug׳s cardiovascular effects.
Peters, Sanne A E; den Ruijter, Hester M; Bots, Michiel L
Abstract Adequate risk assessment for cardiovascular disease (CVD) is essential as a guide to initiate drug treatment. Current methods based on traditional risk factors could be improved considerably. Although brachial flow-mediated dilation (FMD) predicts subsequent cardiovascular events, its predictive value on top of traditional risk factors is unknown. We performed a systematic review to evaluate the incremental predictive value of FMD on top of traditional risk factors in asymptomatic individuals. Using PubMed and reference tracking, three studies were identified that reported on the incremental value of FMD using change in the area under the curve (AUC). Two large cohort studies found no improvement in AUC when FMD was added to traditional risk prediction models, whereas one small case-control study found an improvement. One study used the net reclassification improvement (NRI) to assess whether FMD measurement leads to correct risk stratification in risk categories. Although this study did not find an improvement in AUC, the NRI was statistically significant. Based on the reclassification results of this study, FMD measurement might be helpful in risk prediction. Evidence supporting the use of FMD measurement in clinical practice for risk stratification for CVD on top of traditional risk factors is limited, and future studies are needed.
Dragun, Duska; Philippe, Aurélie; Catar, Rusan; Hegner, Björn
Antibodies directed against G-protein coupled receptors (GPCR) can act as allosteric receptor agonists or antagonists. Prototypic disease for agonistic antibody action is a Graves disease of the thyroid gland where antibodies that stimulate G-protein coupled thyroid-stimulating hormone receptor (TSHR) were first described 50 years ago. Myasthenia gravis is the prototype for antagonistic autoimmune actions, where antibodies directed against the nicotinic acetylcholine receptor (AChR) cause blockade of neuromuscular junctions. Antibodies and B-cells are increasingly recognised as major modulators of various cardiovascular and renal pathologies. We aim to critically review the notion that antibodies targeting other GPCRs may amplify or cause various cardiovascular and renal pathologies and summarise the current state of research, as well as perspectives in diagnostic and therapeutic strategies. In terms of targets we will focus on the alpha-adrenergic receptor (alpha(1)AR), the beta-adrenergic receptor (beta(1)AR), and the angiotensin II type 1 receptor (AT(1)R).
Huebsch, Nathaniel; Lippens, Evi; Lee, Kangwon; Mehta, Manav; Koshy, Sandeep T; Darnell, Max C; Desai, Rajiv; Madl, Christopher M.; Xu, Maria; Zhao, Xuanhe; Chaudhuri, Ovijit; Verbeke, Catia; Kim, Woo Seob; Alim, Karen; Mammoto, Akiko; Ingber, Donald E.; Duda, Georg N; Mooney, David J.
The effectiveness of stem-cell therapies has been hampered by cell death and limited control over fate1. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype2–4. Stem cell behavior can also be controlled in vitro by manipulating the elasticity of both porous and non-porous materials5–7, yet translation to therapeutic processes in vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying, respectively, the hydrogel's elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel's elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direct therapeutic stem-cell behaviors in situ. PMID:26366848
Bachelet, Thomas; Nodimar, Celine; Taupin, Jean-Luc; Lepreux, Sebastien; Moreau, Karine; Morel, Delphine; Guidicelli, Gwendaline; Couzi, Lionel; Merville, Pierre
Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.
Hainz, Ursula; Obexer, Petra; Winkler, Christiana; Sedlmayr, Peter; Takikawa, Osamu; Greinix, Hildegard; Lawitschka, Anita; Pütschger, Ulrike; Fuchs, Dietmar; Ladisch, Stephan; Heitger, Andreas
T-cell dysfunction after human hematopoietic stem-cell transplantation (HSCT) is generally attributed to intrinsic T-cell defects. Here we show that the characteristic impaired proliferative responses to polyclonal stimulation of post-HSCT peripheral blood mononuclear cells (PB-MCs) were markedly (4-fold) improved by T-cell enrichment. Conversely, addback of post-HSCT monocytes to these enriched T cells dampened their proliferative responses, suggesting that post-HSCT monocytes effectively mediate T-cell suppression. As a mechanism possibly contributing to monocyte-mediated T-cell suppression, we investigated monocyte tryptophan catabolism by indoleamine 2,3-dioxygenase into kynurenine, which has been implicated in regulating T-cell responses. Compared with controls, all post-HSCT monocyte-containing cell cultures (total PBMCs, monocytes, and monocyte/T-cell cocultures), but not monocyte-depleted populations, secreted elevated amounts of kynurenine. Blockade of tryptophan catabolism improved the proliferative responses. The slightly increased kynurenine release and substantial release of neopterin by unstimulated post-HSCT monocytes suggests that they were in a state of continuous activation. Superimposed on this state, stimulation of these cells caused a striking, additional increase (10-fold) in kynurenine release, and they triggered marked apoptosis of autologous post-HSCT T cells. We conclude that the amplified kynurenine release by post-HSCT monocytes, particularly induced upon stimulation, may underlie their suppressor activity, which in turn may contribute to the depressed T-cell immune responses after HSCT. PMID:15677560
Liuwantara, David; Chew, Yi Vee; Favaloro, Emmanuel J.; Hawkes, Joanne M.; Burns, Heather L.; O'Connell, Philip J.; Hawthorne, Wayne J.
Introduction The instant blood-mediated inflammatory reaction (IBMIR) causes major loss of islets after transplantation and consequently represents the initial barrier to survival of porcine neonatal islet cell clusters (NICC) after xenotransplantation. Methods This study used novel assays designed to characterize the various immunologic components responsible for xenogeneic IBMIR to identify initiators and investigate processes of IBMIR-associated coagulation, complement activation and neutrophil infiltration. The IBMIR was induced in vitro by exposing NICC to platelet-poor or platelet-rich human plasma or isolated neutrophils. Results We found that xenogeneic IBMIR was characterized by rapid, platelet-independent thrombin generation, with addition of platelets both accelerating and exacerbating this response. Platelet-independent complement activation was observed as early as 30 minutes after NICC exposure to plasma. However, membrane attack complex formation was not observed in NICC histopathology sections until after 60 minutes. We demonstrated for the first time that NICC-mediated complement activation was necessary for neutrophil activation in the xenogeneic IBMIR setting. Finally, using the Seahorse extracellular flux analyzer, we identified substantial loss of islet function (up to 40%) after IBMIR with surviving NICC showing evidence of mitochondrial damage. Conclusions This study used novel assays to describe multiple key pathways by which xenogeneic IBMIR causes islet destruction, allowing further refinement of future interventions aimed at resolving the issue of IBMIR in xenotransplantation. PMID:27500267
Zeng, Lingyao; Willenborg, Christina; Tragante, Vinicius; Kessler, Thorsten; Willer, Cristen J.; Laakso, Markku; Wallentin, Lars; Franks, Paul W.; Salomaa, Veikko; Dehghan, Abbas; Meitinger, Thomas; Samani, Nilesh J.; Asselbergs, Folkert W.; Erdmann, Jeanette; Schunkert, Heribert
Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples. PMID:28829817
Poly-epsilon-caprolactone (PCL) based copolymers have received much attention as drug or growth factor delivery carriers and tissue engineering scaffolds due to their biocompatibility, biodegradability, and tunable biophysical properties. Copolymers of PCL and polydimethylsiloxane (PDMS) also have shape memory behaviors and can be made into thermoresponsive shape memory polymers for various biomedical applications such as smart sutures and vascular stents. However, the influence of biophysical properties of PCL-PDMS-PCL copolymers on stem cell lineage commitment is not well understood. In this study, PDMS was used as soft segments of varying length to tailor the biophysical properties of PCL-based co-polymers. While low elastic modulus (<10 kPa) of the tri-block copolymer PCL-PDMS-PCL affected cardiovascular differentiation of embryonic stem cells, the range of 60-100 MPa PCL-PDMS-PCL showed little influence on the differentiation. Then different size (30-140 mum) of microspheres were fabricated from PCL-PDMS-PCL copolymers and incorporated within embryoid bodies (EBs). Mesoderm differentiation was induced using bone morphogenetic protein (BMP)-4 for cardiovascular differentiation. Differential expressions of mesoderm progenitor marker KDR and vascular markers CD31 and VE-cadherin were observed for the cells differentiated from EBs incorporated with microspheres of different size, while little difference was observed for cardiac marker alpha-actinin expression. Small size of microspheres (30 mum) resulted in higher expression of KDR while medium size of microspheres (94 mum) resulted in higher CD31 and VE-cadherin expression. This study indicated that the biophysical properties of PCL-based copolymers impacted stem cell lineage commitment, which should be considered for drug delivery and tissue engineering applications.
Brænne, Ingrid; Zeng, Lingyao; Willenborg, Christina; Tragante, Vinicius; Kessler, Thorsten; Willer, Cristen J; Laakso, Markku; Wallentin, Lars; Franks, Paul W; Salomaa, Veikko; Dehghan, Abbas; Meitinger, Thomas; Samani, Nilesh J; Asselbergs, Folkert W; Erdmann, Jeanette; Schunkert, Heribert
Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.
Fassini, Aline; Resstel, Leonardo B M; Corrêa, Fernando M A
Stress is a response of the organism to homeostasis-threatening stimuli and is coordinated by two main neural systems: the hypothalamic-pituitary-adrenal and the autonomic nervous system. Acute restraint stress (RS) is a model of unavoidable stress, which is characterized by autonomic responses including an increase in mean arterial pressure (MAP) and heart rate (HR), as well as a drop in tail temperature. The prelimbic cortex (PL) has been implicated in the modulation of functional responses caused by RS. The present study aimed to evaluate the role of PL GABAergic neurotransmission in the modulation of autonomic changes induced by RS. Bilateral microinjection of the GABAA receptor antagonist bicuculline methiodide into the PL reduced pressor and tachycardic responses evoked by RS, in a dose-dependent manner, without affecting the tail temperature drop evoked by RS. In order to investigate which peripheral autonomic effector modulated the reduction in RS-cardiovascular responses caused by the blockade of PL GABAA receptors, rats were intravenously pretreated with either atenolol or homatropine methylbromide. The blockade of the cardiac sympathetic nervous system with atenolol blunted the reducing effect of PL treatment with bicuculline methiodide on RS-evoked pressor and tachycardic responses. The blockade of the parasympathetic nervous system with homatropine methylbromide, regardless of affecting the beginning of the tachycardic response, did not impact on the reduction of RS-evoked tachycardic and pressor responses caused by the PL treatment with bicuculline methiodide. The present results indicate that both cardiac sympathetic and parasympathetic activities are involved in the reduction of RS-evoked cardiovascular responses evidenced after the blockade of PL GABAA receptors by bicuculline methiodide.
Kobayashi, Akimitsu; Takahashi, Takamune; Horita, Shigeru; Yamamoto, Izumi; Yamamoto, Hiroyasu; Teraoka, Satoshi; Tanabe, Kazunari; Hosoya, Tatsuo; Yamaguchi, Yutaka
c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun-positive cells in the tubules and interstitium was correlated with the Banff classification "t" and "i" scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun-positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.
Blydt-Hansen, T D; Sharma, A; Gibson, I W; Mandal, R; Wishart, D S
The goal of this study was to evaluate the utility of urinary metabolomics for noninvasive diagnosis of T cell-mediated rejection (TCMR) in pediatric kidney transplant recipients. Urine samples (n = 277) from 57 patients with surveillance or indication kidney biopsies were assayed for 134 unique metabolites by quantitative mass spectrometry. Samples without TCMR (n = 183) were compared to borderline tubulitis (n = 54) and TCMR (n = 30). Partial least squares discriminant analysis identified distinct classifiers for TCMR (area under receiver operating characteristic curve [AUC] = 0.892; 95% confidence interval [CI] 0.827-0.957) and borderline tubulitis (AUC = 0.836; 95% CI 0.781-0.892), respectively. Application of the TCMR classifier to borderline tubulitis samples yielded a discriminant score (-0.47 ± 0.33) mid-way between TCMR (-0.20 ± 0.34) and No TCMR (-0.80 ± 0.32) (p < 0.001 for all comparisons). Discriminant scoring for combined borderline/TCMR versus No TCMR (AUC = 0.900; 95% CI 0.859-0.940) applied to a validation cohort robustly distinguished between samples with (-0.08 ± 0.52) and without (-0.65 ± 0.54, p < 0.001) borderline/TCMR (p < 0.001). The TCMR discriminant score was driven by histological t-score, ct-score, donor-specific antibody and biopsy indication, and was unaffected by renal function, interstitial or microcirculatory inflammation, interstitial fibrosis or pyuria. These preliminary findings suggest that urinary metabolomics is a sensitive, specific and noninvasive tool for TCMR identification that is superior to serum creatinine, with minimal confounding by other allograft injury processes. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.
Goshima, Yoshio; Nakamura, Fumio; Masukawa, Daiki; Chen, Sandy; Koga, Motokazu
l-3,4-Dihydroxyphenylalanine (DOPA) is the metabolic precursor of dopamine, and the single most effective agent in the treatment of Parkinson's disease. One problem with DOPA therapy for Parkinson's disease is its cardiovascular side effects including hypotension and syncope, the underlying mechanisms of which are largely unknown. We proposed that DOPA is a neurotransmitter in the central nervous system, but specific receptors for DOPA had not been identified. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. It was unknown, however, whether or not OA1 is responsible for the actions of DOPA itself. Immunohistochemical examination revealed that OA1 was expressed in the nucleus tractus solitarii (NTS). OA1-positive cells adjacent to tyrosine hydroxylase-positive cell bodies and nerve fibers were detected in the depressor sites of the NTS. OA1 knockdown using oa1-specific shRNA-adenovirus vectors in the NTS reduced the expression levels of OA1 in the NTS. The prior injection of the shRNA against OA1 suppressed the depressor and bradycardic responses to DOPA but not to glutamate in the NTS of anesthetized rats. Thus OA-1 is a functional receptor of DOPA in the NTS, which warrants reexamination of the mechanisms for the therapeutic and untoward actions of DOPA.
Mainous, Arch G; Pearson, William S
Smokers have elevated C-reactive protein (CRP), an indicator of systemic inflammation and a marker for increased risk for cardiovascular disease (CVD). This study investigated among smokers the relationship between CRP and use of the anti-inflammatories aspirin and ibuprofen. Data from adults (>17 years) collected in the National Health and Nutrition Examination Survey (NHANES III) was analyzed (n = 8,850). Regression models were used to determine the independent relationship between aspirin and ibuprofen use and elevated CRP, controlling for demographics, body mass index, history of CVD, and health status. Frequency of use of aspirin and ibuprofen among "ever smokers," a population that includes current smokers and quitters, was associated with a decreased likelihood of having elevated CRP. Ever smokers with low frequency of use of either aspirin or ibuprofen had a lower likelihood of having elevated CRP similar to that for "never smokers." In adjusted relationships, aspirin use was not significantly related to elevated CRP, while low use of ibuprofen had decreased odds of having elevated CRP compared to no use. These preliminary findings from a nationally representative survey suggest that among patients refractory to smoking cessation interventions, use of ibuprofen may be useful to decrease CVD risk.
Cisneros-Garza, Laura E; López-Hernández, Pedro A; Muñoz-Ramírez, M del Rosario; Castilla-Valdéz, Martha Patricia; Sebastián-Ruiz, M José; Carmona-Martínez, Juan Gerardo; Alvarez-Treviño, Guillermo Alberto; Martínez-Flores, José Guillermo; Olavide-Aguilar, Ramón
Liver transplantation is the best treatment for end stage liver diseases. In April 2003, our institution started a Liver Transplantation Program for both pediatric and adults population. Shown the results of the Liver Transplantation Program in the UMAE 25 Monterrey N.L. This is a retrospective cohort study of patients with liver transplantation. A total of 51 liver transplantations have been done in 49 patients with two retrasplantation, 15 in children and 36 in adults. The principal indication for liver transplantation in children was biliary atresia and hepatitis C cirrhosis in adults. The acute renal failure was the main early complication, the acute cellular rejection in the mediate period, and the cardiovascular diseases as late complication related to obesity, metabolic syndrome, diabetes mellitus and hypertension. Overall survival at 1 and 5 years was 57.1 and 54.2%, respectively. During the first three years post-transplantation, the quality of life was good or very good. Although still a young and perfectible program, the effort of a multidisciplinary team has made possible to perform liver transplantation in two patient populations, pediatric and adults.
Chan, Samuel; Mallett, Andrew J; Patel, Chirag; Francis, Ross S; Johnson, David W; Mudge, David W; Isbel, Nicole M
Disorders in the regulation of the alternate complement pathway often result in complement-mediated damage to the microvascular endothelium and can be associated with both glomerulonephritis and atypical haemolytic uraemic syndrome. Inherited defects in complement regulatory genes or autoantibodies against complement regulatory proteins are predictive of the severity of the disease and the risk of recurrence post kidney transplantation. Heterozygous mutations in CD46, which codes for a transmembrane cofactor glycoprotein membrane cofactor protein, usually have a lower incidence of end-stage kidney disease and decreased risk of recurrent disease post transplant, as wild-type membrane cofactor protein is present in the transplanted kidney. However, some patients with CD46 mutations have a second variant in other complement regulatory genes increasing the severity of disease. The following case report illustrates the course of a young adult patient with end-stage kidney disease initially ascribed to seronegative systemic lupus erythematosus, who presented with biopsy-proven thrombotic microangiopathy following kidney transplantation. It highlights the complexity associated with disorders of complement regulation and the need for a high index of suspicion and genetic testing in patients who present with thrombotic microangiopathy post-transplant.
Mierzejewska, Beata; Schroder, Paul M.; Baum, Caitlin E.; Blair, Annette; Smith, Connie; Duquesnoy, Rene J.; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A.; Stepkowski, Stanislaw
Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA. PMID:24755353
Wood, Sherri; Feng, Jiane; Chung, Jooho; Radojcic, Vedran; Sandy, Ashley R.; Friedman, Ann; Shelton, Amy; Yan, Minhong; Siebel, Christian W.; Bishop, D. Keith; Maillard, Ivan
Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of antibody-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and antibody-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFNγ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8+ T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing antibodies specific for Delta-like1/4 (Dll1/4) Notch ligands in the peri-transplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, but also germinal center B cell and plasmablast numbers as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of theses signals represents a new attractive therapeutic strategy to enhance long-term allograft survival. PMID:25687759
Mierzejewska, Beata; Schroder, Paul M; Baum, Caitlin E; Blair, Annette; Smith, Connie; Duquesnoy, Rene J; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A; Stepkowski, Stanislaw
Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.
Hatam, Masoumeh; Kharazmi, Fatemeh; Nasimi, Ali
The bed nucleus of the stria terminalis (BST) is an important part of the limbic system. It has been shown that chemical stimulation of the BST elicited cardiovascular depressive and bradycardic responses. It was also demonstrated that GABA is present in the BST, though its role in cardiovascular control is not yet understood. This study was performed to find the effects of GABA receptor subtypes in the BST on cardiovascular responses and to find the possible mechanisms that mediate these responses in urethane-anesthetized rats. Microinjection of muscimol (500 pmol/100 nl), a GABA(A) agonist, into the BST produced a weak unsignificant decrease in the mean arterial pressure (MAP) and heart rate (HR). Injection of bicuculline methiodide (BMI, 100 pmol/100 nl), a GABA(A) antagonist, caused a significant increase in the MAP (41.3+/-5.1 mmHg) as well as in the HR (33.2+/-5.6 beats/min). Injection of two doses (500 and 1000 pmol/100 nl) of phaclofen, a GABA(B) antagonist, produced no significant change in either MAP or HR. Administration (i.v.) of the muscarinic receptor blocker, homatropine methyl bromide had no effect on the magnitude of mean arterial pressure or heart rate responses to BMI. This suggests that the parasympathetic system is not involved in these responses. However, administration (i.v.) of the nicotinic receptor blocker, hexamethonium bromide had no effect on the magnitude of mean arterial pressure response but abolished heart rate response to BMI. This suggests that the sympathetic system is involved in the bradycardic effect of GABA. On the other hand, administration (i.v.) of a selective vasopressin V(1) receptor antagonist abolished the pressor effect of BMI, which indicates that the GABAergic system of the BST decreases the arterial pressure via tonic inhibition of vasopressin release. In summary, we demonstrated, for the first time, that GABA exerts its influence in the BST through the activation of GABA(A), but not GABA(B), receptors that, in
Maruhashi, Tatsuya; Soga, Junko; Fujimura, Noritaka; Idei, Naomi; Mikami, Shinsuke; Iwamoto, Yumiko; Kajikawa, Masato; Matsumoto, Takeshi; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Noma, Kensuke; Nakashima, Ayumu; Goto, Chikara; Tomiyama, Hirofumi; Takase, Bonpei; Yamashina, Akira; Higashi, Yukihito
Objective To determine the relationships between flow-mediated vasodilation (FMD) and cardiovascular risk factors, and to evaluate confounding factors for measurement of FMD in a large general population in Japan. Methods This was a cross-sectional study. A total of 5314 Japanese adults recruited from people who underwent health screening from 1 April 2010 to 31 August 2012 at 3 general hospitals in Japan. Patients’ risk factors (age, Body Mass Index, blood pressure, cholesterol parameters, glucose level and HbA1c level) and prevalence of cardiovascular disease (coronary heart disease and cerebrovascular disease) were investigated. Results Univariate regression analysis revealed that FMD correlated with age (r=−0.27, p<0.001), Body Mass Index (r=−0.14, p<0.001), systolic blood pressure (r=−0.18, p<0.001), diastolic blood pressure (r=−0.13, p<0.001), total cholesterol (r=−0.07, p<0.001), triglycerides (r=−0.10, p<0.001), high-density lipoprotein cholesterol (r=0.06, p<0.001), low-density lipoprotein cholesterol (r=−0.04, p=0.01), glucose level (r=−0.14, p<0.001), HbA1c (r=−0.14, p<0.001), and baseline brachial artery diameter (r=−0.43, p<0.001) as well as Framingham Risk score (r=−0.29, p<0.001). Multivariate analysis revealed that age (t value=−9.17, p<0.001), sex (t value=9.29, p<0.001), Body Mass Index (t value=4.27, p<0.001), systolic blood pressure (t value=−2.86, p=0.004), diabetes mellitus (t value=−4.19, p<0.001), smoking (t value=−2.56, p=0.01), and baseline brachial artery diameter (t value=−29.4, p<0.001) were independent predictors of FMD. Conclusions FMD may be a marker of the grade of atherosclerosis and may be used as a surrogate marker of cardiovascular outcomes. Age, sex, Body Mass Index, systolic blood pressure, diabetes mellitus, smoking and, particularly, baseline brachial artery diameter are potential confounding factors in the measurement of FMD. PMID:24153417
Biancone, Luigi; Lavacca, Antonio; Beltramo, Silvia; Ariaudo, Claudia; Gallo, Ester; Segoloni, Giuseppe Paolo
The recognition of antibody-mediated rejection as an important factor in the reduction of long-term renal graft survival represents a new challenge to the immunosuppressive strategies of recent years, which have been quite successful in reducing the acute rejection rates as well as the side effects of pharmacological immunosuppression. The search for an effective treatment of chronic anti-donor antibody disease has been pursued mostly through limited single-center experiences and therefore in a dispersed fashion, without leading to the definition of a consolidated approach. The most frequently used pharmacological approaches stem from the experience of antibody-mediated acute rejection. In this review we will critically analyze the results reported so far of various intervention strategies and we will discuss future pharmacological novelties targeting the humoral immune response.
Politis, Marios; Wu, Kit; Loane, Clare; Quinn, Niall P; Brooks, David J; Rehncrona, Stig; Bjorklund, Anders; Lindvall, Olle; Piccini, Paola
Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson's disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT(1A)) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson's disease with fetal tissue or stem cells.
Roberti, Isabel; Vyas, Shefali
IMN contribute to ESRD in 13% children with renal transplant (txp). Recurrent or de novo IMN can cause graft dysfunction and/or failure, but the details regarding incidence, therapy, and outcome remain poorly understood. Retrospective single-center study of all pediatric kidney txp was carried out since 1998. Clinical presentation, pathology, therapy, and graft outcomes of children with recurrent or de novo IMN were reviewed. IMN was the primary etiology of ESRD in 28 of the 149 txp recipients. Eleven children had biopsy-proven post-txp IMN-six were recurrent and five had de novo. Presentation varied with changes in SCr and/or proteinuria. Initial therapy included higher doses of steroids, MMF, and tacrolimus. Outcome was excellent with only one late graft loss. Full remission was achieved in all other patients, but some had re-recurrence of the IMN. Median follow-up time was 11.8 years. IMN (recurrent or de novo) occurred in 7.4% (11 of 149) of all kidney txp performed at our center. IMN post-txp was often seen late post-txp, usually asymptomatic and noted to have relapsing pattern. Early diagnosis and prompt therapy resulted in excellent long-term outcome in children diagnosed with post-txp IMN.
Stark, Michael J; Clifton, Vicki L; Wright, Ian M R
With male gender as a strong predictor of cardiovascular instability, we hypothesized that gender-specific differences in circulating carbon monoxide levels contributed to dysregulated microvascular function in preterm male infants. Infants born at 24 to 34 weeks of gestation (N = 84) were studied in a regional tertiary neonatal unit. Carboxyhemoglobin levels were measured through spectrophotometry in umbilical arterial blood and at 24, 72, and 120 hours after birth. Microvascular blood flow was determined through laser Doppler flowmetry. Carboxyhemoglobin levels demonstrated a strong inverse relationship with gestational age (r = -0.636; P < .001) and were higher in boys (P = .032). Repeated-measures analysis of variance showed a significant decrease in arterial carboxyhemoglobin levels over time (P < .001), with significant between-subjects effects for gestational age (P = .011) and gender (P = .025). Positive correlations with microvascular blood flow at 24 hours of age (r = 0.495; P < .001) and 120 hours of age (r = 0.548; P < .001) were observed. With controlling for gestational age, carboxyhemoglobin levels at 72 hours were greater for infants who died in the first week of life (P = .035). The gestational age- and gender-specific differences in carboxyhemoglobin levels and the relationship with dysregulated microvascular blood flow, a state related to greater illness severity and hypotension, are novel findings not confined solely to sick preterm infants. Both inducible heme oxygenase-dependent and non-heme oxygenase-dependent pathways may initially play a central role in carbon monoxide production, inducing pathophysiologic processes in a gender-specific manner.
Amaral, Nathalia Oda; Naves, Lara Marques; Ferreira-Neto, Marcos Luiz; Freiria-Oliveira, André Henrique; Colombari, Eduardo; Rosa, Daniel Alves; Reis, Angela Adamski da Silva; Ianzer, Danielle; Xavier, Carlos Henrique; Pedrino, Gustavo Rodrigues
Changes in plasma osmolarity, through central and peripheral osmoreceptors, activate the median preoptic nucleus (MnPO) that modulates autonomic and neuroendocrine adjustments. The present study sought to determine the participation of MnPO in the cardiovascular recovery induced by hypertonic saline infusion (HSI) in rats submitted to hemorrhagic shock. The recordings of mean arterial pressure (MAP) and renal vascular conductance (RVC) were carried out on male Wistar rats (250-300 g). Hemorrhagic shock was induced by blood withdrawal over 20 min until the MAP values of approximately 60 mmHg were attained. The nanoinjection (100 nL) of GABAA agonist (Muscimol 4 mM; experimental group (EXP)) or isotonic saline (NaCl 150 mM; control (CONT)) into MnPO was performed 2 min prior to intravenous overload of sodium through HSI (3 M NaCl, 1.8 mL/kg, b.wt.). Hemorrhagic shock reduced the MAP in control (62 ± 1.1 mmHg) and EXP (61 ± 0.4 mmHg) equipotently. The inhibition of MnPO impaired MAP (CONT: 104 ± 4.2 versus EXP: 60 ± 6.2 mmHg) and RVC (CONT: 6.4 ± 11.4 versus EXP: -53.5 ± 10.0) recovery 10 min after HSI. The overall results in this study demonstrated, for the first time, that the MnPO plays an essential role in the HSI induced resuscitation during hypovolemic hemorrhagic shock.
Agarwal, Arnav; Prasad, G V Ramesh
Post-transplant dyslipidemia is highly prevalent and presents unique management challenges to the clinician. The two major outcomes to consider with post-transplant therapies for dyslipidemia are preserving or improving allograft function, and reducing cardiovascular risk. Although there are other cardiovascular risk factors such as graft dysfunction, hypertension, and diabetes, attention to dyslipidemia is warranted because interventions for dyslipidemia have an impact on reducing cardiac events in clinical trials specific to the transplant population. Dyslipidemia is not synonymous with hyperlipidemia. Numerous mechanisms exist for the occurrence of post-transplant dyslipidemia, including those mediated by immunosuppressive drug therapy. Statin therapy has received the most attention in all solid organ transplant recipient populations, although the effect of proper dietary advice and adjuvant pharmacological and non-pharmacological agents should not be dismissed. At all stages of treatment appropriate monitoring strategies for side effects should be implemented so that the benefits from these therapies can be achieved. Clinicians have a choice when there is a conflict between various transplant society and lipid society guidelines for therapy and targets. PMID:27011910
Adams, Julye M.; Bardgett, Megan E.; Stocker, Sean D.
Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses evoked from the rostral ventrolateral medulla (RVLM). The purpose of the present study was to determine whether neurons of the forebrain lamina terminalis (LT) mediated these changes in the RVLM. Male Sprague-Dawley rats with and without LT lesions were fed normal chow and given access to water or 0.9% NaCl for 14-15 days. Unilateral injection of L-glutamate into the RVLM produced significantly larger increases in renal sympathetic nerve activity (SNA) and arterial blood pressure (ABP) of sham rats ingesting 0.9% NaCl versus water. However, these differences were not observed between ventral LT-lesioned rats drinking 0.9% NaCl versus water. Similar findings were observed when angiotensin II or GABA were injected into the RVLM. Interestingly, a subset of animals drinking 0.9% but with damage restricted to the organum vasculosum of the lamina terminalis did not show enhanced responses to L-glutamate or GABA. In marked contrast, RVLM injection of L-glutamate or GABA produced exaggerated SNA and ABP responses in animals drinking 0.9% NaCl versus water after an acute ventral LT lesion or chronic lesion of the subfornical organ. Additional experiments demonstrate plasma sodium concentration and osmolality were increased at night in rats ingesting 0.9% NaCl. These findings suggest that neurons of the ventral LT mediate the ability of increased dietary salt to enhance the responsiveness of RVLM sympathetic neurons. PMID:19506102
Marco, M R L; Dons, E M; van der Windt, D J; Bhama, J K; Lu, L T; Zahorchak, A F; Lakkis, F G; Cooper, D K C; Ezzelarab, M B; Thomson, A W
Repopulation of memory T cells (Tmem) in allograft recipients after lymphodepletion is a major barrier to transplant tolerance induction. Ineffective depletion of naïve T cells (Tn) and Tmem may predispose to repopulation of Tmem after transplantation. Cynomolgus macaque monkeys given heart allografts were lymphodepleted using Alemtuzumab (Campath-1H; anti-CD52). Peripheral blood (PB) and lymph nodes (LN) were analyzed for CD95(-) (Tn) and CD95(+) cells (Tmem), one day, one month and up to three months after Alemtuzumab infusion. CD52 expression, susceptibility to Alemtuzumab cytotoxicity and pro-apoptotic caspase-3 were evaluated in Tn and Tmem. In vivo, Alemtuzumab induction profoundly depleted lymphocytes in PB (99% reduction) but exerted a lesser effect in LN (70% reduction), with similar depletion of Tn and Tmem subsets. After transplantation, Tmem comprised the majority of lymphocytes in PB and LN. In vitro, LN T cells were more resistant to Alemtuzumab-mediated cytotoxicity than PB lymphocytes. CD4(+) Tn and Tmem were equally susceptible to Alemtuzumab-mediated cytotoxicity, whereas CD8(+) Tn were more resistant than CD8(+) Tmem. However, no significant differences in CD52 expression between lymphocyte subsets in PB and LN were observed. Caspase-3 expression was higher in PB than LN T cells. CD4(+) and CD8(+) Tn expressed lower levels of Caspase-3 than Tmem, in both PB and LN. Thus, after Alemtuzumab infusion, residual Tn in secondary lymphoid tissue may predispose to rapid recovery of Tmem in allograft recipients. © 2013.
Chung, Byung Ha; Joo, Yu Young; Lee, Jaesin; Kim, Hyung Duk; Kim, Ji-Il; Moon, In Sung; Choi, Bum Soon; Oh, Eun-Jee; Park, Cheol Whee; Kim, Yong-Soo; Yang, Chul Woo
Whether the coexistence of anti-A/B antibody and donor specific anti-HLA antibody (HLA-DSA) has a synergistic impact on the development of acute antibody-mediated rejection (AAMR) in kidney transplant recipients (KTRs) is unclear. This study includes 92 KTRs who received a kidney from an ABO-incompatible (ABOi) donor or were presensitized to donor HLA (HLAs) and 292 controls (CONT). HLAs was defined as a crossmatch positivity or the presence of HLA-DSA. We compared the incidence of AAMR among ABOi (n = 58), ABOi+HLAs (n = 12), HLAs (n = 22), and CONT (n = 292) groups and evaluated the risk factors and antibody type (anti-A/B vs. HLA-DSA) responsible for AAMR. AAMR developed less frequently in ABOi and CONT than in the ABOi+HLAs or HLAs (P < 0.05 for all); however, there was no difference between the ABOi+HLAs and HLAs groups. AAMR developed more frequently with strong HLA-DSA at baseline; however, high baseline anti-A/B titer did not affect AAMR development. Strong baseline HLA-DSA was an independent predictor for AAMR, however the baseline anti-A/B titer was not. All four AAMR episodes in ABOi+HLAs were positive to HLA-DSA but not to anti-A/B. In conclusion, ABO incompatibility does not increase the risk for AAMR in HLAs KTRs. PMID:25897756
Chung, Byung Ha; Joo, Yu Young; Lee, Jaesin; Kim, Hyung Duk; Kim, Ji-Il; Moon, In Sung; Choi, Bum Soon; Oh, Eun-Jee; Park, Cheol Whee; Kim, Yong-Soo; Yang, Chul Woo
Whether the coexistence of anti-A/B antibody and donor specific anti-HLA antibody (HLA-DSA) has a synergistic impact on the development of acute antibody-mediated rejection (AAMR) in kidney transplant recipients (KTRs) is unclear. This study includes 92 KTRs who received a kidney from an ABO-incompatible (ABOi) donor or were presensitized to donor HLA (HLAs) and 292 controls (CONT). HLAs was defined as a crossmatch positivity or the presence of HLA-DSA. We compared the incidence of AAMR among ABOi (n = 58), ABOi+HLAs (n = 12), HLAs (n = 22), and CONT (n = 292) groups and evaluated the risk factors and antibody type (anti-A/B vs. HLA-DSA) responsible for AAMR. AAMR developed less frequently in ABOi and CONT than in the ABOi+HLAs or HLAs (P < 0.05 for all); however, there was no difference between the ABOi+HLAs and HLAs groups. AAMR developed more frequently with strong HLA-DSA at baseline; however, high baseline anti-A/B titer did not affect AAMR development. Strong baseline HLA-DSA was an independent predictor for AAMR, however the baseline anti-A/B titer was not. All four AAMR episodes in ABOi+HLAs were positive to HLA-DSA but not to anti-A/B. In conclusion, ABO incompatibility does not increase the risk for AAMR in HLAs KTRs.
Ishibashi-Ueda, Hatsue; Ikeda, Yoshihiko; Matsuyama, Taka-Aki; Ohta-Ogo, Keiko; Sato, Takuma; Seguchi, Osamu; Yanase, Masanobu; Fujita, Tomoyuki; Kobayashi, Junjiro; Nakatani, Takeshi
Heart transplantation started in Japan in 1999. Since then, 50 transplants have been performed at our center. We performed histopathological analyses of the 50 explanted hearts and the post-transplant biopsy specimens. The median age of recipients was 39 years. The primary diseases before transplant were idiopathic dilated cardiomyopathy in 33 patients (66%), hypertrophic cardiomyopathy in seven (14%), restrictive cardiomyopathy in one, arrhythmogenic right ventricular cardiomyopathy in one, and secondary cardiomyopathy in eight (16%). Before transplantation, 47 patients (94%) had left ventricular assist devices. No severe cardiovascular failure due to allograft rejection occurred. The post-transplant survival rate was 97.6% at 1 year and 93.1% at 10 years. One recipient was lost to sepsis from myelodysplastic syndrome in the fourth year, one died of multiple organ failure and peritonitis 8 months after transplant. Another patient died of recurrent post-transplant lymphoproliferative disorders (PTLD). Mild cardiac dysfunction occurred in seven recipients in the early postoperative period. Moderate acute cellular rejection occurred in six patients (12%), and antibody-mediated rejection occurred in three (6%). The number of heart transplants performed in Japan is very small. However, the outstanding 10-year survival rate is due to donor evaluation and post-transplant care resulting in low grade rejection. Pathological evaluation has also greatly contributed to the results.
Kuo, Hsiao-Hsuan; Morrell, Craig N; Baldwin, William M
The early histological studies of organ allografts noted platelets attached to vascular endothelium. Platelets adhere to vessels before any morphological evidence of endothelial injury. Subsequently, in vitro and in vivo experiments have demonstrated that alloantibodies can induce exocytosis of von Willebrand factor and P-selectin from endothelial cells and attachment of platelets within minutes. Platelets also adhere to and stimulate leukocytes. These interactions are increased by complement activation. After attachment platelets degranulate, releasing preformed mediators. Some chemokines stored together in platelet granules can form heteromers with synergistic functions. Heteromers containing platelet factor 4 (PF4; CXCL4) are specific to platelets and provide insights to unique platelet functions and opportunities for therapeutic intervention. Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Vo, Ashley A; Sinha, Aditi; Haas, Mark; Choi, Jua; Mirocha, James; Kahwaji, Joseph; Peng, Alice; Villicana, Rafael; Jordan, Stanley C
Desensitization with intravenous immunoglobulin and rituximab (I+R) significantly improves transplant rates in highly sensitized patients, but antibody-mediated rejection (ABMR) remains a concern. Between July 2006 and December 2012, 226 highly sensitized patients received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Two groups were examined: ABMR (n = 181) and ABMR (n = 45, 20%). Risk factors for ABMR, pathology, and outcomes were assessed. Significant risks for ABMR included previous transplants and pregnancies as sensitizing events, donor-specific antibody (DSA) relative intensity scores greater than 17, presence of both class I and II DSAs at transplant and time on waitlist. The ABMR showed a significant benefit for graft survival and glomerular filtration rate at 5 years (P < 0.0001). Banff pathology characteristics for ABMR patients with or without graft loss did not differ. C4d versus C4d ABMR did not predict graft loss (P = 0.086). Thrombotic microangiopathy (TMA) significantly predicted graft failure (P = 0.045). The ABMR episodes were treated with I+R (n = 25), or, in more severe ABMR, plasma exchange (PLEX)+I+R (n = 20). Graft survival for patients treated with I+R was superior (P = 0.028). Increased mortality was seen in ABMR patients experiencing graft loss after ABMR treatment (P = 0.004). The PLEX + Eculizumab improved graft survival for TMA patients (P = 0.036). Patients desensitized with I+R who remain ABMR have long-term graft and patient survival. The ABMR patients have significantly reduced graft survival and glomerular filtration rate at 5 years, especially TMA. Severe ABMR episodes benefit from treatment with PLEX + Eculizumab. The DSA-relative intensity scores at transplant was a strong predictor of ABMR. Donor-specific antibody avoidance and reduction strategies before transplantation are critical to avoiding ABMR and improving long-term outcomes.
Greco, A; Steca, P; Pozzi, R; Monzani, D; D'Addario, M; Villani, A; Rella, V; Giglio, A; Malfatto, G; Parati, G
Many studies have investigated the relationships between cardiovascular diseases and patients' depression; nevertheless, few is still known as regard the impact of illness severity on depression and whether psychosocial variables mediate this association. The aim of this study is to investigate the putative mediating role of illness representations, self-efficacy beliefs, and perceived social support on the relationship between illness severity and depression. A total of 75 consecutive patients with cardiovascular disease (80 % men; mean age = 65.44, SD = 10.20) were enrolled in an Italian hospital. Illness severity was measured in terms of left ventricular ejection fraction, whereas psychological factors were assessed using self-report questionnaires. The relationship between left ventricular ejection fraction and depression was mediated by identity illness perception, self-efficacy beliefs in managing cardiac risk factors, and perceived social support. The treatment of depression in cardiovascular disease patients may therefore benefit from a psychological intervention focused on patients' illness representations, self-efficacy beliefs, and their perceived social support.
Fortaleza, E A T; Scopinho, A A; Corrêa, F M A
The medial amygdaloid nucleus (MeA) is a part of the limbic system and is involved in cardiovascular modulation. We previously reported that microinjection of noradrenaline (NA) into the MeA of unanesthetized rats caused pressor and bradycardiac responses, which were mediated by acute vasopressin release into the systemic circulation. In the present study, we tested the possible involvement of magnocellular neurons of the paraventricular (PVN) and/or supraoptic (SON) of the hypothalamus that synthesize vasopressin in the cardiovascular pathway activated by the microinjection of NA into the MeA. Pressor and bradycardiac responses to the microinjection of NA (27 nmol/100 nL) into the MeA were blocked by pretreatment of either the PVN or the SON with cobalt chloride (CoCl(2), 1 mM/100 nL), thus indicating that both hypothalamic nuclei mediate the cardiovascular responses evoked by microinjection of NA into the MeA. Our results suggest that the pressor and bradycardiac response caused by the microinjection of NA into the MeA is mediated by magnocellular neurons in both the PVN and SON.
Nafar, Mohsen; Sahraei, Zahra; Salamzadeh, Jamshid; Samavat, Shiva; Vaziri, Nosartolah D
Oxidative stress is a major mediator of adverse outcomes throughout the course of transplantation. Transplanted kidneys are prone to oxidative stress-mediated injury by pre-transplant and post-transplant conditions that cause reperfusion injury or imbalance between oxidants and antioxidants. Besides adversely affecting the allograft, oxidative stress and its constant companion, inflammation, cause cardiovascular disease, cancer, metabolic syndrome, and other disorders in transplant recipients. Presence and severity of oxidative stress can be assessed by various biomarkers produced from interaction of reactive oxygen species with lipids, proteins, nucleic acids, nitric oxide, glutathione, etc. In addition, expression and activities of redox-sensitive molecules such as antioxidant enzymes can serve as biomarkers of oxidative stress. Via activation of nuclear factor kappa B, oxidative stress promotes inflammation which, in turn, amplifies oxidative stress through reactive oxygen species generation by activated immune cells. Therefore, inflammation markers are indirect indicators of oxidative stress. Many treatment options have been evaluated in studies conducted at different stages of transplantation in humans and animals. These studies have provided useful strategies for use in donors or in organ preservation solutions. However, strategies tested for use in post-transplant phase have been largely inconclusive and controversial. A number of therapeutic options have been exclusively examined in animal models and only a few have been tested in humans. Most of the clinical investigations have been of short duration and have provided no insight into their impact on the long-term survival of transplant patients. Effective treatment of oxidative stress in transplant population remains elusive and awaits future explorations.
Giaretta, Fulvia; Bussolino, Stefania; Beltramo, Silvia; Fop, Fabrizio; Rossetti, Maura; Messina, Maria; Cantaluppi, Vincenzo; Ranghino, Andrea; Basso, Elisa; Camussi, Giovanni; Segoloni, Giuseppe Paolo; Biancone, Luigi
Comparative analysis of the different subsets of CD4(+) T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant. We analyzed peripheral regulatory CD4(+) T cells (Tregs) and CD4(+) cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2-4 years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (>15 years, LTKT) and in normal healthy subjects (NHS). Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4(+)CD25(high) T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4(+)CD25(high) Foxp3(+) cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4(+)CD25(high) T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4(+)CD25(high) and CD4(+)Foxp3(+) T cells in the LTKT in respect to the other transplant groups. CD4(+)CD25(high)CD45RO(+) and CD4(+)Foxp3(+)CD45RO(+) regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group. Finally, CD4(+)CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4(+)CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups. In conclusion, different profiles of Tregs and CD4(+)CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development
Marco, M.R.L.; Dons, E.M.; van der Windt, D.J.; Bhama, J.K.; Lu, L.T.; Zahorchak, A.F.; Lakkis, F.G.; Cooper, D.K.C.; Ezzelarab, M.B.; Thomson, A.W.
Repopulation of memory T cells (Tmem) in allograft recipients after lymphodepletion is a major barrier to transplant tolerance induction. Ineffective depletion of naïve T cells (Tn) and Tmem may predispose to repopulation of Tmem after transplantation. Cynomolgus macaque monkeys given heart allografts were lymphodepleted using Alemtuzumab (Campath-1H; anti-CD52). Peripheral blood (PB) and lymph nodes (LN) were analyzed for CD95− (Tn) and CD95+ cells (Tmem), one day, one month and up to three months after Alemtuzumab infusion. CD52 expression, susceptibility to Alemtuzumab cytotoxicity and pro-apoptotic caspase-3 were evaluated in Tn and Tmem. In vivo, Alemtuzumab induction profoundly depleted lymphocytes in PB (99% reduction) but exerted a lesser effect in LN (70% reduction), with similar depletion of Tn and Tmem subsets. After transplantation, Tmem comprised the majority of lymphocytes in PB and LN. In vitro, LN T cells were more resistant to Alemtuzumabmediated cytotoxicity than PB lymphocytes. CD4+ Tn and Tmem were equally susceptible to Alemtuzumab-mediated cytotoxicity, whereas CD8+ Tn were more resistant than CD8+ Tmem. However, no significant differences in CD52 expression between lymphocyte subsets in PB and LN were observed. Caspase-3 expression was higher in PB than LN T cells. CD4+ and CD8+ Tn expressed lower levels of Caspase-3 than Tmem, in both PB and LN. Thus, after Alemtuzumab infusion, residual Tn in secondary lymphoid tissue may predispose to rapid recovery of Tmem in allograft recipients. PMID:24120957
Furuya, Maiko; Yamamoto, Izumi; Kobayashi, Akimitsu; Nakada, Yasuyuki; Sugano, Naoki; Tanno, Yudo; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoyama, Keitaro; Yokoo, Takashi
We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature.
Stirban, Alin; Laude, Dominique; Elghozi, Jean-Luc; Sander, Denise; Agelink, Marcus W; Hilz, Max J; Ziegler, Dan
Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study. A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured. Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo. Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS. Copyright (c) 2008 John Wiley & Sons, Ltd.
Wang, Ning; Li, Wei; Zhang, Sheng
目的：研究肾移植受者的术前供者特异性抗体(donor specific antibody，DSA)与其术后发生抗体介导的体液排斥反应(antibody-mediated rejection，AMR)及移植肾功能的关系。方法：选取符合要求的肾移植受者88例。术前采用Luminex流式法对肾移植受者进行DSA检测，并将受者分为DSA阳性组(n=20)与DSA阴性组(n=68)。随访时间为2年。术后参照Banff 2005标准对移植肾病理形态进行评估分级，并观察移植肾的情况。结果： DSA阳性组与阴性组AMR发生率分别为20.0%和1.5%，移植物丢失发生率分别为15.0%和1.5%，两组比较差异均有统计学意义(分别P<0.01，P<0.05)；AMR受者最高DSA的荧光指数中值(mean fluorescence intensity，MFI)较非AMR受者差异明显(P<0.01)；受试者工作特征(receiver operating characteristic，ROC)曲线显示肾移植术后受者发展为AMR的最高MFI阈值为7909.5。两组移植肾功能延迟回复的发生相比较，差异无统计学意义(P>0.05)。结论：肾移植术前检测DSA水平，可以预测AMR的发生风险和移植肾功能状态。最高DSA值的MFI截点(7909.5)能够预测AMR发生的风险。.
Hong, Suzi; Dimitrov, Stoyan; Cheng, Tiefu; Redwine, Laura; Pruitt, Christopher; Mills, Paul J; Ziegler, Michael G; Green, J Michael; Shaikh, Farah; Wilson, Kathleen
Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate βAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10(-8)M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1β, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p's<.05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p<.05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p's<.0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p<.05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to
Hong, Suzi; Dimitrov, Stoyan; Cheng, Tiefu; Redwine, Laura; Pruitt, Christopher; Mills, Paul J.; Ziegler, Michael G.; Green, J. Michael; Shaikh, Farah; Wilson, Kathleen
Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate βAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10−8 M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1β, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p’s< .05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p< .05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p’s< .0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p< .05). This differing nature of the BARIC-SBP relationship between the two BP groups may be
Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...
Luckett, Keith; Dummer, J Stephen; Miller, Geraldine; Hester, Sydney; Thomas, Lora
Background. Histoplasmosis causes severe disease in patients with defects of cell-mediated immunity. It is not known whether outcomes vary related to the type of immunodeficiency or class of antifungal treatment. Methods. We reviewed cases of active histoplasmosis that occurred at Vanderbilt University Medical Center from July 1999 to June 2012 in patients with human immunodeficiency virus (HIV) infection, a history of transplantation, or tumor necrosis factor (TNF)-α inhibitor use. These groups were compared for differences in clinical presentation and outcomes. In addition, outcomes were related to the initial choice of treatment. Results. Ninety cases were identified (56 HIV, 23 transplant, 11 TNF-α inhibitor). Tumor necrosis factor-α patients had milder disease, shorter courses of therapy, and fewer relapses than HIV patients. Histoplasma antigenuria was highly prevalent in all groups (HIV 88%, transplant 95%, TNF-α 91%). Organ transplant recipients received amphotericin B formulation as initial therapy less often than other groups (22% vs 57% HIV vs 55% TNF-α; P = .006). Treatment failures only occurred in patients with severe disease. The failure rate was similar whether patients received initial amphotericin or triazole therapy. Ninety-day histoplasmosis-related mortality was 9% for all groups and did not vary significantly with choice of initial treatment. Conclusions. Histoplasmosis caused milder disease in patients receiving TNF-α inhibitors than patients with HIV or solid organ transplantation. Treatment failures and mortality only occurred in patients with severe disease and did not vary based on type of immunosuppression or choice of initial therapy.
Nasimi, Ali; Kafami, Marzieh
The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
Monahan, Kevin D
Prospective studies indicate that high intake of dietary flavanols, such as those contained in cocoa/chocolate, are associated with reduced rates of cardiovascular-related morbidity and mortality in humans. Numerous mechanisms may underlie these associations such as favorable effects of flavanols on blood pressure, platelet aggregation, thrombosis, inflammation, and the vascular endothelium. The brachial artery flow-mediated dilation (FMD) technique has emerged as a robust method to quantify endothelial function in humans. Collectively, the preponderance of evidence indicates that FMD is a powerful surrogate measure for firm cardiovascular endpoints, such as cardiovascular-related mortality, in humans. Thus, literally thousands of studies have utilized this technique to document group differences in FMD, as well as to assess the effects of various interventions on FMD. In regards to the latter, numerous studies indicate that both acute and chronic ingestion of cocoa/chocolate increases FMD in humans. Increases in FMD after cocoa/chocolate ingestion appear to be dose-dependent such that greater increases in FMD are observed after ingestion of larger quantities. The mechanisms underlying these responses are likely diverse, however most data suggest an effect of increased nitric oxide bioavailability. Thus, positive vascular effects of cocoa/chocolate on the endothelium may underlie (i.e., be linked mechanistically to) reductions in cardiovascular risk in humans.
Bierl, Charlene; Miller, Barry; Prak, Eline Luning; Gasiewski, Allison; Kearns, Jane; Tsai, Donald; Jessup, Mariell; Kamoun, Malek
We present four patients with late AMR following cardiac transplantation, which was associated with de novo post-transplant anti-HLA class II antibody production. All patients had negative anti-HLA class I and class II antibodies prior to transplantation (as assessed by sensitive Flow PRA bead assays) and had a negative retrospective T- and B-cell flow cytometric cross-match. Upon presentation with late graft rejection due to AMR, all patients were treated with rituximab and serial plasmapheresis with IVIg plus triple-drug immunosuppression therapy. Despite initial responses to therapy, relapses occurred in all of the patients and necessitated prolonged or multiple hospital admissions and second transplants in two cases. Post-transplant serum antibody monitoring did not prove to be predictive of treatment success or failure. Serum anti-HLA antibodies should be monitored after heart transplantation. We recommend an assessment of anti-HLA antibodies following a decline in immunosuppressant drug levels or in the presence of heart failure symptoms. Anti-HLA antibody detection should be performed using very sensitive techniques such as microparticle-based assays.
Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; ...
Versluys, Birgitta; Bierings, Marc; Murk, Jean Luc; Wolfs, Tom; Lindemans, Caroline; Vd Ent, Kors; Boelens, Jaap Jan
Alloimmune-mediated lung syndromes (allo-LSs) are life-threatening complications after hematopoietic cell transplantation (HCT). Respiratory virus (RV) has been suggested to play a role in the pathogenesis. We studied the relation between RV DNA/RNA detection in the upper/lower airways before HCT and the occurrence of allo-LSs. We retrospectively analyzed all HCT recipients between 2004 and 2014, in whom real-time PCR for RV was performed in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluid before HCT. The main outcome of interest was the presence of an allo-LS, which was defined as idiopathic pneumonia syndrome or bronchiolitis obliterans syndrome. Other outcomes were overall survival and treatment-related mortality. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regression for analyses. One hundred seventy-nine children (median age, 6.8 years) were included. RVs were found in 61% (41% in BAL fluid/NPAs and 20% in NPAs only). Rhinovirus was the most frequently detected RV (42%). Allo-LSs occurred in 13%. RV positivity in BAL fluid was a predictor for allo-LSs (hazard ratio, 3.8; 95% CI, 1.4-10.7; P = .01), whereas RV positivity in NPAs only was not. No other predictors were found. Grade II to IV acute graft-versus-host disease related to steroid treatment shows a trend toward a protective effect (odds ratio, 0.16; 95% CI, 0.0-1.3; P = .08). Allo-LSs significantly increased treatment-related mortality (52% ± 10% in allo-LSs and 20% ± 4% in non-allo-LSs, P = .007). These results show that pre-HCT BAL fluid RV positivity was a predictor for allo-LSs. Screening for RVs before HCT might identify patients at risk for allo-LSs. This could have implications for prevention and treatment and might subsequently influence the outcomes of HCT. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Treweeke, A.; Hall, J.; Lambie, S.; Leslie, S. J.; Megson, I. L.
Background Evidence points to activation of pro-inflammatory and pro-thrombotic stimuli during the haemodialysis process in end-stage renal disease (ESRD) with potential to predispose to cardiovascular events. Diabetes is associated with a higher incidence of cardiovascular disease in haemodialysis patients. We tested the hypothesis that a range of mediators and markers that modulate cardiovascular risk are elevated in haemodialysis patients with diabetes compared to those without. Methods Men and women with diabetes (n = 6) and without diabetes (n = 6) aged 18–90 years receiving haemodialysis were recruited. Blood samples were collected and analysed pre- and post-haemodialysis sessions for (platelet-monocyte conjugates (PMC), oxidised LDL (Ox-LDL), endothelin 1 (ET-1) and vascular endothelial growth factor (VEGF-A). Results PMC levels significantly increased after haemodialysis in both groups (diabetes p = 0.047; non-diabetes p = 0.005). Baseline VEGF-A was significantly higher in people with diabetes (p = 0.009) and post-dialysis levels were significantly reduced in both groups (P = 0.002). Ox-LDL and CRP concentrations were not significantly different between groups nor affected in either group post-dialysis. Similarly, ET-1 concentrations were comparable in all patients at baseline, with no change post-dialysis in either group. Conclusions In this pilot study, we have confirmed that circulating PMCs are increased following dialysis irrespective of diabetes status. This is likely to be a mechanistic process and offers a potential explanation for high rates of vascular events associated with haemodialysis. The higher VEGF-A concentrations between patients with and without diabetes is a previously unreported finding in diabetic ESRD. Further research is merited to establish whether VEGF-A is a marker or mediator (or both) of cardiovascular risk in haemodialysis. PMID:28542479
Treweeke, A; Hall, J; Lambie, S; Leslie, S J; Megson, I L; MacRury, S M
Evidence points to activation of pro-inflammatory and pro-thrombotic stimuli during the haemodialysis process in end-stage renal disease (ESRD) with potential to predispose to cardiovascular events. Diabetes is associated with a higher incidence of cardiovascular disease in haemodialysis patients. We tested the hypothesis that a range of mediators and markers that modulate cardiovascular risk are elevated in haemodialysis patients with diabetes compared to those without. Men and women with diabetes (n = 6) and without diabetes (n = 6) aged 18-90 years receiving haemodialysis were recruited. Blood samples were collected and analysed pre- and post-haemodialysis sessions for (platelet-monocyte conjugates (PMC), oxidised LDL (Ox-LDL), endothelin 1 (ET-1) and vascular endothelial growth factor (VEGF-A). PMC levels significantly increased after haemodialysis in both groups (diabetes p = 0.047; non-diabetes p = 0.005). Baseline VEGF-A was significantly higher in people with diabetes (p = 0.009) and post-dialysis levels were significantly reduced in both groups (P = 0.002). Ox-LDL and CRP concentrations were not significantly different between groups nor affected in either group post-dialysis. Similarly, ET-1 concentrations were comparable in all patients at baseline, with no change post-dialysis in either group. In this pilot study, we have confirmed that circulating PMCs are increased following dialysis irrespective of diabetes status. This is likely to be a mechanistic process and offers a potential explanation for high rates of vascular events associated with haemodialysis. The higher VEGF-A concentrations between patients with and without diabetes is a previously unreported finding in diabetic ESRD. Further research is merited to establish whether VEGF-A is a marker or mediator (or both) of cardiovascular risk in haemodialysis.
Honaramooz, Ali; Megee, Susan; Zeng, Wenxian; Destrempes, Margret M; Overton, Susan A; Luo, Jinping; Galantino-Homer, Hannah; Modelski, Mark; Chen, Fangping; Blash, Stephen; Melican, David T; Gavin, William G; Ayres, Sandra; Yang, Fang; Wang, P Jeremy; Echelard, Yann; Dobrinski, Ina
We explored whether exposure of mammalian germ line stem cells to adeno-associated virus (AAV), a gene therapy vector, would lead to stable transduction and transgene transmission. Mouse germ cells harvested from experimentally induced cryptorchid donor testes were exposed in vitro to AAV vectors carrying a GFP transgene and transplanted to germ cell-depleted syngeneic recipient testes, resulting in colonization of the recipient testes by transgenic donor cells. Mating of recipient males to wild-type females yielded 10% transgenic offspring. To broaden the approach to nonrodent species, AAV-transduced germ cells from goats were transplanted to recipient males in which endogenous germ cells had been depleted by fractionated testicular irradiation. Transgenic germ cells colonized recipient testes and produced transgenic sperm. When semen was used for in vitro fertilization (IVF), 10% of embryos were transgenic. Here, we report for the first time that AAV-mediated transduction of mammalian germ cells leads to transmission of the transgene through the male germ line. Equally important, this is also the first report of transgenesis via germ cell transplantation in a nonrodent species, a promising approach to generate transgenic large animal models for biomedical research.
Steca, P; Greco, A; Monzani, D; Politi, A; Gestra, R; Ferrari, G; Malfatto, G; Parati, G
Numerous empirical studies have investigated the relationships between cardiovascular diseases (CVD) and patients' psychological well-being, with a focus almost exclusively on its dark side. Very little is known on the impact of illness severity on both negative and positive indicators of patients' well-being, as well as on the psychosocial variables that may mediate this association. Aim of the study was to investigate the impact of illness severity on depression as well as on health satisfaction and life satisfaction of patients undergoing a cardiovascular rehabilitation. It also aimed at testing the mediation of illness perception and self-efficacy beliefs in managing cardiac risk factors. The study involved 172 patients (mean age = 66.43 years; SD = 9.99 years; 76.2% men). Illness severity was measured in terms of left ventricular ejection fraction at discharge from the cardiology department, whereas all psychological dimensions were assessed one week later. Results showed significant relationships among illness severity, depression and health satisfaction that were fully mediated by illness perception and self-efficacy beliefs, but not significant relation between disease severity and life satisfaction (χ2 (1) = 2.30, p = n.s.). Overall, findings underline the importance of working on illness perception and self-efficacy beliefs to contrast depression and to improve health and life satisfaction in patients with CVD.
Matignon, M; Aissat, A; Canoui-Poitrine, F; Grondin, C; Pilon, C; Desvaux, D; Saadoun, D; Barathon, Q; Garrido, M; Audard, V; Rémy, P; Lang, P; Cohen, J; Grimbert, P
Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell-mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell-mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il-17 and T-bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell-mediated rejection reversal (p = 0.03). The presence of IL-17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell-mediated rejection in recipients of expanded criteria allograft.
Fujimoto, Toshinari; Nakada, Yasuyuki; Yamamoto, Izumi; Kobayashi, Akimitsu; Tanno, Yudo; Yamada, Hiroki; Miki, Jun; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi
We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases.
Chou, Hong-Shiue; Hsieh, Ching-Chuan; Charles, Ronald; Wang, Lianfu; Wagner, Timothy; Fung, John J.; Qian, Shiguang; L, Lina Lu
Background Side effects of lifetime immunosuppression for cell transplants often outweigh the benefits, therefore, induction of transplant tolerance is needed. We have shown that cotransplantation with myeoid-derived suppressor cells (MDSC) effectively protect islet allografts from rejection without requirement of immunosuppression. This study was to investigate the underlying mechanisms. Methods MDSC were generated by addition of hepatic stellate cells (HpSC) from various stain mice into dendritic cell (DC) culture. The quality of MDSC was monitored by phenotype and function analyses. MDSC mixed with islet allografts were transplanted into diabetic recipients. T cell response was analyzed following transplant by flow and histochemical analyses, and compared to islet alone and islet/DC transplant groups. B7-H1 knockout mice were used to determine the role of B7-H1 on MDSC in regulation of T cell response. Results Cotransplantation with MDSC (not DC) effectively protected islet allografts without requirement of immunosuppression. This is associated with attenuation of CD8 T cells in the grafts and marked expansion of T regulatory (Treg) cells, which contributed to MDSC-induced T cell hyporesponsiveness. Antigen-specific Treg cells were prone to accumulate in lymphoid organs close to the grafts. Both in vitro and in vivo data demonstrated that B7-H1 was absolutely required for MDSC to exert immune regulatory activity and induction of Treg cells. Conclusion The described approach holds great clinical application potential, and may overcome the limitation of requiring chronic administration of immunosuppression in cell transplants. Understanding the underlying mechanisms will facilitate the development of this novel therapeutic strategy. PMID:22179405
Gervasini, Guillermo; Luna, Enrique; García-Cerrada, Montserrat; García-Pino, Guadalupe; Cubero, Juan José
Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetraenoic acid (20-HETE), which play an important role both in renal transplant and diabetes mellitus (DM). We searched for associations between polymorphisms in this metabolic pathway and the risk of post-transplant diabetes mellitus (PTDM) in kidney recipients. One-hundred-sixty-four patients were genotyped for common SNPs in this route, namely CYP2C8*3, CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2J2*7, CYP4A11 F434S and CYP4F2 V433M. Demographic and clinical parameters were retrospectively collected at four time-points in the first year after grafting. Thirty-four patients (20.73%) developed PTDM, which was more prevalent among older patients [OR for older age = 1.06 (1.03-1.10), p < 0.001] and in those with higher body mass index (BMI) [OR for higher average BMI in the first year = 1.13 (1.04-1.23); p < 0.01]. Creatinine clearance [OR = 0.97 (0.95-0.99); p < 0.01] and exposure to tacrolimus [OR = 3.25 (1.15-9.19); p < 0.05] were also relevant for PTDM risk. With regard to genetic variants, logistic regression analysis controlling for significant demographic and clinical variables showed that the V433M polymorphism in CYP4F2, responsible for 20-HETE synthesis, was an independent risk factor for PTDM [OR = 3.94 (1.08-14.33); p < 0.05]. We have shown that a genetic variant in the CYP4F2 gene, the main gene implicated in 20-HETE synthesis, is associated with the risk for PTDM. Our findings suggest that genes in the metabolic pathways of AA may become good candidates in genetic association studies for PTDM.
Chambers, Earle C; Rosenbaum, Emily
Studies have shown that households subsidized with vouchers live in higher quality units and exhibit fewer physical, mental, and social problems than do their peers living in public housing. However, none of these studies have included cardiovascular outcomes. The objective of this study was to assess if use/type of rental assistance is independently associated with poor cardiovascular health among Latino adults (ages ≥ 18) who are eligible for federal low-income rental assistance and living in the Bronx, NY. Data from the cross-sectional, Affordable Housing as an Obesity Mediating Environment study, collected over 18 months (January 2011 to August 2012) were used. The prevalence of cardiovascular disease (CVD) outcomes was determined by measured high blood pressure and self-reported heart attack and/or stroke. Type of housing status was defined as: public housing units, units subsidized by section 8 vouchers, and units unassisted by either federal program. Statistical techniques used were analysis of variance and multivariate logistic regression. The prevalence of CVD was significantly higher among public housing residents than unassisted participants even in the presence of all individual level covariates. Public housing residents also have higher levels of CVD than do section 8 participants. The prevalence of CVD was similar for unassisted and section 8 participants. These findings point to the potential for health benefits arising from housing voucher use even within a fairly delimited geographic area.
Abreu, A R; de Abreu, A R; Santos, L T; de Souza, A A; da Silva, L G; Chianca, D A; de Menezes, R C
Rats fed a high-fat diet (HFD) present an exaggerated endocrine response to stress conditions, which, like obesity, show a high correlation with cardiovascular diseases. Meanwhile the GABAergic neurotransmission within the dorsomedial hypothalamus (DMH) is involved in the regulation of the physiological responses during emotional stress. Here we evaluated the influence of obesity, induced by a HFD, on the cardiovascular responses induced by air jet stress in rats, and the role of the GABAergic tonus within the DMH in these changes. Our results showed that consumption of a HFD (45% w/w fat) for 9 weeks induced obesity and increases in baseline mean arterial pressure (MAP) and heart rate (HR). Moreover, obesity potentiated stress responsiveness, evidenced by the greater changes in MAP and HR induced by stress in obese rats. The injection of muscimol into the DMH reduced the maximal increases in HR and MAP induced by stress in both groups; however, the reduction in the maximal increases in MAP in the HFD group was less pronounced. Moreover, the injection of muscimol into the DMH of obese rats was less effective in reducing the stress-induced tachycardia, since the HR attained the same levels at the end of the stress paradigm as after the vehicle injection. Injection of bicuculline into DMH induced increases in MAP and HR in both groups. Nevertheless, obesity shortened the tachycardic response to bicuculline injection. These data show that obesity potentiates the cardiovascular response to stress in rats due to an inefficient GABAA-mediated inhibition within the DMH.
Liu, Hui; Liu, Hong-Yang; Jiang, Yi-Nong; Li, Nan
Thymoquinone is the main active monomer extracted from black cumin and has anti‑inflammatory, antioxidant and anti‑apoptotic functions. However, the protective effects of thymoquinone on cardiovascular function in diabetes remain to be fully elucidated. The present study aimed to investigate the molecular mechanisms underling the beneficial effects of thymoquinone on the cardiovascular function in streptozotocin‑induced diabetes mellitus (DM) rats. Supplement thymoquinone may recover the insulin levels and body weight, inhibit blood glucose levels and reduce the heart rate in DM‑induced rats. The results indicated that the heart, liver and lung to body weight ratios, in addition to the blood pressure levels, were similar for each experimental group. Treatment with thymoquinone significantly reduced oxidative stress damage, inhibited the increased endothelial nitric oxide synthase protein expression and suppressed the elevation of cyclooxygenase‑2 levels in DM‑induced rats. In addition, thymoquinone significantly suppressed the promotion of tumor necrosis factor‑α and interleukin‑6 levels in the DM‑induced rats. Furthermore, administration of thymoquinone significantly reduced caspase‑3 activity and the promotion of phosphorylated‑protein kinase B (Akt) protein expression levels in DM‑induced rats. These results suggest that the protective effect of thymoquinone improves cardiovascular function and attenuates oxidative stress, inflammation and apoptosis by mediating the phosphatidylinositol 3‑kinase/Akt pathway in DM‑induced rats.
Anastácio, Lucilene Rezende; de Oliveira, Marina Chaves; Diniz, Kiara Gonçalves; Ferreira, Adaliene Matos Versiane; Lima, Agnaldo Soares; Correia, Maria Isabel Toulson Davisson; Vilela, Eduardo Garcia
The role of adipokines in liver transplantation (LTx) recipients who have metabolic syndrome (MetS) has seldom been assessed. The aim of this study was to investigate the concentrations of adipokines, inflammatory mediators, and insulin-resistance markers in liver recipients with MetS and its components. Serum samples from 34 patients (55.9% male; 54.9 ± 13.9 y; 7.7 ± 2.9 y after LTx; 50% presented with MetS) were assessed for adiponectin, resistin, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, C-reactive protein (CRP), homeostatic model assessment-insulin resistance (HOMA-IR) and free fatty acid (FFA) levels. The dosages were uni- and multivariate analyzed to cover MetS (using the Harmonizing MetS criteria), its components, and dietary intake. A higher concentration of adiponectin (P < 0.05) was observed among patients with MetS (5.2 ± 3.2 μg/mL) compared with those without MetS (3.2 ± 1.2 μg/mL), as well as those with MetS components versus those without them: abdominal obesity (4.6 ± 2.6 μg/mL versus 2.6 ± 0.6 μg/mL), high triacylglycerols (TGs; 5.6 ± 3.1 μg/mL versus 3 ± 0.9 μg/mL) and low high-density lipoprotein (HDL; 6.1 ± 2.7 μg/mL versus 3.3 ± 1.9 μg/mL). Increased TNF-α and HOMA-IR values were seen in patients with abdominal obesity. Patients with high TGs also had greater FFA values. Independent predictors for adiponectin were waist-to-hip ratio, low HDL and high TGs. High TGs and fasting blood glucose were independent predictors for HOMA-IR. Independent predictors could not be identified for CRP, TNF-α, MCP-1, IL-6, or FFA. MetS and its components are related to an increased HOMA-IR concentration and FFA. Adiponectin, resistin, and inflammatory markers, such as TNF-α, IL-6, MCP-1, and CRP, were not associated with MetS in this sample of post-LTx patients. Copyright © 2016 Elsevier Inc. All rights reserved.
Chapman, Jeremy R.; Webster, Angela C.; Wong, Germaine
Malignancy has become one of the three major causes of death after transplantation in the past decade and is thus increasingly important in all organ transplant programs. Death from cardiovascular disease and infection are both decreasing in frequency from a combination of screening, prophylaxis, aggressive risk factor management, and interventional therapies. Cancer, on the other hand, is poorly and expensively screened for; risk factors are mostly elusive and/or hard to impact on except for the use of immunosuppression itself; and finally therapeutic approaches to the transplant recipient with cancer are often nihilistic. This article provides a review of each of the issues as they come to affect transplantation: cancer before wait-listing, cancer transmission from the donor, cancer after transplantation, outcomes of transplant recipients after a diagnosis of cancer, and the role of screening and therapy in reducing the impact of cancer in transplant recipients. PMID:23818517
Maurice, Donald H
Numerous pharmacological and physiological agents acting via either cAMP- or cGMP-mediated impact the activities of cells of the cardiovascular system. While most define cAMP and cGMP signaling systems as separate and independent, recent advances in our understanding of cyclic nucleotide signaling, and more specifically, of the roles which cyclic nucleotide phosphodiesterases (PDEs) play in these events, have altered this view. In this short chapter, I will review the data identifying expression of several PDEs in cells of the cardiovascular system. In addition, I will review the data that identify PDEs as enzymes capable of allowing integration between cAMP and cGMP signaling in cells, and propose that cAMP and cGMP signaling systems can represent parallel and interdependent signaling systems. Moreover, I will propose that cGMP-mediated effects on the activities of variants of the Phosphodiesterase 2 (PDE2), PDE3 and PDE5 families may act to coordinate linkage between cAMP and cGMP signaling in these cells.
Malluche, Hartmut H.; Monier-Faugere, Marie-Claude; Herberth, Johann
In light of greatly improved long-term patient and graft survival after renal transplantation, improving other clinical outcomes such as risk of fracture and cardiovascular disease is of paramount importance. After renal transplantation, a large percentage of patients lose bone. This loss of bone results from a combination of factors that include pre-existing renal osteodystrophy, immunosuppressive therapy, and the effects of chronically reduced renal function after transplantation. In addition to low bone volume, histological abnormalities include decreased bone turnover and defective mineralization. Low bone volume and low bone turnover were recently shown to be associated with cardiovascular calcifications, highlighting specific challenges for medical therapy and the need to prevent low bone turnover in the pretransplant patient. This Review discusses changes in bone histology and mineral metabolism that are associated with renal transplantation and the effects of these changes on clinical outcomes such as fractures and cardiovascular calcifications. Therapeutic modalities are evaluated based on our understanding of bone histology. PMID:19918255
Thomas, Peter; Pang, Yefei
The protective functions of progesterone in the cardiovascular system have received little attention even though evidence has accumulated that progesterone lowers blood pressure, inhibits coronary hyperactivity and has powerful vasodilatory and natriuretic effects. One possible reason why potential beneficial actions of progesterone on cardiovascular functions have not been extensively studied is that divergent effects to those of progesterone have been observed in many clinical trials with synthetic progestins such as medroxyprogesterone acetate which are associated with increased risk of coronary disease. Evidence that progesterone exerts protective effects on cardiovascular functions is briefly reviewed. The finding that progesterone administration decreases blood vessel vasoconstriction in several animal models within a few minutes suggests that rapid, nongenomic progesterone mechanisms are of physiological importance in regulating vascular tone. Rapid activation of second messenger pathways by progesterone has been observed in vascular endothelial and smooth muscle cells, resulting in alterations in endothelial nitric oxide synthase (eNOS) activity and calcium influx, respectively. Both nuclear progesterone receptors (PRs) and novel membrane progesterone receptors (mPRs) are candidates for the intermediaries in these rapid, cell-surface initiated progesterone actions in endothelial and smooth muscle vascular cells. PRs have been detected in both cell types. New data are presented showing mPRα, mPRβ and mPRγ are also present in human endothelial and smooth muscle vascular cells. Preliminary evidence suggests mPRs mediate rapid progestin signaling in these endothelial cells, resulting in down-regulation of cAMP production and increased nitric oxide synthesis. The role of mPRs in progesterone regulation of cardiovascular functions warrants further investigation. Copyright © 2013 Elsevier Inc. All rights reserved.
Barriers to successful outcomes following pediatric transplantation have shifted from ischemic reperfusion injury and rejection to more long-term complications. Of particular concern is the high prevalence of CKD owing to preexisting damage and nephrotoxicity, as well as other CV complications such as hypertension and cardiomyopathy. All of these contribute to graft loss and shortened life expectancy, thereby limiting the success story of solid-organ transplantation. Managing CKD and related CV morbidity should be integral to the care of pediatric transplant patients, and timely detection of any irregularities would increase the chances of restoring lost kidney function. GFR is still the widely accepted indicator of renal function, and nuclear medicine techniques are the gold standard measurement methods. These methods are limited by costs, radiation exposure and substrate injection, and current practice still uses the Schwartz estimate, despite its well-documented limitations. Newer endogenous markers of GFR, such as cystatin C clearance, give a more accurate measure of true GFR but have not been embraced in the management of pediatric transplant recipients. Furthermore, indirect markers (e.g., microalbuminuria and hypertension) could also aid early detection of renal damage. The effects of mainstay immunosuppressants on kidney and heart function are varied, with available data indicating favorable outcomes with tacrolimus compared with ciclosporin. There is a need for appropriately designed and powered randomized controlled trials to validate innovative concepts for tailored immunosuppression in the pediatric population. To date, very few studies have generated long-term data in pediatric renal transplant patients - results of 1-4-yr study favored tacrolimus over ciclosporin, but other immunosuppressive agents also need to be evaluated.
Tsimikas, Sotirios; Duff, Gordon W.; Berger, Peter B.; Rogus, John; Huttner, Kenneth; Clopton, Paul; Brilakis, Emmanuel; Kornman, Kenneth S; Witztum, Joseph L
Objective To assess the influence of pro-inflammatory IL-1 genotype status on the risk of CAD, defined as >50% diameter stenosis, and cardiovascular events mediated by OxPL and Lp(a). Background Oxidized phospholipids (OxPL) are pro-inflammatory, circulate on lipoprotein (a) [Lp(a)] and mediate coronary artery disease (CAD). Genetic variations in the interleukin-1 (IL-1) region are associated with increased inflammatory mediators. Methods IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB) and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by three single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(−). Results Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk of CAD compared to the lowest quartile (OR 2.84, P=0.001). This effect was accentuated in patients ≤60 years old (OR 7.03, P<0.001). In IL-1(−) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR 1.99, P=0.004) and Lp(a) (OR 1.96, P<0.001) in IL-1(+) versus IL-1(−) groups for patients ≤60 years old but not for patients >60 years old. In IL-1(+) patients ≤60 years old, after adjusting for established risk factors, high sensitivity C-reactive protein and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (P=0.002) and had worse 4-year event-free survival (death, MI, stroke, and revascularization) compared to other groups (P=0.006). Conclusion Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically-relevant biological link between pro-inflammatory IL-1 genotypes
Transplant - bone marrow - discharge; Stem cell transplant - discharge; Hematopoietic stem cell transplant - discharge; Reduced intensity; Non-myeloablative transplant - discharge; Mini transplant - discharge; Allogenic bone marrow transplant - ...
Ren, ZH; Zhang, L; Brown, BN; Cui, XT; Badylak, SF; Cai, YN; Guan, YQ; Leak, Rehana K.; Chen, J; Ji, X; Chen, L
Traumatic brain injury (TBI) is a leading cause of cell death and disability among young adults and lacks a successful therapeutic strategy. The multiphasic injuries of TBI severely limit the success of conventional pharmacological approaches. Recent successes with transplantation of stem cells in bioactive scaffolds in other injury paradigms provide new hope for the treatment of TBI. In this study, we transplanted neural stem cells (0.5×105 cells/μl) cultured in a bioactive scaffold derived from porcine urinary bladder matrix (UBM; 4 injection sites, 2.5μl each) into the rat brain following controlled cortical impact (CCI, velocity, 4.0 m/sec; duration, 0.5 sec; depth, 3.2mm). We evaluated the effectiveness of this strategy to combat the loss of motor, memory and cognitive faculties. Before transplantation, compatibility experiments showed that UBM was able to support extended proliferation and differentiation of neural stem cells. Together with its reported anti-inflammatory properties and rapid degradation characteristics in vivo, UBM emerged to be an ideal scaffold. The transplants reduced neuron/tissue loss and white matter injury, and also significantly ameliorated motor, memory, and cognitive impairments. Furthermore, exposure to UBM alone was sufficient to decrease the loss of sensorimotor skills from TBI (examined 3–28 days post-CCI). However, only UBMs that contained proliferating neural stem cells helped attenuate memory and cognitive impairments (examined 26–28 days post-CCI). In summary, these results demonstrate the therapeutic efficacy of stem cells in bioactive scaffolds against TBI and show promise for translation into future clinical use. PMID:23469853
Lim, Hong-Gook; Lee, Hak-Mo; Oh, Byoung Chol; Lee, Jeong Ryul
Sertoli cells (SC) have immunomodulative properties, and chemokine receptor 7 (CCR7) can optimize the systemic immunomodulatory effect by guiding SC from the periphery to the secondary lymphoid organs. The effect of immortalized neonatal porcine SC (NPSCi) was evaluated by analysis of cytokine levels. Hyporesponsiveness to donor cells was determined by MLC and analysis of splenocyte phenotypes using a murine allogeneic skin graft model. The effect of CCR7-expressing NPSCi (NPSCi-CCR7) combined with cobra venom factor (CVF) was evaluated using a heterotopically transplanted murine allogeneic heart model. Expression of immune cytokines was markedly modulated by NPSCi. The lymphocyte proliferation and splenocyte phenotypes were significantly suppressed by NPSCi-CCR7. Although pre-transplantation of NPSCi or NPSCi-CCR7 did not prolong graft survival of allogeneic cardiac grafts, CVF treatment facilitated pre-transplantation of NPSCi-CCR7 to prolong survival of allogeneic cardiac grafts (25.5 +/- 7.05 vs 9.5 +/- 0.58 days, p < 0.01). NPSCi may be used as a powerful immunomodulatory tool, and our strategy to traffic NPSCi to lymphoid organs using CCR7 optimizes the systemic immunomodulatory effect in vivo. With the help of initial immunosuppression for humoral mechanisms using CVF, the host immune response against allogeneic cardiac grafts can be effectively ameliorated by immunomodulation of the cellular mechanism with NPSCi-CCR7.
Sun, Cong; Zhu, Gu; Healey, Paul R.; Spector, Tim D.; Martin, Nicolas G.; Mitchell, Paul; Wong, Tien Y.; Mackey, David A.; Hammond, Christopher J.; Andrew, Toby
Purpose. Retinal arteriolar and venular calibers are highly heritable and associated with cardiovascular disease. This study was designed to investigate the relative influence of genetic and environmental factors on the high phenotypic correlation (r = 0.59) between these two traits and to assess the shared and specific influence of established and novel cardiovascular disease risk factors on them. Methods. A total of 1463 Caucasian female twins (706 monozygotic and 757 dizygotic), between 24 and 79 years of age, underwent retinal photography from which retinal arteriolar (mean, 153.75 ± 22.1 μm, SD) and venular (mean, 232.1 ± 36.6 μm) calibers were measured with semiautomated software. A bivariate heritability model was used to assess the genetic and environmental influences underlying both specific trait variance and the covariance between the vessel traits. The investigation was an assessment of phenotypic associations between retinal arteriolar and venular calibers and cardiovascular disease risk factors. Results. Additive genetic factors accounted for approximately three fourths of the covariance between retinal arteriolar and venular calibers within the cohort. This finding was replicated in a sample of 1981 twins from the Australian Twins Eye Study. The partial correlation showed that known risk factors accounted for only 5% of the covariance between arteriolar and venular calibers. Novel associations were found between venular caliber and β-cell function (P = 0.011) and insulin sensitivity (P = 0.002). Conclusions. These results suggest that future gene-mapping studies may identify pleiotropic genetic variants influencing both retinal arteriolar and venular calibers. Genetic variants associated with retinal caliber and (risk factors for) cardiovascular disease should provide new etiologic insights into this complex disease. PMID:20926817
Bauer, Jochen; Ripperger, Anne; Frantz, Stefan; Ergün, Süleyman; Schwedhelm, Edzard; Benndorf, Ralf A
Isoprostanes are free radical-catalysed PG-like products of unsaturated fatty acids, such as arachidonic acid, which are widely recognized as reliable markers of systemic lipid peroxidation and oxidative stress in vivo. Moreover, activation of enzymes, such as COX-2, may contribute to isoprostane formation. Indeed, formation of isoprostanes is considerably increased in various diseases which have been linked to oxidative stress, such as cardiovascular disease (CVD), and may predict the atherosclerotic burden and the risk of cardiovascular complications in the latter patients. In addition, several isoprostanes may directly contribute to the functional consequences of oxidant stress via activation of the TxA2 prostanoid receptor (TP), for example, by affecting endothelial cell function and regeneration, vascular tone, haemostasis and ischaemia/reperfusion injury. In this context, experimental and clinical data suggest that selected isoprostanes may represent important alternative activators of the TP receptor when endogenous TxA2 levels are low, for example, in aspirin-treated individuals with CVD. In this review, we will summarize the current understanding of isoprostane formation, biochemistry and (patho) physiology in the cardiovascular context. PMID:24646155
Bauer, Jochen; Ripperger, Anne; Frantz, Stefan; Ergün, Süleyman; Schwedhelm, Edzard; Benndorf, Ralf A
Isoprostanes are free radical-catalysed PG-like products of unsaturated fatty acids, such as arachidonic acid, which are widely recognized as reliable markers of systemic lipid peroxidation and oxidative stress in vivo. Moreover, activation of enzymes, such as COX-2, may contribute to isoprostane formation. Indeed, formation of isoprostanes is considerably increased in various diseases which have been linked to oxidative stress, such as cardiovascular disease (CVD), and may predict the atherosclerotic burden and the risk of cardiovascular complications in the latter patients. In addition, several isoprostanes may directly contribute to the functional consequences of oxidant stress via activation of the TxA2 prostanoid receptor (TP), for example, by affecting endothelial cell function and regeneration, vascular tone, haemostasis and ischaemia/reperfusion injury. In this context, experimental and clinical data suggest that selected isoprostanes may represent important alternative activators of the TP receptor when endogenous TxA2 levels are low, for example, in aspirin-treated individuals with CVD. In this review, we will summarize the current understanding of isoprostane formation, biochemistry and (patho) physiology in the cardiovascular context. © 2014 The British Pharmacological Society.
Wu, Lisa M.; Austin, Jane; Hamilton, Jada G.; Isola, Luis; Rowley, Scott; Warbet, Rachel; Winkel, Gary; Redd, William H.; Rini, Christine
Objective Cognitive problems are commonly reported by hematopoietic stem cell transplant (HSCT) survivors, and are associated with poorer physical and mental well-being. It was hypothesized that adverse effects of subjective cognitive impairment occur because cognitive difficulties reduce survivors’ confidence that they can manage HSCT-related symptoms—that is, self-efficacy for symptom management. Methods HSCT survivors (n = 245) 9-months to 3-years post-HSCT completed measures of subjective cognitive functioning, self-efficacy for symptom management, and clinically important outcomes: depressed mood, anxiety, and quality of life. Mediation analyses using bootstrapping were conducted to investigate whether effects of subjective cognitive impairment on these outcomes were mediated by self-efficacy for cognitive (SE-Cognitive), emotional (SE-Emotional), social (SE-Social), and physical (SE-Physical) symptom management. Results Self-efficacy mediated relations between subjective cognitive impairment and depressed mood (total indirect effect = −.0064 and 95% confidence interval [CI] −.0097 to −.0036), anxiety (total indirect effect = −.0045, CI −.0072 to −.0021), and quality of life (total indirect effect = .0952, CI .0901 to .2642). SE-Emotional was a unique mediator when the outcome was depressed mood and anxiety. SE-Social, SE-Physical and SE-Emotional were specific mediators when outcome was quality of life. Conclusions Findings support the conclusion that subjective cognitive impairment reduces HSCT survivors’ confidence in their ability to manage common post-HSCT symptoms, with implications for physical and mental well-being. Interventions that help enhance survivors’ self-efficacy are likely to benefit HSCT survivors who report subjective cognitive impairment. PMID:21739524
3-Bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth
WANG, TING-AN; ZHANG, XIAO-DONG; GUO, XING-YU; XIAN, SHU-LIN; LU, YUN-FEI
Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT. PMID:26708213
3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.
Wang, Ting-An; Zhang, Xiao-Dong; Guo, Xing-Yu; Xian, Shu-Lin; Lu, Yun-Fei
Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.
Zhang, Yi; Zhang, Cuihua
Dendritic cells (DCs) are potent antigen-presenting cells that bridge innate and adaptive immune responses. Recent work has elucidated the DC life cycle, including several important stages such as maturation, migration and homeostasis, as well as DC classification and subsets/locations, which provided etiological insights on the role of DCs in disease processes. DCs have a close relationship to endothelial cells and they interact with each other to maintain immunity. DCs are deposited in the atherosclerotic plaque and contribute to the pathogenesis of atherosclerosis. In addition, the necrotic cardiac cells induced by ischemia activate DCs by Toll-like receptors, which initiate innate and adaptive immune responses to renal, hepatic and cardiac ischemia reperfusion injury (IRI). Furthermore, DCs are involved in the acute/chronic rejection of solid organ transplantation and mediate transplant tolerance as well. Advancing our knowledge of the biology of DCs will aid development of new approaches to treat many cardiovascular diseases, including atherosclerosis, cardiac IRI and transplantation. PMID:21179302
Wu, Zhao-Tang; Ren, Chang-Zhen; Yang, Ya-Hong; Zhang, Ru-Wen; Sun, Jia-Cen; Wang, Yang-Kai; Su, Ding-Feng; Wang, Wei-Zhong
Angiotensin-1-7 [Ang-(1-7)], acting via the Mas receptor in the central nervous system, is involved in the regulation of cardiovascular activity. Nitric oxide (NO) is implicated as an important modulator in the nucleus tractus solitarii (NTS), a key region involved in control of cardiovascular activity. The aim of the present study was to determine the role of phosphatidylinositol 3-kinase (PI3K) signaling in mediating the effect of Ang-(1-7) on NO generation in the NTS. In Sprague-Dawley rats, acute injection of Ang-(1-7) into the NTS significantly increased NO generation and neuronal/endothelial NO synthase (n/eNOS) activity, which were abolished by the selective Mas receptor antagonist d-Alanine-[Ang-(1-7)] (A-779), the PI3K inhibitor LY294002, or the Akt inhibitor triciribine (TCN). Western blotting analysis further demonstrated that Ang-(1-7) significantly increased levels of Akt/NOS phosphorylation in the NTS, and Ang-(1-7)-induced e/nNOS phosphorylation was antagonized by LY294002 or TCN. Furthermore, gene knockdown of PI3K by lentivirus containing small hairpin RNA in the NTS prevented the Ang-(1-7)-induced increases in NOS/Akt phosphorylation and NO production. The physiological (in vivo) experiments showed that pretreatment with the NOS inhibitor l-NAME, LY294002, or TCN abolished the decreases in blood pressure, heart rate, and renal sympathetic nerve activity induced by Ang-(1-7) injected into the NTS. Our findings suggest that nitric oxide release meditated by the Mas-PI3K-NOS signaling pathway is involved in the cardiovascular effects of Ang-(1-7) in the NTS.
Increasing evidence suggests that time-varying and static magnetic fields in the environment might affect the cardiovascular system. To explore the underlying physiology, the effect of static magnetic fields (SMFs) on the carotid baroreflex control of microcirculation was studied. Twenty-four hemodynamic monitorings were performed in rabbits sedated by pentobarbital infusion (5 mg/kg/h) during experiments that lasted 120 min. Mean femoral artery blood pressure, heart rate, and ear lobe skin microcirculatory blood flow, measured by microphotoelectric plethysmogram (MPPG), were simultaneously recorded before and after a 40 min exposure of the sinocarotid baroreceptors to Nd(2)-Fe(14)-B alloy magnets (n = 14) or sham magnets (n = 10, control series). The local SMF field was 350 mT, at the baroreceptors' site. Arterial baroreflex sensitivity (BRS) was estimated from heart rate/blood pressure response to intravenous bolus injections of nitroprusside and phenylephrine. A significant positive correlation was found between the SMF-induced increase in BRS (DeltaBRS = BRS(afterSMF) - BRS(priorSMF)) and the increment in microvascular blood flow (DeltaMPPG = MPPG(afterSMF) - MPPG(priorSMF)) (r = 0.66, p < 0.009). The SMF probably modulated the arterial baroreflex-mediated microcirculatory control. This could represent one possible mechanism how environmental magnetic fields act on the cardiovascular system, and a method how to complexly adjust macro- and microcirculation with potential clinical implementation.
Brown, Christopher B; Wenning, Jennifer M; Lu, Min Min; Epstein, Douglas J; Meyers, Erik N; Epstein, Jonathan A
Tbx1 has been implicated as a candidate gene responsible for defective pharyngeal arch remodeling in DiGeorge/Velocardiofacial syndrome. Tbx1(+/-) mice mimic aspects of the DiGeorge phenotype with variable penetrance, and null mice display severe pharyngeal hypoplasia. Here, we identify enhancer elements in the Tbx1 gene that are conserved through evolution and mediate tissue-specific expression. We describe the generation of transgenic mice that utilize these enhancer elements to direct Cre recombinase expression in endogenous Tbx1 expression domains. We use these Tbx1-Cre mice to fate map Tbx1-expressing precursors and identify broad regions of mesoderm, including early cardiac mesoderm, which are derived from Tbx1-expressing cells. We test the hypothesis that fibroblast growth factor 8 (Fgf8) functions downstream of Tbx1 by performing tissue-specific inactivation of Fgf8 using Tbx1-Cre mice. Resulting newborn mice display DiGeorge-like congenital cardiovascular defects that involve the outflow tract of the heart. Vascular smooth muscle differentiation in the great vessels is disrupted. This data is consistent with a model in which Tbx1 induces Fgf8 expression in the pharyngeal endoderm, which is subsequently required for normal cardiovascular morphogenesis and smooth muscle differentiation in the aorta and pulmonary artery.
Kidney transplant Overview By Mayo Clinic Staff A kidney transplant is a surgical procedure to place a healthy kidney ... bloodstream via a machine (dialysis) or a kidney transplant to stay alive. Mayo Clinic's approach . Mayo Clinic ...
Lung transplant Overview By Mayo Clinic Staff A lung transplant is a surgical procedure to replace a diseased or ... lung, usually from a deceased donor. A lung transplant is reserved for people who have tried other ...
Renal transplant; Transplant - kidney ... Barry JM, Conlin MJ. In: Renal transplantation. Wein AJ, ed. Campbell-Walsh Urology . 10th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 44. Kidney Disease: Improving Global Outcomes ( ...
Zheng, Rui-mao; Zou, Chang-jiang; Zhu, Shi-gong
To investigate the roles of p38 mitogen-activated protein kinase (p38 MAPK) in the cardiovascular and behavioral responses induced by intracerebral ventricular injection (i.c.v.) of interleukin-1 beta (IL-1 beta) or footshock. We examined the effects of p38 MAPK on mean artery blood pressure (mABP), heart rate (HR), and motor activity (MA) during central administration of IL-1 beta, or footshock after i.c.v. SB203580 (a specific inhibitor of the p38 MAPK) with Cardiovascular and Behavior Telemetry System in conscious SD rats. (1) IL-1 beta (i.c.v.) or footshock remarkably rise the mABP, and the maximal changes are (7.8+/-1.8) and (12.3+/-3.5) mmHg, respectively, which was abrogated by the pretreatment with p38 inhibitor SB203580 intracerebroventricularly. (2) Compared with icv saline group, the motor activity was significantly decreased in SB203580 group with maximal changes (-7.6+/-1.1) counts/min after footshock. p38 MAPK plays an important role in the pressor response induced by central administration of IL-1 beta or footshock and change of motor activity after footshock in conscious rats.
Fafi-Kremer, Samira; Fofana, Isabel; Soulier, Eric; Carolla, Patric; Meuleman, Philip; Leroux-Roels, Geert; Patel, Arvind H.; Cosset, François-Loïc; Pessaux, Patrick; Doffoël, Michel; Wolf, Philippe
End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft. PMID:20713596
The mechanisms by which air pollutants induce cardiac and vascular injuries are unknown. We hypothesized that these injuries involve alterations in'aortic membrane lipids and lipid-mediators. We exposed male Wistar Kyoto rats (12-15 wk old), nose-only to air, ozone (03; 0.5 ppm),...
The mechanisms by which air pollutants induce cardiac and vascular injuries are unknown. We hypothesized that these injuries involve alterations in'aortic membrane lipids and lipid-mediators. We exposed male Wistar Kyoto rats (12-15 wk old), nose-only to air, ozone (03; 0.5 ppm),...
Remme, W J
In addition to being accepted therapy in hypertension and heart failure, ACE inhibitors may well offer a new dimension in anti-ischaemic therapy. Currently, anti-ischaemic properties have been demonstrated by ACE inhibitors in selected patient groups, including patients with left ventricular dysfunction with or without a direct temporal relationship with myocardial infarction. Anti-ischaemic effects of ACE inhibitors become apparent late after initiation of treatment and suggest a structural rather than a functional effect. Underlying mechanisms may include a reduction in ventricular dilatation and (abnormal) cardiac hypertrophy, leading to less myocardial oxygen demand and, possibly, improved subendocardial blood supply, and vasculoprotective effects, i.e. anti-atherosclerotic and antiremodelling properties, a beneficial effect on the fibrinolytic system and an improvement in abnormal endothelial vasodilator function. The latter aspect is most probably the pivotal mode of action where the anti-ischaemic profile of ACE inhibition is concerned. An improvement in endothelial dysfunction has been shown in patients with mild to moderate coronary artery disease [Trial on Reversing ENdothelial Dysfunction (TREND)]. It is of importance that, in both clinical experiments and human studies, the role of bradykinin appears central in the structural and functional cardiovascular effects of ACE inhibition. This is particularly true for the improvement of impaired endothelial function. Myocardial ischaemia evokes vasoconstrictor neurohormonal activation, which may lead to coronary vasoconstriction in diseased coronary segments. The subsequent abnormal endothelial function leads to diminished coronary flow and also increases systemic vasotone and afterload, thus unfavourably altering the myocardial oxygen supply/demand ratio. Under laboratory conditions, acute ACE inhibition counteracts this activation in humans. However, it is speculated that this anti-ischaemic mechanism may
Young, James S; Wu, Tao; Chen, Yuhong; Zhao, Dongchang; Liu, Hongjun; Yi, Tangsheng; Johnston, Heather; Racine, Jeremy; Li, Xiaofan; Wang, Audrey; Todorov, Ivan; Zeng, Defu
We reported that both donor CD4+ T and B cells in transplants were required for induction of an autoimmune-like chronic graft versus host disease (cGVHD) in a murine model of DBA/2 donor to BALB/c recipient, but mechanisms whereby donor B cells augment cGVHD pathogenesis remain unknown. Here, we report that, although donor B cells have little impact on acute GVHD (aGVHD) severity, they play an important role in augmenting the persistence of tissue damage in the acute and chronic GVHD overlapping target organs (i.e. skin and lung); they also markedly augment damage in a prototypical cGVHD target organ- the salivary gland. During cGVHD pathogenesis, donor B cells are activated by donor CD4+ T cells to upregulate MHC II and co-stimulatory molecules. Acting as efficient APCs, donor B cells augment donor CD4+ T clonal expansion, autoreactivity, IL-7Rα expression, and survival. These qualitative changes markedly augment donor CD4+ T cells' capacity in mediating autoimmune-like cGVHD, so that they mediate disease in the absence of donor B cells in secondary recipients. Therefore, a major mechanism whereby donor B cells augment cGVHD is through augmenting the clonal expansion, differentiation and survival of pathogenic CD4+ T cells. PMID:22649197
Tobisawa, Yuki; Mori, Kazuyuki; Hashimoto, Yasuhiro; Koie, Takuya; Tanaka, Masakazu; Nishimura, Shin-Ichiro; Sasaki, Hideo; Saito, Mitsuru; Harada, Hiroshi; Chikaraishi, Tatsuya; Ishida, Hideki; Tanabe, Kazunari; Satoh, Shigeru; Ohyama, Chikara
We determined if the serum N-glycan profile can be used as a diagnostic marker of antibody-mediated rejection (ABMR) in living donor kidney transplant (LKTx) recipients. Glycoblotting, combined with mass spectrometry, was used to retrospectively examine N-glycan levels in the postoperative sera of 197 LKTx recipients of whom 16 recipients had ABMR with or without T-cell-mediated rejection (TCMR), 40 recipients had TCMR, and 141 recipients had no adverse events. Multivariate discriminant analysis for prediction of ABMR was performed by inputting an ABMR event as an explanatory variable and sex, age, and serum N-glycan level as objective variables. The N-glycan score was calculated by multiplying the level of candidate objective variables by objective function values. The ABMR predictive performance of the N-glycan score was assessed by receiver operator characteristic curve and Kaplan–Meier curve analyses. The N-glycan score discriminated ABMR with 81.25% sensitivity, 87.85% specificity, and an area under the curve (AUC) of 0.892 that was far superior to that of preformed donor-specific antibody status (AUC, 0.761). Recipients with N-glycan-positive scores >0.8770 had significantly shorter ABMR survival than that of recipients with N-glycan-negative scores. Although the limitations of our study includ its small sample size and retrospective nature, the serum N-glycan score may contribute to prediction of ABMR. PMID:28786963
Noro, Daisuke; Yoneyama, Tohru; Hatakeyama, Shingo; Tobisawa, Yuki; Mori, Kazuyuki; Hashimoto, Yasuhiro; Koie, Takuya; Tanaka, Masakazu; Nishimura, Shin-Ichiro; Sasaki, Hideo; Saito, Mitsuru; Harada, Hiroshi; Chikaraishi, Tatsuya; Ishida, Hideki; Tanabe, Kazunari; Satoh, Shigeru; Ohyama, Chikara
We determined if the serum N-glycan profile can be used as a diagnostic marker of antibody-mediated rejection (ABMR) in living donor kidney transplant (LKTx) recipients. Glycoblotting, combined with mass spectrometry, was used to retrospectively examine N-glycan levels in the postoperative sera of 197 LKTx recipients of whom 16 recipients had ABMR with or without T-cell-mediated rejection (TCMR), 40 recipients had TCMR, and 141 recipients had no adverse events. Multivariate discriminant analysis for prediction of ABMR was performed by inputting an ABMR event as an explanatory variable and sex, age, and serum N-glycan level as objective variables. The N-glycan score was calculated by multiplying the level of candidate objective variables by objective function values. The ABMR predictive performance of the N-glycan score was assessed by receiver operator characteristic curve and Kaplan-Meier curve analyses. The N-glycan score discriminated ABMR with 81.25% sensitivity, 87.85% specificity, and an area under the curve (AUC) of 0.892 that was far superior to that of preformed donor-specific antibody status (AUC, 0.761). Recipients with N-glycan-positive scores >0.8770 had significantly shorter ABMR survival than that of recipients with N-glycan-negative scores. Although the limitations of our study includ its small sample size and retrospective nature, the serum N-glycan score may contribute to prediction of ABMR.
Wager, Tor D.; van Ast, Vanessa A.; Hughes, Brent L.; Davidson, Matthew L.; Lindquist, Martin A.; Ochsner, Kevin N.
Social evaluative threat (SET) is a potent stressor in humans linked to autonomic and endocrine responses, and multiple health problems. Neuroimaging has recently begun to elucidate the brain correlates of SET, but as yet little is known about the mediating cortical-brainstem pathways in humans. This paper replicates and extends findings in a companion paper (Wager et al., submitted) using an independent cohort of participants and different image acquisition parameters. Here, we focused specifically on relationships between the medial prefrontal cortex (MPFC), midbrain periaqueductal gray (PAG), and heart rate (HR). We applied multi-level path analysis to localize brain mediators of SET effects on HR and self-reported anxiety. HR responses were mediated by opposing signals in two distinct sub-regions of the MPFC—increases in rostral dorsal anterior cingulate cortex (rdACC) and deactivation in ventromedial prefrontal cortex (vmPFC). In addition, HR responses were mediated by PAG. Additional path analyses provided support for two cortical subcortical pathways: one linking vmPFC, PAG, and HR, and another linking rdACC, thalamus, and HR. PAG responses were linked with HR changes both before and during SET, whereas cortical regions showed stronger connectivity with HR during threat. Self-reported anxiety showed a partially overlapping, but weaker, pattern of mediators, including the vmPFC, dorsomedial PFC (dmPFC), and lateral frontal cortex, as well as substantial individual differences that were largely unexplained. Taken together, these data suggest pathways for the translation of social threats into both physiological and experiential responses, and provide targets for future research on the generation and regulation of emotion. PMID:19465135
Grzeda, E; Schlicker, E; Luczaj, W; Harasim, E; Baranowska-Kuczko, M; Malinowska, B
The activation of cannabinoid CB1 receptors decreases and increases blood pressure (BP) in anaesthetized and conscious rats, respectively. The aim of our study was to check the possible involvement of CB1 receptors in the paraventricular nucleus of the hypothalamus (PVN) in the cardiovascular effects of cannabinoids in rats. Methanandamide (metabolically stable analogue of the endocannabinoid anandamide) and the synthetic cannabinoid receptor agonist CP55940 were microinjected into the PVN of urethane-anaesthetized rats twice (S1 and S2, 20 min apart). Receptor antagonists were administered intravenously (i.v.) 5 min before S1. Methanandamide and CP55940 decreased blood pressure by 15 - 20%. The CB1 receptor antagonist AM251 reversed the depressor effect into a pressor response of 20 - 30%. The pressor effect of CP55940 observed in the presence of AM251 i.v. was reduced by AM251 given additionally into the PVN but not by the i.v. injection of the CB2 antagonist SR144528 or the vanilloid TRPV1 antagonist ruthenium red. In the presence of the peripherally restricted CB1 receptor antagonist AM6545, CP55940 given into the PVN increased BP by 40%. AM6545 reversed the decrease in BP induced by CP55940 i.v. into a marked increase. Bilateral chemical lesion of the PVN by kainic acid abolished all cardiovascular effects of CP55940 i.v. In conclusion, the cannabinoid CP55940 administered to the PVN of urethane-anaesthetized rats can induce depressor and pressor effects. The direction of the response probably depends on the sympathetic tone. The centrally induced hypertensive response of CP55940 can, in addition, be masked by peripheral CB1 receptors.
Greco, Andrea; Steca, Patrizia; Pozzi, Roberta; Monzani, Dario; Malfatto, Gabriella; Parati, Gianfranco
The importance of psychological factors in improving conditions of cardiovascular disease (CVD) patients is stressed by the guidelines for their prevention and rehabilitation, but little is known about the impact of illness severity on patients' well-being, and on the psychosocial variables that may mediate this association. The aim of this study was to investigate the role of illness perception and self-efficacy beliefs on the relationship between illness severity and health satisfaction in 75 CVD patients undergoing rehabilitation (80% men; mean age = 65.44) at the St. Luca Hospital, Istituto Auxologico Italiano, Milan, Italy. Illness severity was measured in terms of left ventricular ejection fraction; psychological factors were assessed at the beginning and end of rehabilitation. Results from path analyses showed that the relationships among CVD severity and health satisfaction were mediated by illness perception and self-efficacy beliefs. Findings underscored the importance of considering illness representations and self-efficacy beliefs to improve well-being in CVD patients.
Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António
The relevance of preformed donor specific antibodies (DSA) detected by Luminex assays, with a negative complement-dependent cytotoxicity (CDC) crossmatch, remains unsettled in kidney transplantation (KT). We aimed to analyze the impact of preformed DSA characteristics on kidney graft outcomes. In 462 patients that received a kidney graft in our unit, between 2007 and 2012, pre-transplant sera were analyzed by Luminex screening assay to determine the presence of anti-human leukocyte antigen (HLA) antibodies and single-antigen bead assay [positive if mean fluorescence intensity (MFI) ≥ 1000] to assign anti-HLA specificities. Anti-HLA antibodies were present in 95 patients (20.6%), but only 40 (8.7%) had DSA. Antibody-mediated rejection (AMR) at 1-year was higher in patients with DSA (35.0%) than in those without them (0.9%) (P < 0.001). Only DSA with a MFI of >3000 were significantly associated with AMR occurrence. Receiver operator curves revealed that a MFI of >4900 in the highest DSA bead had a high sensitivity (85.7%) and that the sum of all DSA beads MFI > 11,000 had a high specificity (92.3%) for AMR prediction. Anti-thymocyte globulin versus basiliximab induction was more frequent in DSA+ AMR- (65.4%) versus DSA+ AMR+ (34.6%) patients (P = 0.072). Five-year censored graft survival was lower in DSA+ than in DSA- patients (respectively, 84.8% versus 94.9%, P = 0.006), although survival was only reduced in DSA+ AMR+ (68.8%) versus DSA+ AMR- (96.0%) patients (P = 0.038). Preformed DSA is associated with kidney graft loss, in relation with AMR occurrence. DSA strength may be used to improve immunological risk stratification of sensitized patients and their clinical management. Copyright © 2015 Elsevier B.V. All rights reserved.
Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António
Detrimental impact of preformed donor-specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody-mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney-transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti-HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q-binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q-binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q- high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q-binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q-binding ability was a better predictor of AMR and correlated with graft survival, C1q-SAB may be a particularly useful tool.
Xiao, Ya; Song, Ya-Jun; Song, Bo; Huang, Chi-Bing; Ling, Qing; Yu, Xiao
Objective: This study aimed to explore the role of the transforming growth factor-β/mitogen activated protein kinase (TGF-β/MAPK) signaling pathway in the effects of bone marrow mesenchymal stem cells (BMSCs) on urinary control and interstitial cystitis in a rat model of urinary bladder transplantation. Methods: A urinary bladder transplantation model was established using Sprague-Dawley rats. Rats were assigned to normal (blank control), negative control (phosphate-buffered saline injection), BMSCs (BMSC injection), sp600125 (MAPK inhibitor injection), or protamine sulfate (protamine sulfate injection) groups. Immunohistochemistry, urodynamic testing, hematoxylin-eosin staining, Western blotting, enzyme-linked immunosorbent assay, and MTT assay were used to assess BMSC growth, the kinetics of bladder urinary excretion, pathological changes in bladder tissue, bladder tissue ultrastructure, the expression of TGF-β/MAPK signaling pathway-related proteins, levels of inflammatory cytokines, and the effects of antiproliferative factor on cell proliferation. Results: Compared with normal, negative control, BMSCs, and sp600125 groups, rats in the PS group exhibited decreased discharge volume, maximal micturition volume, contraction interval, and bladder capacity but increased residual urine volume, bladder pressure, bladder peak pressure, expression of TGF-β/MAPK signaling pathway-related proteins, levels of inflammatory cytokines, and growth inhibition rate. Levels of inflammatory cytokines and the growth inhibition rate were positively correlated with the expression of TGF-β/MAPK signaling pathway-related proteins. Conclusions: Our findings demonstrate that the TGF-β/MAPK signaling pathway mediates the beneficial effects of BMSCs on urinary control and interstitial cystitis. PMID:28386345
Hobo, Willemijn; Norde, Wieger J; Schaap, Nicolaas; Fredrix, Hanny; Maas, Frans; Schellens, Karen; Falkenburg, J H Frederik; Korman, Alan J; Olive, Daniel; van der Voort, Robbert; Dolstra, Harry
Allogeneic stem cell transplantation (allo-SCT) can cure hematological malignancies by inducing alloreactive T cell responses targeting minor histocompatibility antigens (MiHA) expressed on malignant cells. Despite induction of robust MiHA-specific T cell responses and long-term persistence of alloreactive memory T cells specific for the tumor, often these T cells fail to respond efficiently to tumor relapse. Previously, we demonstrated the involvement of the coinhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8(+) T cell immunity. In this study, we investigated whether B and T lymphocyte attenuator (BTLA) plays a similar role in functional impairment of MiHA-specific T cells after allo-SCT. In addition to PD-1, we observed higher BTLA expression on MiHA-specific CD8(+) T cells compared with that of the total population of CD8(+) effector-memory T cells. In addition, BTLA's ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by myeloid leukemia, B cell lymphoma, and multiple myeloma cells. Interference with the BTLA-HVEM pathway, using a BTLA blocking Ab, augmented proliferation of BTLA(+)PD-1(+) MiHA-specific CD8(+) T cells by HVEM-expressing dendritic cells. Notably, we demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8(+) T cells in respectively 7 and 9 of 11 allo-SCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Furthermore, these expanded MiHA-specific CD8(+) T cells competently produced effector cytokines and degranulated upon Ag reencounter. Together, these results demonstrate that BTLA-HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation therapies.
Lindner, Jonathan R
The cellular immune response plays an important role in almost every major form of cardiovascular disease. The ability to image the key aspects of the immune response in the clinical setting could be used to improve diagnostic information, to provide important prognostic or risk information, and to customize therapy according to disease phenotype. Accordingly, targeted imaging probes for assessing inflammation have been developed for essentially all forms of medical imaging. Molecular imaging of inflammation with contrast ultrasound relies on the detection of targeted microbubble or other gas-filled particle contrast agents. These agents are confined to the vascular space and, hence, have been targeted to either activated leucocytes or endothelial cell adhesion molecules that are upregulated in inflammation and mediate leucocyte recruitment and adhesion. This review focuses on the inflammation-targeting strategies for ultrasound contrast agents and how they have been matched to cardiovascular disease states such as myocardial ischaemia, infarction, atherosclerosis, transplant rejection, and arteriogenesis.
Yao, Weifeng; Li, Haobo; Luo, Gangjian; Li, Xiang; Chen, Chaojin; Yuan, Dongdong; Chi, Xinjin; Xia, Zhengyuan; Hei, Ziqing
Postoperative acute lung injury (ALI) is a severe complication after liver transplantation, which severely affects postoperative patients' survival. The underlying mechanism is largely unknown and effective treatment limited. We explored the role of serpin protease inhibitor B1 (SERPINB1), a potent inhibitor of neutrophil serine proteases, in ALI in liver transplantation and its interplay with signal transducer and activator of transcription 3 (STAT3) and heme oxygenase-1 (HO-1). Sprague-Dawley rats underwent orthotopic autologous liver transplantation (OALT) were treated with recombinant SB1 (rSB1) in the absence or presence of STAT3 specific inhibitor, WP1066. Then SB1-siRNA was used to knockdown endogenous SERPINB1. Also, alveolar epithelial cells RLE-6TN and BEAS-2B were exposed to TNF-α without or with SERPINB1 and the roles of STAT3 and HO-1 were examined by respective gene knockdown. Finally, rats were treated with ERK1/2 inhibitor U0126, p38 MAPK inhibitor SB20358, or JNK inhibitor SP600125 after rSB1 pretreatment and then subjected to OALT. OALT resulted in increased pulmonary inflammation and oxidative stress, accompanied by severe lung injury that was coincident with increased pulmonary SERPINB1, HO-1, and STAT3. SERPINB1 gene knockdown increased post-OALT lung injury and pulmonary inflammation. rSB1 administration dose-dependently reduced post-OALT lung injury and decreased pulmonary inflammation and oxidative stress with concomitant enhanced HO-1 and STAT3 protein expression. These protective effects of SERPINB1 were abolished by STAT3 inhibition. Similarly, in RLE-6TN cells and BEAS-2B cells, TNF-α induced cell injury and increased HO-1 and STAT3. SERPINB1 further increased HO-1 and STAT3 protein expression and attenuated TNF-α-induced cellular oxidative stress, apoptotic cells, and mitochondria damage, which were cancelled by STAT3 or HO-1 gene knockdown. Furthermore, these SERPINB1-mediated STAT3/HO-1 activation and pulmonary protective effects
Hüsing, Anna; Kabar, Iyad; Schmidt, Hartmut H
Hyperlipidemia is very common after liver transplantation and can be observed in up to 71% of patients. The etiology of lipid disorders in these patients is multifactorial, with different lipid profiles observed depending on the immunosuppressive agents administered and the presence of additional risk factors, such as obesity, diabetes mellitus and nutrition. Due to recent improvements in survival of liver transplant recipients, the prevention of cardiovascular events has become more important, especially as approximately 64% of liver transplant recipients present with an increased risk of cardiovascular events. Management of dyslipidemia and of other modifiable cardiovascular risk factors, such as hypertension, diabetes and smoking, has therefore become essential in these patients. Treatment of hyperlipidemia after liver transplantation consists of life style modification, modifying the dose or type of immunosuppressive agents and use of lipid lowering agents. At the start of administration of lipid lowering medications, it is important to monitor drug-drug interactions, especially between lipid lowering agents and immunosuppressive drugs. Furthermore, as combinations of various lipid lowering drugs can lead to severe side effects, such as myopathies and rhabdomyolysis, these combinations should therefore be avoided. To our knowledge, there are no current guidelines targeting the management of lipid metabolism disorders in liver transplant recipients. This paper therefore recommends an approach of managing lipid abnormalities occurring after liver transplantation. PMID:27022213
Park, S-C; Yoon, Y-D; Jung, H-Y; Kim, K-H; Choi, J-Y; Park, S-H; Kim, C-D; Kim, Y-L; Kim, H-K; Huh, S; Cho, J-H
Hyperglycemia occurs frequently after kidney transplantation and may be reversed when the dosage of the immunosuppressive agents is tapered. However, the effect of transient post-transplantation hyperglycemia (PTH) on transplantation outcomes is not well described. Kidney transplant recipients without diabetes who underwent kidney transplantation between 2001 and 2012 were enrolled in the study. Transient PTH was defined as recovery from PTH without further antidiabetic therapy and the maintenance of glycated hemoglobin levels <6.5% at 1 year after transplantation. Persistent PTH until 1 year after transplantation was considered to be new-onset diabetes after transplantation (NODAT). The factors associated with increased risk of PTH were analyzed. We compared the development of diabetes mellitus, cardiovascular disease, and other transplantation outcomes among patients with no PTH, transient PTH, and NODAT. Among 176 kidney transplant recipients, 106 (60.2%) developed PTH and 58 (54.7%) of 106 patients with PTH had transient PTH. Older age, high body mass index (BMI), and female gender were independent risk factors for transient PTH. The incidence of diabetes was not significantly different between patients with no PTH and those with transient PTH. The incidence of cardiovascular disease was significantly increased in NODAT group compared with that in no PTH and transient PTH groups. However, the incidences of acute rejection, allograft loss, and patient death were comparable among the three groups. Transient hyperglycemia after kidney transplantation was found to be associated with older age, high body mass index, and female gender. Transient elevation of blood glucose level did not affect post-transplantation outcomes, including diabetes mellitus and cardiovascular disease. However, patients with NODAT should be carefully monitored for the occurrence of cardiovascular disease. Copyright © 2015 Elsevier Inc. All rights reserved.
Dai, Chen; Lu, Fang-Na; Jin, Ning; Yang, Bo; Gao, Chang; Zhao, Bin; Fu, Jia-Zhao; Hong, Shi-Fu; Liang, Han-Ting; Chen, Li-Hong; Chen, Zhi-Shui; Chen, Jie; Qi, Zhong-Quan
Interleukin (IL)-33 is a novel IL-1 family member, and its administration has been associated with promotion of T helper type-2 (Th2) cell activity and cytokines, particularly IL-4 and IL-5 in vivo. Recently, IL-33 was shown to increase CD4(+)Foxp3(+) regulatory T cells (Tregs) and to suppress levels of the Th1-type cytokine IFN-γ in allogeneic heart transplantation in mice. Therefore, we hypothesized that IL-33 and leflunomide (Lef) could prolong graft survival in the concordant mouse-to-rat heart transplantation model. In this model, xenografts undergo acute humoral xenograft rejection (AHXR) typically on day 3 or cell-mediated rejection approximately on day 7 if AHXR is inhibited by Lef treatment. Recipients were treated with Lef (n=6), IL-33 (n=6), IL-33 combined with Lef (n=6), or left untreated (n=6) for survival studies. Heart grafts were monitored until they stopped beating. Mouse heterotopic grafts were performed, and recipients were sacrificed on days 2 and 7 for histological and flow cytometric analyses. The combination of IL-33 and Lef significantly prolonged the grafts from 17.3±2.3 to 2.8±0.4 days, compared to untreated controls. IL-33 administration with Lef, while facilitating Th2-associated cytokines (IL-4 on day 2 but not day 7), also decreased IFN-γ on day 2 and day 7, compared with Lef treatment only. Furthermore, IL-33 with Lef administration caused an expansion of suppressive CD4(+)Foxp3(+) Tregs in rats. The IL-33 and Lef combination therapy resulted in significantly prolonged graft survival, associated with markedly decreased Th1 cells and increased IL-10 levels. In addition, the combination therapy significantly decreased the percentage of CD-45(+) B cells on days 2 and 7, compared with monotherapy. These findings reveal a new immunoregulatory property of IL-33. Specifically, it facilitates regulatory cells, particularly functional CD4(+)Foxp3(+) Tregs that underlie IL-33-mediated cardiac xenograft survival. Moreover, it can decrease Th
Widlansky, Michael E.; Vita, Joseph A.; Keyes, Michelle J.; Larson, Martin G.; Hamburg, Naomi M.; Levy, Daniel; Mitchell, Gary F.; Osypiuk, Ewa W.; Vasan, Ramachandran S.; Benjamin, Emelia J.
Multiple studies have documented an increased incidence of cardiovascular events in the winter, but the pathophysiological mechanisms remain incompletely understood. We hypothesized that brachial flow and flow-mediated dilation (FMD) would vary by season and temperature. We related season and temperature to ultrasonic brachial artery endothelium-dependent FMD% (n=2587), baseline flow velocity and maximal reactive hyperemia (n=1973) in the Framingham Offspring cohort (mean age 61±10 years; 53% women). We obtained outdoor temperature from National Climate Data Center records for Bedford, Massachusetts (about 14 miles from testing site) and we measured the examination room temperature. In multivariable models, FMD% was highest in summer and lowest in winter (3.01±0.09 vs. 2.56±0.10%, respectively; P=0.02 for differences across all 4 seasons). FMD% was highest in the warmest and lowest in the coldest outdoor temperature quartiles. In stepwise models adjusting for risk factors, and selecting among season, outdoor temperature, and room temperature, FMD% was associated with season (P=0.02); temperature did not enter the model. In contrast, hyperemic flow velocity was significantly lower for cooler, and higher for warmer room temperatures (P=0.02 overall); season did not enter the model. Season, outdoor and room temperature were each retained in a stepwise model of baseline flow velocity (P<0.0001, P=0.02, P<0.0001, respectively). In conclusion, we observed a significant association between season and FMD. Microvascular vasodilator function, as reflected by hyperemic flow, was more strongly related to temperature than season. In conclusion, we speculate that endothelial dysfunction may be 1 of the mechanisms influencing seasonal variation in cardiovascular events. PMID:17659939
Amer, Hatem; Carlsen, Brian T; Dusso, Jennifer L; Edwards, Brooks S; Moran, Steven L
The first successful hand transplant was performed in 1998, opening up a new possibility for patients who have suffered mutilating hand injuries. Since then, more than 60 such procedures have been performed throughout the world. This article describes the evolution of hand transplantation, outcomes of patients listed in the International Registry of Hand and Composite Tissue Transplantation, and ethical issues involved in hand transplantation. It also describes the hand transplantation program at Mayo Clinic, which was established in 2010.
Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation - A systematic review of randomized trials, observational studies and case reports.
Croce, Evelina; Hatz, Christoph; Jonker, Emile F; Visser, L G; Jaeger, Veronika K; Bühler, Silja
Live vaccines are generally contraindicated on immunosuppressive therapy due to safety concerns. However, data are limited to corroborate this practice. To estimate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) or solid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrow transplantation (BMT). A search was conducted in electronic databases (Cochrane, Pubmed, Embase) and additional literature was identified by targeted searches. Randomized trials, observational studies and case reports. Patients with IMID or SOT on immunosuppressive treatment and BMT patients <2years after transplantation. Live vaccinations: mumps, measles, rubella (MMR), yellow fever (YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette-Guérin (BCG), smallpox. One author performed the data extraction using predefined data fields. It was cross-checked by two other authors. 7305 articles were identified and 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the administration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine strain; in most cases the infection was mild. However, in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dexamethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than 20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancy received the BCG vaccine at the age of three months and developed disseminated BCG infection and died. An immunogenicity assessment was performed in 43 studies. In most cases the patients developed satisfactory seroprotection rates. In the IMID group, YFV and VV
Cooper, Andrew J R; Dholakia, Shamik; Holland, Celia V; Friend, Peter J
With transplantation becoming an increasingly routine form of treatment for diverse populations, and with international travel becoming ever more accessible and affordable, the danger of transplantation-mediated helminth infections, exacerbated by coincident immunosuppression, must be considered. In this Review, we attempt to catalogue all clinically-relevant helminthiases that have been reported to coincide with transplantation, whether by transplantation-mediated transmission, reactivation of latent infections in an immunosuppressed context, or possible de-novo infection during the immunosuppressed peritransplant period. Helminthiasis has been reported in cases of kidney, liver, bowel, pancreas, heart, lung, and stem-cell transplant, and blood transfusion. For each helminthiasis, known risk factors, symptoms, and suggested options for screening and treatment are given. We conclude that helminths are a small but important and potentially severe source of disease after transplantation, and, with options for diagnosis and treatment, these pathogens warrant greater consideration during organ implantation. The achievement of immunological tolerance using helminth-derived products is also an exciting future prospect. Copyright © 2017 Elsevier Ltd. All rights reserved.
Xavier, Carlos Henrique; Ianzer, Danielle; Lima, Augusto Martins; Marins, Fernanda Ribeiro; Pedrino, Gustavo Rodrigues; Vaz, Gisele; Menezes, Gustavo Batista; Nalivaiko, Eugene; Fontes, Marco Antônio Peliky
The dorsomedial hypothalamus (DMH) and lateral/dorsolateral periaqueductal gray (PAG) are anatomically and functionally connected. Both the DMH and PAG depend on glutamatergic inputs for activation. We recently reported that removal of GABA-ergic tone in the unilateral DMH produces: asymmetry, that is, a right- (R-) sided predominance in cardiac chronotropism, and lateralization, that is, a greater increase in ipsilateral renal sympathetic activity (RSNA). In the current study, we investigated whether excitatory amino acid (EAA) receptors in the DMH-PAG pathway contribute to the functional interhemispheric difference. In urethane (1.2 to 1.4 g/kg, i.p.) anesthetized rats, we observed that: (i) nanoinjections of N-methyl D-aspartate (NMDA 100 pmol/100 nl) into the unilateral DMH produced the same right-sided predominance in the control of cardiac chronotropy, (ii) nanoinjections of NMDA into the ipsilateral DMH or PAG evoked lateralized RSNA responses, and (iii) blockade of EAA receptors in the unilateral DMH attenuated the cardiovascular responses evoked by injection of NMDA into either the R- or left- (L-) PAG. In awake rats, nanoinjection of kynurenic acid (1 nmol/100 nL) into the L-DMH or R- or L-PAG attenuated the tachycardia evoked by air stress. However, the magnitude of stress-evoked tachycardia was smallest when the EAA receptors of the R-DMH were blocked. We conclude that EAA receptors contribute to the right-sided predominance in cardiac chronotropism. This interhemispheric difference that involves EAA receptors was observed in the DMH but not in the PAG.
Xavier, Carlos Henrique; Ianzer, Danielle; Lima, Augusto Martins; Marins, Fernanda Ribeiro; Pedrino, Gustavo Rodrigues; Vaz, Gisele; Menezes, Gustavo Batista; Nalivaiko, Eugene; Fontes, Marco Antônio Peliky
The dorsomedial hypothalamus (DMH) and lateral/dorsolateral periaqueductal gray (PAG) are anatomically and functionally connected. Both the DMH and PAG depend on glutamatergic inputs for activation. We recently reported that removal of GABA-ergic tone in the unilateral DMH produces: asymmetry, that is, a right- (R-) sided predominance in cardiac chronotropism, and lateralization, that is, a greater increase in ipsilateral renal sympathetic activity (RSNA). In the current study, we investigated whether excitatory amino acid (EAA) receptors in the DMH–PAG pathway contribute to the functional interhemispheric difference. In urethane (1.2 to 1.4 g/kg, i.p.) anesthetized rats, we observed that: (i) nanoinjections of N-methyl D-aspartate (NMDA 100 pmol/100 nl) into the unilateral DMH produced the same right-sided predominance in the control of cardiac chronotropy, (ii) nanoinjections of NMDA into the ipsilateral DMH or PAG evoked lateralized RSNA responses, and (iii) blockade of EAA receptors in the unilateral DMH attenuated the cardiovascular responses evoked by injection of NMDA into either the R- or left- (L-) PAG. In awake rats, nanoinjection of kynurenic acid (1 nmol/100 nL) into the L-DMH or R- or L-PAG attenuated the tachycardia evoked by air stress. However, the magnitude of stress-evoked tachycardia was smallest when the EAA receptors of the R-DMH were blocked. We conclude that EAA receptors contribute to the right-sided predominance in cardiac chronotropism. This interhemispheric difference that involves EAA receptors was observed in the DMH but not in the PAG. PMID:25397884
Huang, Jijun; Zhang, Min; Zhang, Peng; Liang, He; Ouyang, Kunfu; Yang, Huang-Tian
Purinergic signaling mediated by P2 receptors (P2Rs) plays important roles in embryonic and stem cell development. However, how it mediates Ca(2+) signals in human embryonic stem cells (hESCs) and derived cardiovascular progenitor cells (CVPCs) remains unclear. Here, we aimed to determine the role of P2Rs in mediating Ca(2+) mobilizations of these cells. hESCs were induced to differentiate into CVPCs by our recently established methods. Gene expression of P2Rs and inositol 1,4,5-trisphosphate receptors (IP3Rs) was analyzed by quantitative/RT-PCR. IP3R3 knockdown (KD) or IP3R2 knockout (KO) hESCs were established by shRNA- or TALEN-mediated gene manipulations, respectively. Confocal imaging revealed that Ca(2+) responses in CVPCs to ATP and UTP were more sensitive and stronger than those in hESCs. Consistently, the gene expression levels of most P2YRs except P2Y1 were increased in CVPCs. Suramin or PPADS blocked ATP-induced Ca(2+) transients in hESCs but only partially inhibited those in CVPCs. Moreover, the P2Y1 receptor-specific antagonist MRS2279 abolished most ATP-induced Ca(2+) signals in hESCs but not in CVPCs. P2Y1 receptor-specific agonist MRS2365 induced Ca(2+) transients only in hESCs but not in CVPCs. Furthermore, IP3R2KO but not IP3R3KD decreased the proportion of hESCs responding to MRS2365. In contrast, both IP3R2 and IP3R3 contributed to UTP-induced Ca(2+) responses while ATP-induced Ca(2+) responses were more dependent on IP3R2 in the CVPCs. In conclusion, a predominant role of P2Y1 receptors in hESCs and a transition of P2Y-IP3R coupling in derived CVPCs are responsible for the differential Ca(2+) mobilization between these cells.
Xu, Ya-Li; Gao, Yun-Hua; Liu, Zheng; Tan, Kai-Bin; Hua, Xing; Fang, Zhen-Qiang; Wang, Ya-Li; Wang, Ya-Jie; Xia, Hong-Mei; Zhuo, Zhong-Xiong
Therapeutic ultrasound-mediated microbubble destruction has been applied in the targeted delivery of genes, drugs and stem cells. We intended to study whether diagnostic US irradiating lipid-coated microbubble destruction combined with bone-marrow derived MSC infusion could enable the targeted delivery of MSCs into the myocardium and improve cardiac function of the myocardial infarction of New Zealand rabbits. Diagnostic ultrasound was applied to the anterior chest for 10 min after intravenous injection of lipid-coated microbubble followed by infusion of BM-MSCs. Echocardiography, histological examination, and western blotting were performed 4 weeks after cell transplantation. The cardiac function (assessed by fractional shortening and ejection fraction) was markedly improved by US+Microbubble+MSC treatment. The number of capillaries stained by HE in US+Microbubble+MSC group (47+/-23) was much greater than that of the MSCs infusion group (26+/-7), US+Microbubble group(22+/-5) and PBS infusion group (19+/-10), P<0.01. US+Microbubble stimulation induced the expression of adhesion molecule (VCAM-1) in capillaries and enhanced the myocardial permeability of microvessels. US+Microbubble-mediated supply of MSCs increased the level of VEGF in ischemic myocardium. Area of cardiac fibrosis in the US+Microbubble+MSC group was significantly decreased by 25.6%,40.1% and 46.8% when compared with MSC infusion group, US+Microbubble group and PBS infusion group, respectively. This non-invasive cell delivery system may be useful as a novel and efficient approach for angiogenic cell therapy to the infarcted myocardium. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.
Barnard, Abbey; Konyn, Peter; Saab, Sammy
Improved short- and long-term survival of liver transplant recipients has led to increased focus on complications of both the early and late posttransplant periods. A variety of metabolic complications have been observed in the post-orthotopic liver transplant population, including hypertension, hyperlipidemia, obesity, diabetes mellitus, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Although only a small proportion of patients experience metabolic complications prior to transplantation, the prevalence of these complications posttransplantation reaches or exceeds that of the general population. This is of particular concern, as cardiovascular disease is the second leading cause of death in the late transplant period. A number of mechanisms mediate these metabolic complications, including reversal of cirrhosis pathophysiology, patient lifestyle factors, and immunosuppressive medications. Titration and modification of immunosuppression have been demonstrated to improve and sometimes even eliminate these conditions. Therefore, given the multiple etiologies contributing to the metabolic derangements, an effective management approach must incorporate lifestyle modifications, immunosuppression titration, and medical management. Best practices and understanding of the mechanisms underlying these complications allow for discussion of initial therapies and strategies; however, further study is necessary to determine the optimal management of metabolic complications over time.
Barnard, Abbey; Konyn, Peter
Improved short- and long-term survival of liver transplant recipients has led to increased focus on complications of both the early and late posttransplant periods. A variety of metabolic complications have been observed in the post–orthotopic liver transplant population, including hypertension, hyperlipidemia, obesity, diabetes mellitus, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Although only a small proportion of patients experience metabolic complications prior to transplantation, the prevalence of these complications posttransplantation reaches or exceeds that of the general population. This is of particular concern, as cardiovascular disease is the second leading cause of death in the late transplant period. A number of mechanisms mediate these metabolic complications, including reversal of cirrhosis pathophysiology, patient lifestyle factors, and immunosuppressive medications. Titration and modification of immunosuppression have been demonstrated to improve and sometimes even eliminate these conditions. Therefore, given the multiple etiologies contributing to the metabolic derangements, an effective management approach must incorporate lifestyle modifications, immunosuppression titration, and medical management. Best practices and understanding of the mechanisms underlying these complications allow for discussion of initial therapies and strategies; however, further study is necessary to determine the optimal management of metabolic complications over time. PMID:27917074
Montgomery, R A; Orandi, B J; Racusen, L; Jackson, A M; Garonzik-Wang, J M; Shah, T; Woodle, E S; Sommerer, C; Fitts, D; Rockich, K; Zhang, P; Uknis, M E
Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.
Holdaas, Hallvard; de Fijter, Johan W; Cruzado, Josep M; Massari, Pablo; Nashan, Björn; Kanellis, John; Witzke, Oliver; Gutierrez-Dalmau, Alex; Turkmen, Aydin; Wang, Zailong; Lopez, Patricia; Bernhardt, Peter; Kochuparampil, Jossy; van der Giet, Markus; Murbraech, Klaus
Mammalian target of rapamycin (mTOR) inhibitors may confer cardioprotective advantages but clinical data are limited. In the open-label ELEVATE trial, kidney transplant patients were randomized at 10-14 weeks posttransplant to convert from calcineurin inhibitor (CNI) to everolimus or remain on standard CNI therapy. Prespecified endpoints included left ventricular mass index (LVMi) and, in a subpopulation of patients, arterial stiffness as measured by pulse wave velocity (PWV). The mean change in LVMi from randomization was similar with everolimus versus CNI (month 24: -4.37 g/m versus -5.26 g/m; mean difference 0.89 [p=0.392]). At month 24, LVH was present in 41.7% versus 37.7% of everolimus and CNI patients, respectively. Mean PWV remained stable with both everolimus (mean change from randomization to month 12: -0.24 m/s; month 24: -0.03 m/s) or CNI (month 12: 0.11 m/s; month 24: 0.16 m/s). The change in mean ambulatory night time blood pressure from randomization showed a benefit for diastolic pressure at month 12 (p=0.039) but not month 24. Major adverse cardiac events occurred in 1.1% and 4.2% of everolimus-treated and CNI-treated patients, respectively by month 12 (p=0.018) and 2.3% (8/353) and 4.5% by month 24 (p=0.145). Overall, these data do not suggest a clinically relevant effect on cardiac endpoints following early conversion from CNI to a CNI-free everolimus-based regimen.
Rosina, Kelli T C; Menna Barreto, Ana Paula M; Pontes, Karine S S; Martins, Cyro J M; Souza, Edison; Bregman, Rachel; Barreto Silva, Maria Inês; Klein, Márcia R S T
Recent evidence suggests that vitamin D deficiency is associated with CVD, impaired kidney function and proteinuria. To date, no study has evaluated these associations in renal transplant recipients (RTR) adjusting for body adiposity assessed by a 'gold standard' method. This study aimed to evaluate the vitamin D status and its association with body adiposity, CVD risk factors, estimated glomerular filtration rate (eGFR) and proteinuria in RTR, living in Rio de Janeiro, Brazil (a low-latitude city (22°54'10"S)), taking into account body adiposity evaluated by dual-energy X-ray absorptiometry (DXA). This cross-sectional study included 195 RTR (114 men) aged 47·6 (sd 11·2) years. Nutritional evaluation included anthropometry and DXA. Risk factors for CVD were hypertension, diabetes mellitus, dyslipidaemia and the metabolic syndrome. eGFR was evaluated using the Chronic Kidney Disease Epidemiology Collaboration equation. Serum 25-hydroxyvitamin D (25(OH)D) concentration was used to define vitamin D status as follows: 10 % (n 19) had vitamin D deficiency (30 ng/ml). Percentage of body fat (DXA) was significantly associated with vitamin D deficiency independently of age, sex and eGFR. Lower 25(OH)D was associated with higher odds of the metabolic syndrome and dyslipidaemia after adjustment for age, sex and eGFR, but not after additional adjustment for body fat. Hypertension and diabetes were not related to 25(OH)D. Lower serum 25(OH)D was associated with increasing proteinuria and decreasing eGFR even after adjustments for age, sex and percentage of body fat. This study suggests that in RTR of a low-latitude city hypovitaminosis D is common, and is associated with excessive body fat, decreased eGFR and increased proteinuria.
McCarty, Mark F; DiNicolantonio, James J
Increased fasting serum phosphate within the normal physiological range has been linked to increased cardiovascular risk in prospective epidemiology; increased production of fibroblast growth factor 23, and direct vascular effects of phosphate, may mediate this risk. Although dietary phosphate intake does not clearly influence fasting serum phosphate in individuals with normal renal function, increased phosphate intake can provoke a rise in fibroblast growth factor 23, and in diurnal phosphate levels, and hence may adversely influence vascular health. Dietary phosphate absorption can be moderated by emphasizing plant-based dietary choices (which provide phosphate in less bioavailable forms); avoidance of processed foods containing inorganic phosphate food additives; and by ingestion of phosphate-binder drugs, magnesium supplements, or niacin, which precipitate phosphate or suppress its gastrointestinal absorption. The propensity of dietary phosphate to promote vascular calcification may be opposed by optimal intakes of magnesium, vitamin K, and vitamin D; the latter should also counter the tendency of phosphate to elevate parathyroid hormone. Copyright © 2014 Elsevier Inc. All rights reserved.
Maier, Mirela; Takano, Tomoko; Sapir-Pichhadze, Ruth
Purpose of review: P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine’s relevance to the various stages of the kidney transplant cycle. Sources of information: A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. Findings: Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients’ care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. Limitations: For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. Implications: Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care. PMID:28270929
Földes, Gábor; von Haehling, Stephan; Anker, Stefan D
Toll-like receptors (TLRs) form a family of pattern recognition receptors that have emerged as key mediators of innate immunity. These receptors sense invading microbes and initiate the immune response. TLR-mediated inflammation is an important pathogenic link between innate immunity and a diverse panel of clinical disorders. Among the processes in which TLRs play a role are cardiovascular disorders such as cardiac ischaemia, coronary artery disease, ventricular remodelling, cancer angiogenesis or transplant rejection. From these, many important opportunities for disease modification through TLR signalling manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated and this article reviews the current status of these treatment strategies for cardiovascular disease.
Gul-Uludag, Hilal; Xu, Peng; Marquez-Curtis, Leah A; Xing, James; Janowska-Wieczorek, Anna; Chen, Jie
The chemokine stromal cell-derived factor (SDF)-1α/CXCL12 and its receptor CXC chemokine receptor 4 (CXCR4) play a crucial role in the homing/engraftment and retention of hematopoietic stem/progenitor cells (HSPCs) in the bone marrow. It has been shown using the viral gene transfer technique that CXCR4 overexpression on human CD34(+) HSPC significantly improves their engraftment in murine models. However, clinical trials with gene therapy have revealed safety concerns related to the immunogenicity of the viral carriers, due to the random integration of viral genes into the host genome. Therefore, a method for CXCR4 gene delivery into HSPC that is safe, nonviral, and highly efficient is needed to improve clinical transplantation and gene therapies. In this work, we investigated the nonviral CXCR4 gene delivery into HSPC using the cationic liposome agent IBAfect. We used CD34(+) cells from cord blood and the models of immature hematopoietic cells expressing CD34 antigen, namely, leukemic cell lines KG-1a and KG-1. Transfection efficiency was determined by flow cytometric analysis 12, 24, 48, and 72 h after transfection, and the viability of cells analyzed by trypan blue exclusion and MTS assays. The functional response of CXCR4-transfected HSPC toward an SDF-1α gradient was determined by chemotaxis assay. We found that ~25% transfection is achieved for KG-1a and KG-1 cells and 20% for HSPC, and that the viability of CXCR4-transfected HSPC is not significantly altered. More importantly, overexpression of CXCR4 using IBAfect significantly increased the chemotaxis of KG-1 cells and HSPC toward SDF-1α. However, we tested 2 other commercially available cationic liposomes (Lipofectamine 2000 and 1,2-dioleoyl-3-trimethylammonium-propane [DOTAP]) in parallel, and we found that they failed to deliver the CXCR4 gene into cells under the same conditions. These results suggest that IBAfect-mediated in vitro gene delivery to overexpress CXCR4 on HSPC is a safe and efficient
Lee, Hyeyoung; Min, Ji Won; Kim, Ji-Il; Moon, In-Sung; Park, Ki-Hyun; Yang, Chul Woo; Chung, Byung Ha; Oh, Eun-Jee
With the development of the single antigen beads assay, the role of donor specific alloantibody (DSA) against human leukocyte antigens in kidney transplantation (KT) has been highlighted. This study aimed to investigate the clinical significance of DQ-DSA detected at renal allograft biopsy. We evaluated 263 KT recipients who underwent allograft biopsy and DSA detection at the same time. Among them, 155 patients who were nonsensitized before transplantation were selected to investigate the role of de-novo DQ-DSA. Both the total and nonsensitized subgroup was categorized into 4 groups each according to DSA results as: DQ only, DQ + non-DQ, non-DQ, and no DSA. In the total patient group, post-KT DSA was positive in 79 (30.0%) patients and DQ-DSA was most prevalent (64.6%). In the nonsensitized subgroup, de-novo DSAs were detected in 45 (29.0%) patients and DQ-DSA was also most prevalent (73.3%). The DQ only group showed a significantly longer post-KT duration compared to the other groups (P < 0.05). The overall incidence of antibody-mediated rejection (AMR) was 17.9%. B-DSA, DR-DSA, and DQ-DSA were associated with AMR (P < 0.05), but in the analysis for chronic AMR, only DQ-DSA showed significance in both the total and the nonsensitized subgroup (P < 0.05). On comparison of Banff scores among groups, those representing humoral immunity were significantly dominant in all DSA positive groups compared to the no DSA group (P < 0.05), and higher scores of markers representing chronic tissue injury were more frequently detected in the groups with DQ-DSA. The worst postbiopsy survival was seen in the DQ + non-DQ group of the total patient group, and patients with de-novo DQ-DSA showed poorer graft survival in the nonsensitized subgroup compared to the no DSA group (P < 0.05). In the multivariate analysis, de-novo DQ-DSA was the only significant risk factor associated with late allograft failure (P < 0.05). Our study is the first to demonstrate
Evans, Jonathan D W; Kaptoge, Stephen; Caleyachetty, Rishi; Di Angelantonio, Emanuele; Lewis, Clive; Parameshwar, K Jayan; Pettit, Stephen J
Socioeconomic deprivation (SED) is associated with shorter survival across a range of cardiovascular and noncardiovascular diseases. The association of SED with survival after heart transplantation in England, where there is universal healthcare provision, is unknown. Long-term follow-up data were obtained for all patients in England who underwent heart transplantation between 1995 and 2014. We used the United Kingdom Index of Multiple Deprivation (UK IMD), a neighborhood level measure of SED, to estimate the relative degree of deprivation for each recipient. Cox proportional hazard models were used to examine the association between SED and overall survival and conditional survival (dependant on survival at 1 year after transplantation) during follow-up. Models were stratified by transplant center and adjusted for donor and recipient age and sex, ethnicity, serum creatinine, diabetes mellitus, and heart failure cause. A total of 2384 patients underwent heart transplantation. There were 1101 deaths during 17 040 patient-year follow-up. Median overall survival was 12.6 years, and conditional survival was 15.6 years. Comparing the most deprived with the least deprived quintile, adjusted hazard ratios for all-cause mortality were 1.27 (1.04-1.55; P=0.021) and 1.59 (1.22-2.09; P=0.001) in the overall and conditional models, respectively. Median overall survival and conditional survival were 3.4 years shorter in the most deprived quintile than in the least deprived. Higher SED is associated with shorter survival in heart transplant recipients in England and should be considered when comparing outcomes between centers. Future research should seek to identify modifiable mediators of this association. © 2016 American Heart Association, Inc.
... who have severe COPD Cystic fibrosis Idiopathic pulmonary fibrosis Alpha-1 antitrypsin deficiency Pulmonary hypertension Complications of lung transplantation include rejection of the transplanted lung and infection. NIH: National Heart, Lung, and Blood Institute
... Home > Your Liver > Liver Disease Information > Liver Transplant Liver Transplant Explore this section to learn more about ... resource. www.paulcox.com.au Why is the liver important? The liver is the second largest organ ...
... who had several conditions, such as certain central nervous system conditions, infections, and prior eye surgery or eye conditions, or from people who died from an unknown cause. During your cornea transplant On the day of your cornea transplant, you' ...
... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Intestine Transplant Although it is possible for a living donor to donate an intestine segment, most intestine transplants involve a whole organ ...
... In: Cameron JL, Cameron AM, eds. Current Surgical Therapy . 11th ed. Philadelphia, PA: Elsevier Saunders; 2014:511-5. Gruessner AC, Gruessner RWG. Pancreas and kidney transplantation for diabetic nephropathy. In: Morris PJ, Knechtle SJ, eds. Kidney Transplantation: ...
Chen, Zhi-Yi; Liang, Kun; Xie, Ming-Xing; Wang, Xin-Fang; Lü, Qing; Zhang, Jing
This study was designed to evaluate the consequences of survivin down-modulation on tumor growth in a nude mice model combined with short hairpin RNA recombinant vector (shRNA) and ultrasound-mediated microbubble destruction (UMMD). BALB/c nude mice were inoculated subcutaneously with cervical cancer cells (HeLa) and tumors (5-10 mm) developed. A shRNA recombinant vector that targeted the survivin gene (survivin-shRNA) was constructed. The mice were divided into three groups (n=6 in each group) and injected with survivin-shRNA: plasmid group (P), plasmid+ultrasound exposure group (P+US), and plasmid+microbubble (SonoVue(R))+ultrasound group (P+UMMD). Protein expression of survivin, proliferating cell nuclear antigen (PCNA), and caspase-3 were investigated by immunohistochemistry, and proliferation index (PI) and apoptotic index (AI) were measured. The protein expression of survivin and PCNA was markedly downregulated, while caspase-3 was markedly upregulated in the P+UMMD group as compared with that of the P group and P+US group. PI decreased significantly (P<0.05), whereas AI increased remarkably (P<0.01) in the P+UMMD group as compared with that of the P group and P+US group. These data indicate that the combined strategy of UMMD and survivin-shRNA effectively induces silencing of the survivin gene, resulting in inhibition of proliferation and induction of apoptosis in nude mice. Survivin could be regarded as an ideal target for anticancer intervention of cervical cancer. The combination of shRNA and UMMD could enhance antitumor efficacy as a result of synergism. This may be a powerful, promising non-viral technology that could be used in tumor gene therapy.
Grupper, Avishay; Nestorovic, Emilija M.; Daly, Richard C.; Milic, Natasa M.; Joyce, Lyle D.; Stulak, John M.; Joyce, David L.; Edwards, Brooks S.; Pereira, Naveen L.; Kushwaha, Sudhir S.
Background Pregnancies may result in antibodies against HLA, a risk factor for antibody-mediated rejection (AMR) and subsequent cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). The aim of this study was to evaluate sex differences in the incidence of AMR events and subsequent risk of CAV among HTx recipients. Methods The study comprised 160 patients (51 [32%] women) who underwent HTx in 2008 to 2014. The cumulative effect of AMR events was calculated by AMR score (sum of myocardial biopsy grading divided by number of biopsies taken during 3 years post-HTx). Results Females had higher levels of anti-HLA I antibodies pre-HTx compared to males which was associated with a history of pregnancies, total number of children and with a higher AMR score at 6 months post-HTx (P < 0.05). Women demonstrated a significant increase in the total incidence of AMR events (27 vs. 7%, P = 0.001) and in AMR scores at 6, 12, 24 and 36 months post-HTx compared to men (P < 0.05). There were no differences in cellular rejection between the groups. A history of AMR events was associated with a significantly increased risk of severe CAV onset (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.012). Conclusions Women are at higher risk for AMR post-HTx which subsequently increases their risk for CAV. Females recipients may benefit from closer surveillance to identify AMR at an earlier stage post-HTx, and targeted immunosuppressive therapy to attenuate the development of CAV. PMID:27795988
Patel, Jignesh K; Kobashigawa, Jon A
Although great progress has been achieved in thoracic organ transplantation through the development of effective immunosuppression, there is still significant risk of rejection during the early post-transplant period, creating a need for routine monitoring for both acute antibody and cellular mediated rejection. The currently available multiplexed, microbead assays utilizing solubilized HLA antigens afford the capability of sensitive detection and identification of HLA and non-HLA specific antibodies. These assays are being used to assess the relative strength of donor specific antibodies; to permit performance of virtual crossmatches which can reduce the waiting time to transplantation; to monitor antibody levels during desensitization; and for heart transplants to monitor antibodies post-transplant. For cell mediated immune responses, the recent development of gene expression profiling has allowed noninvasive monitoring of heart transplant recipients yielding predictive values for acute cellular rejection. T cell immune monitoring in heart and lung transplant recipients has allowed individual tailoring of immunosuppression, particularly to minimize risk of infection. While the current antibody and cellular laboratory techniques have enhanced the ability to manage thoracic organ transplant recipients, future developments from improved understanding of microchimerism and graft tolerance may allow more refined allograft monitoring techniques.
Until recently, only life and death situations warranted organ transplantation. Nonvital transplantation, to further a patient s wishes and goals, was not considered justified. It can be argued, however, that this distinction is not morally significant. Patients with kidney failure, for example, can be kept alive by dialysis. But their quality of life would be greatly enhanced by kidney transplant, which is thus considered a justified procedure. So a spectrum of rationales may justify transplantation. Transplantation of the uterus would relieve the anguish of women who greatly desire to conceive a child. Some women do not have a uterus. In some cases this is due to a congenital absence (Rokitansky s syndrome). In other cases, surgical removal of the uterus was required to repair an obstetrical rupture. With a transplanted uterus, many of these women could have the opportunity to become pregnant as a result of nonvital organ transplant. While other organ transplant donations most often come from cadavers and less often from living donors (kidney or partial liver), the donor source for a uterus may be an otherwise healthy living patient who requires uterus removal as a standard care procedure. Furthermore, it should be possible to remove the transplanted uterus from the recipient after successful pregnancies, so the patient would not be subjected to lifelong antirejection medications. Since animal uterus transplantation has been done successfully, human uterus transplantation might be considered for select cases. One such case has been reported.
Sutherland, David ER
Diabetes mellitus is generally treated with oral diabetic drugs and/or insulin. However, the morbidity and mortality associated with this condition increases over time, even in patients receiving intensive insulin treatment, and this is largely attributable to diabetic complications or the insulin therapy itself. Pancreas transplantation in humans was first conducted in 1966, since when there has been much debate regarding the legitimacy of this procedure. Technical refinements and the development of better immunosuppressants and better postoperative care have brought about marked improvements in patient and graft survival and a reduction in postoperative morbidity. Consequently, pancreas transplantation has become the curative treatment modality for diabetes, particularly for type I diabetes. An overview of pancreas transplantation is provided herein, covering the history of pancreas transplantation, indications for transplantation, cadaveric and living donors, surgical techniques, immunosuppressants, and outcome following pancreas transplantation. The impact of successful pancreas transplantation on the complications of diabetes will also be reviewed briefly. PMID:21253293
Mizia-Stec, Katarzyna; Wieczorek, Joanna; Orszulak, Michał; Mizia, Magdalena; Gieszczyk-Strózik, Klaudia; Sikora-Puz, Agnieszka; Haberka, Maciej; Lasota, Bartosz; Chmiel, Artur
Since flow-mediated dilatation (FMD) is influenced by different factors, its clinical usefulness and validation is widely discussed. To assess the major factors that determine FMD values in a wide range of subjects with and without cardiovascular (CV) risk factors/diseases (CVRF/CVD). 617 consecutive patients (mean age: 50.1 ± 14.9 years, males: 349/56.5%) hospitalised between 2005 and 2011 were enrolled into the study. Demographic data and CVRF/CVD with a significant impact on FMD values were analysed: hyperlipidaemia, active smoking, arterial hypertension, coronary artery disease, diabetes mellitus and heart valve disease. The population was divided depending on the number of coexisting CVRF/CVD (0-, 1-, 2-, 3-, 4-, 5-CVRF/CVD groups). The median FMD value in the entire group of patients was 10% (5-17). An analysis of the FMD percentage in particular groups showed significantly higher FMD values in patients without any CVRF/CVD (group 0), as well as in patients with one coexisting CVRF/CVD (group 1) compared to the other groups. The presence of two or more CVRF/CVD was not associated with a significantly higher FMD reduction. The analysis of patients with only one CVRF/CVD revealed the lowest FMD values in patients with coronary artery disease. FMD is related to the number of traditional CVRF/CVDs; however, coronary artery disease has the most significant influence on FMD decrease among analysed factors. The value of FMD assessment in high risk patients is limited.
Sugita, K; Nojima, Y; Tachibana, K; Soiffer, R J; Murray, C; Schlossman, S F; Ritz, J; Morimoto, C
One of the major obstacles in allogeneic bone marrow transplantation (allo-BMT) is prolonged T cell dysfunction resulting in a variety of infectious complications in the months to years after hematologic engraftment. We previously showed that immobilized extracellular matrix (ECM) proteins such as fibronectin (FN), the CS-1 domain of FN, or collagen (CO) acted synergistically with immobilized anti-CD3 to induce T cell proliferation. In addition, the comitogenic effect of ECMs could be mimicked by immobilized mAb reactive with a common beta 1 chain (CD29) of very late activating (VLA) antigens which include ECM receptors. Since the interaction of T cells with ECMs appears to play an important role in the process of T cell reconstitution following allo-BMT, we examined the expression of VLA antigens (alpha 1-alpha 6, beta 1) and their functional roles in CD3-mediated T cell proliferation at various times after T cell depleted allo-BMT. VLA beta 1 as well as VLA alpha 4, alpha 5, and alpha 6 expression was lower than normal controls during the first 3 mo after allo-BMT and auto-BMT, whereas these expressions returned to normal levels by 4 mo after allo-BMT and auto-BMT. Although alpha 1 and alpha 2 were not expressed on lymphocytes from normal controls, these antigens were expressed on lymphocytes at the detectable levels (5-15%) from patients after allo-BMT and auto-BMT. Both CD29 and CD3 were expressed at normal levels on lymphocytes from patients > 3 mo after allo-BMT, whereas T cell interaction with ECM through VLA proteins or crosslinking of VLA beta 1 expressed by T cells with anti-CD29 mAb results in poor induction of CD3-mediated T cell proliferation for a prolonged period (> 1 yr) after allo-BMT. In contrast, T cell proliferation induced by crosslinking of anti-CD2 or anti-CD26 with anti-CD3 was almost fully recovered by 1 yr post-allo-BMT. After autologous BMT, impaired VLA-mediated T cell proliferation via the CD3 pathway after auto-BMT returned to normal
Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel
ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550
Shumway, N E
Experimental orthotopic transplantation of the heart was accomplished in 1959. Long-term survival was achieved in 1965 with a chemical immunosuppression protocol substantially different from that used for renal and hepatic transplants. Performance characteristics of the transplanted denervated heart were found to differ only slightly from normal. It appeared by the time of the Clinical Congress of the American College of Surgeons in October 1967 that clinical heart transplantation might be justified if the concept of brain death could be legally recognized. The Stanford program in clinical heart transplantation was inaugurated on January 6, 1968 and has been in continuous operation. To date, more than 1000 patients have undergone transplantation of the heart with the 5-year survival at 75%. The first long-term success in lung transplantation occurred at Stanford in 1981, with transplantation of the heart and both lungs. In 1990 the concept of living pulmonary lobar donors was introduced and is slowly finding its clinical role. The steroid-sparing capability of cyclosporine made possible both successful lung and pediatric heart transplantation. Only the donor shortage remains as a substantial barrier to widespread thoracic transplantation. Xenotransplantation is under intense scrutiny, with some encouraging experimental results. Development of the artificial heart continues to offer some relief for patients with end-stage heart disease.
Zerillo, Jeron; Kim, Sang; Hill, Bryan; DeMaria, Samuel; Sakai, Tetsuro
More than 400 peer-reviewed publications on the topic of pancreas transplantation, more than 400 on intestine transplantation, and more than 3000 on renal transplantation were published in 2016. This review will highlight the most pertinent literature for anesthesiologists caring for patients undergoing non-liver abdominal organ transplantation. This review is the second part in an annual series to review relevant contributions in the field of abdominal organ transplantation focusing on pancreas, intestine, and renal transplantation. We explore a myriad of topics, including outcomes determined by center size, novel assessment of intestine graft function, the effect of Zika virus on the transplant population, appropriate fluid management for renal transplantation, cardiovascular risk assessment in the transplant population, and several topics pertinent to optimizing patient and graft survival.
Pacher, P.; Bátkai, S.; Kunos, G.
Cannabinoids and their synthetic and endogenous analogs affect a broad range of physiological functions, including cardiovascular variables, the most important component of their effect being profound hypotension. The mechanisms of the cardiovascular effects of cannabinoids in vivo are complex and may involve modulation of autonomic outflow in both the central and peripheral nervous systems as well as direct effects on the myocardium and vasculature. Although several lines of evidence indicate that the cardiovascular depressive effects of cannabinoids are mediated by peripherally localized CB1 receptors, recent studies provide strong support for the existence of as-yet-undefined endothelial and cardiac receptor(s) that mediate certain endocannabinoid-induced cardiovascular effects. The endogenous cannabinoid system has been recently implicated in the mechanism of hypotension associated with hemorrhagic, endotoxic, and cardiogenic shock, and advanced liver cirrhosis. Furthermore, cannabinoids have been considered as novel antihypertensive agents. A protective role of endocannabinoids in myocardial ischemia has also been documented. In this chapter, we summarize current information on the cardiovascular effects of cannabinoids and highlight the importance of these effects in a variety of pathophysiological conditions. PMID:16596789
McCarty, Mark F.
The arginine metabolite asymmetric dimethylarginine (ADMA) is a competitive inhibitor and uncoupler of endothelial nitric oxide synthase (eNOS), an enzyme that acts in multifarious ways to promote cardiovascular health. This phenomenon likely explains, at least in part, why elevated ADMA has been established as an independent risk factor for cardiovascular events, ventricular hypertrophy, and cardiovascular mortality. Fortunately, the suppressive impact of ADMA on eNOS activity can be offset by increasing intracellular arginine levels with supplemental citrulline. Although the long-term impact of supplemental citrulline on cardiovascular health in patients with elevated ADMA has not yet been studied, shorter-term clinical studies of citrulline administration demonstrate effects suggestive of increased NO synthesis, such as reductions in blood pressure and arterial stiffness, improved endothelium-dependent vasodilation, increased erection hardness, and increased ejection fractions in patients with heart failure. Supplemental citrulline could be a practical option for primary or secondary prevention of cardiovascular events and mortality, as it is inexpensive, has a mild flavor, and is well tolerated in doses (3–6 g daily) that can influence eNOS activity. Large and long-term clinical trials, targeting patients at high risk for cardiovascular events in whom ADMA is elevated, are needed to evaluate citrulline’s potential for aiding cardiovascular health. PMID:27417628
Corti, Roberto; Flammer, Andreas J; Hollenberg, Norman K; Lüscher, Thomas F
Epidemiological data demonstrate that regular dietary intake of plant-derived foods and beverages reduces the risk of coronary heart disease and stroke. Among many ingredients, cocoa might be an important mediator. Indeed, recent research demonstrates a beneficial effect of cocoa on blood pressure, insulin resistance, and vascular and platelet function. Although still debated, a range of potential mechanisms through which cocoa might exert its benefits on cardiovascular health have been proposed, including activation of nitric oxide and antioxidant and antiinflammatory effects. This review summarizes the available data on the cardiovascular effects of cocoa, outlines potential mechanisms involved in the response to cocoa, and highlights the potential clinical implications associated with its consumption.
Ramon, Daniel S; Huang, Yihung; Zhao, Lili; Rendulic, TrisAnn; Park, Jeong M; Sung, Randall S; Samaniego, Milagros
The Luminex® single antigen bead assay (SAB) is the method of choice for monitoring the treatment for antibody-mediated rejection (AMR). A ⩾50% reduction of the dominant donor-specific antibody (IgG-DSA) mean fluorescence intensity (MFI) has been associated with improved kidney allograft survival, and C1q-fixing DSA activity is associated with poor outcomes in patients with AMR. We aimed to investigate if C1q-DSA can be used as a reliable predictor of response to therapy and allograft survival in patients with biopsy-proven AMR. We tested pre- and post-treatment sera of 30 kidney transplant patients receiving plasmapheresis and low-dose IVIG for biopsy-proven AMR. IgG-DSA and C1q-DSA MFI were measured and correlated with graft loss or survival. Patients were classified as nonresponders (NR) when treatment resulted in <50% reduction in MFI of IgG-DSA and/or C1q-DSA was detectable following therapy. Differences in the percentage of patients deemed NR depended upon the end-point criterion (73% by reduction in IgG-DSA MFI vs. 50% by persistent C1q-DSA activity). None of the seven patients with <50% reduction of IgG-DSA but non-detectable C1q-DSA-fixing activity after therapy experienced graft loss, suggesting that C1q-DSA activity may better correlate with response. Reduction of C1q-DSA activity predicted graft survival better than IgG-DSA in the univariate Cox analysis (20.1% vs. 5.9% in NR; log-rank P-value=0.0147). A rapid reduction of DSA concentration below the threshold required for complement activation is associated with better graft survival, and C1q-DSA is a better predictor of outcomes than IgG-DSA MFI reduction. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Charles, John B.; Fritsch-Yelle, Janice M.; Whitson, Peggy A.; Wood, Margie L.; Brown, Troy E.; Fortner, G. William
Spaceflight causes adaptive changes in cardiovascular function that may deleteriously affect crew health and safety. Over the last three decades, symptoms of cardiovascular changes have ranged from postflight orthostatic tachycardia and decreased exercise capacity to serious cardiac rhythm disturbances during extravehicular activities (EVA). The most documented symptom of cardiovascular dysfunction, postflight orthostatic intolerance, has affected a significant percentage of U.S. Space Shuttle astronauts. Problems of cardiovascular dysfunction associated with spaceflight are a concern to NASA. This has been particularly true during Shuttle flights where the primary concern is the crew's physical health, including the pilot's ability to land the Orbiter, and the crew's ability to quickly egress and move to safety should a dangerous condition arise. The study of astronauts during Shuttle activities is inherently more difficult than most human research. Consequently, sample sizes have been small and results have lacked consistency. Before the Extended Duration Orbiter Medical Project (EDOMP), there was a lack of normative data on changes in cardiovascular parameters during and after spaceflight. The EDOMP for the first time allowed studies on a large enough number of subjects to overcome some of these problems. There were three primary goals of the Cardiovascular EDOMP studies. The first was to establish, through descriptive studies, a normative data base of cardiovascular changes attributable to spaceflight. The second goal was to determine mechanisms of cardiovascular changes resulting from spaceflight (particularly orthostatic hypotension and cardiac rhythm disturbances). The third was to evaluate possible countermeasures. The Cardiovascular EDOMP studies involved parallel descriptive, mechanistic, and countermeasure evaluations.
Cardiovascular technology has been applied in the treatment of various diseases in Indonesia since its development in the late 1970s. Medical experts who have completed their training abroad began to implement their knowledge in cardiovascular service while a multifactorial limitation occurred in the country. The major limiting factor is still the country's infrastructure, which should support the treatment measures in modern cardiovascular technology. Other limiting factors concern nonmedical subjects, e.g., ethics, beliefs, religion, and the financial and basic organization of organ transplantation. Organ replacement started with artificial kidney/hemodialysis in the late 1970s, and was successfully carried out together with the further commencement of living related donor renal transplantation. Development of cardiac surgery with extracorporeal circulation gave rise to the stimulation of animal trials of cardiac transplant, pancreas transplant, and other subsets of organ transplantation. With the increasing modus of modernization, major hospitals in 3 large cities have shown increasing needs for organ transplant, and, parallel to that, the increasing number of potential organ donors, the cause of death dominated by brain death resulting from traffic accidents. The emerging need for liver and cardiopulmonary transplants has also been observed during the last 5 years, despite the improvement of general health care. However, similar to many Asian countries, because of religious and cultural considerations, it may be difficult to find donors whose relatives are willing to donate organs from their deceased relatives, especially for heart, lung, liver, and pancreas transplants. Alternative methods for artificial organs should receive more emphasis. We present the activities which have been established so far and how we should cope with the question of how present technology brings answers to the needs of organ transplant and artificial organs. Some innovative steps
Al-Hamoudi, Waleed K.
Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation, cirrhotic cardiomyopathy, and pulmonary vascular abnormalities. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include neurohumoral and vascular dysregulations. Accumulating evidence suggests that cirrhosis-related cardiovascular abnormalities play a major role in the pathogenesis of multiple life-threatening complications including hepatorenal syndrome, ascites, spontaneous bacterial peritonitis, gastroesophageal varices, and hepatopulmonary syndrome. Treatment targeting the circulatory dysfunction in these patients may improve the short-term prognosis while awaiting liver transplantation. Careful fluid management in the immediate post-transplant period is extremely important to avoid cardiac-related complications. Liver transplantation results in correction of portal hypertension and reversal of all the pathophysiological mechanisms that lead to the cardiovascular abnormalities, resulting in restoration of a normal circulation. The following is a review of the pathogenesis and clinical implications of the cardiovascular changes in cirrhosis. PMID:20616408
Zelle, Dorien M.; Corpeleijn, Eva; Klaassen, Gerald; Schutte, Elise; Navis, Gerjan; Bakker, Stephan J. L.
Background Physical activity (PA) and exercise are commonly used as preventive measures for cardiovascular disease in the general population, and could be effective in the management of post-transplantation cardiovascular risk. PA levels are low after renal transplantation and very few renal transplant recipients (RTR) meet the PA guidelines. Identification of barriers to regular PA is important to identify targets for intervention to improve PA levels after renal transplantation. We investigated fear of movement and physical self-efficacy as barriers to PA in RTR. Methods RTR were investigated between 2001–2003. The Tampa Score of Kinesiophobia–Dutch Version (TSK-11) was used to assess fear of movement. Physical self-efficacy was measured with the LIVAS-scale. PA was assessed using validated questionnaires (Tecumseh Occupational Activity Questionnaire and the Minnesota Leisure Time Physical Activity Questionnaire). Results A total of 487 RTR (age 51±12 years, 55% men) were studied. Median score [interquartile range] on TSK-11 was 22 [17–26]. Low physical self-efficacy (Exp B:0.41[0.31–0.54], p<0.001) and history of myocardial infarction, transient ischemic attack and cerebrovascular accident (Exp B:1.30[1.03–1.63],p = 0.03) were independent determinants for fear of movement. Fear of movement was associated with lower daily PA, occupational, sports and leisure time PA. Mediation-analysis showed that a large part (73%) of the effect of fear of movement on PA was explained by low physical self-efficacy. Conclusions This study was the first to examine fear of movement and self-efficacy in relation to PA in RTR. Fear of movement was associated with a low PA level, and the larger part of this relation was mediated by low physical self-efficacy. Both fear of movement and physical self-efficacy level are important targets for intervention during rehabilitation after renal transplantation. PMID:26844883
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Innovative and exciting advances in the clinical sciences in organ transplantation were presented at the American Transplant Congress 2012. The full spectrum of transplantation was covered with important advancements in many topics. Key areas covered by presentations included living donor outcomes, organ preservation, optimal allocation of deceased donors, new immunosuppression regimens, antibody mediated rejection and the regulatory environment. This review will highlight some of the most interesting and innovative clinical presentations from the meeting.
Sung, R S
Innovative and exciting advances in the clinical sciences in organ transplantation were presented at the American Transplant Congress 2015. The full spectrum of transplantation was covered, with important developments in many topics. Key areas covered by presentations included living donor outcomes, optimal utilization and allocation of deceased donors, new immunosuppression regimens, antibody-mediated rejection and tolerance induction. This review highlights some of the most interesting and noteworthy clinical presentations from the meeting.
Miyairi, Satoshi; Hirai, Toshihito; Ishii, Rumi; Okumi, Masayoshi; Nunoda, Shinichi; Yamazaki, Kenji; Ishii, Yasuyuki; Tanabe, Kazunari
Mixed chimerism induction is the most reliable method for establishing transplantation tolerance. We previously described a novel treatment using a suboptimal dose of anti-CD40 ligand (anti-CD40L) and liposomal formulation of a ligand for invariant natural killer T cells administered to sub-lethally irradiated recipient mice after donor bone marrow cell (BMC) transfer. Recipient mice treated with this regimen showed expansion of a Foxp3-positive regulatory T(Treg) cell phenotype, and formation of mixed chimera. However, the mechanism of expansion and bioactivity of Treg cells remains unclear. Here, we examine the role of donor BMCs in the expansion of bioactive Treg cells. The mouse model was transplanted with a heart allograft the day after treatment. The results showed that transfer of spleen cells in place of BMCs failed to deplete host interferon (IFN)-γ-producing CD8(+) T cells, expand host Ki67(+) CD4(+) CD25(+) Foxp3(+) Treg cells, and prolong graft survival. Severe combined immunodeficiency mice who received Treg cells obtained from BMC-recipients accepted skin grafts in an allo-specific manner. Myeloid-derived suppressor cells, which were a copious cell subset in BMCs, enhanced the Ki67 expression of Treg cells. This suggests that donor BMCs are indispensable for the expansion of host bioactive Treg cells in our novel treatment for transplant tolerance induction.
Pourmand, Gholamreza; Dehghani, Sanaz; Rahmati, Mohamad Reza; Mehrsai, Abdolrasoul; Gooran, Shahram; Alizadeh, Farimah; Khaki, Siavash; Mortazavi, Seyede Hamideh; Pourmand, Naghmeh
Hypertension is a common complication of kidney transplantation with the prevalence of 80%. Studies in adults have shown a high prevalence of hypertension (HTN) in the first three months of transplantation while this rate is reduced to 50- 60% at the end of the first year. HTN remains as a major risk factor for cardiovascular diseases, lower graft survival rates and poor function of transplanted kidney in adults and children. In this retrospective study, medical records of 400 kidney transplantation patients of Sina Hospital were evaluated. Patients were followed monthly for the 1st year, every two months in the 2nd year and every three months after that. In this study 244 (61%) patients were male. Mean ± SD age of recipients was 39.3 ± 13.8 years. In most patients (40.8%) the cause of end-stage renal disease (ESRD) was unknown followed by HTN (26.3%). A total of 166 (41.5%) patients had been hypertensive before transplantation and 234 (58.5%) had normal blood pressure. Among these 234 individuals, 94 (40.2%) developed post-transplantation HTN. On the other hand, among 166 pre-transplant hypertensive patients, 86 patients (56.8%) remained hypertensive after transplantation. Totally 180 (45%) patients had post-transplantation HTN and 220 patients (55%) didn't develop HTN. Based on the findings, the incidence of post-transplantation hypertension is high, and kidney transplantation does not lead to remission of hypertension. On the other hand, hypertension is one of the main causes of ESRD. Thus, early screening of hypertension can prevent kidney damage and reduce further problems in renal transplant recipients.
Williams, Jonathan Richard
Bereavement in the elderly is becoming a more frequent phenomenon as a result of the aging of the population. The death of an elderly spouse increases psychologic morbidity, particularly depressive symptoms, as well as mortality. Depression increases the risk of death independent of age or bereavement, and can thus exacerbate the health effects of losing a spouse. This magnifier effect is especially pernicious because bereavement and depression both tend to increase cardiovascular mortality rates. Primary care physicians should be alert for signs of mood disorders in elderly persons who have recently lost a spouse. Potential therapies for depression in an elderly bereaved individual include pharmacologic agents, psychotherapy, and psychosocial support. Data also support the value of encouraging religious patients to continue with spiritual observances. Although these approaches decrease mood disorders, it is not yet clear whether they also reduce the risk of death or cardiovascular disease.
Singer, Jonathan P.; Koth, Laura; Mooney, Joshua; Golden, Jeff; Hays, Steven; Greenland, John; Wolters, Paul; Ghio, Emily; Jones, Kirk D.; Leard, Lorriana; Kukreja, Jasleen; Blanc, Paul D.
BACKGROUND: Hypersensitivity pneumonitis (HP) is an inhaled antigen-mediated interstitial lung disease (ILD). Advanced disease may necessitate the need for lung transplantation. There are no published studies addressing lung transplant outcomes in HP. We characterized HP outcomes compared with referents undergoing lung transplantation for idiopathic pulmonary fibrosis (IPF). METHODS: To identify HP cases, we reviewed records for all ILD lung transplantation cases at our institution from 2000 to 2013. We compared clinical characteristics, survival, and acute and chronic rejection for lung transplant recipients with HP to referents with IPF. We also reviewed diagnoses of HP discovered only by explant pathology and looked for evidence of recurrent HP after transplant. Survival was compared using Kaplan-Meier methods and Cox proportional hazard modeling. RESULTS: We analyzed 31 subjects with HP and 91 with IPF among 183 cases undergoing lung transplantation for ILD. Survival at 1, 3, and 5 years after lung transplant in HP compared with IPF was 96%, 89%, and 89% vs 86%, 67%, and 49%, respectively. Subjects with HP manifested a reduced adjusted risk for death compared with subjects with IPF (hazard ratio, 0.25; 95% CI, 0.08-0.74; P = .013). Of the 31 cases, the diagnosis of HP was unexpectedly made at explant in five (16%). Two subjects developed recurrent HP in their allografts. CONCLUSIONS: Overall, subjects with HP have excellent medium-term survival after lung transplantation and, relative to IPF, a reduced risk for death. HP may be initially discovered only by review of the explant pathology. Notably, HP may recur in the allograft. PMID:25412059
Manni, Luigi; Di Fausto, Veronica; Fiore, Marco; Aloe, Luigi
Chronic stress and increased sympathetic nerve activity have been associated with cardiovascular disorders such as hypertension, myocardial infarction and stroke. The aim of this study was to investigate the role of nerve growth factor (NGF) on the expression of tyrosine hydroxylase (TH), vascular-endothelial growth factor (VEGF) and leptin receptor (OB-R) in brain, adrenal and cardiovascular tissues of adult male and female mice following a chronic stress procedure. It was found that daily restraint for 10 consecutive days alters TH levels in hypothalamic and brainstem areas related to sympathetic activation, in both male and female mice. Chronic stress procedure also modifies heart and aorta VEGF levels in male mice, and adrenal glands TH in female mice. The NGF administration in stressed mice reverted the stress-induced up-regulation of TH levels in male and female mice hypothalamic nuclei and in male locus coeruleus. Administration of NGF in stressed animals also down-regulated OB-R levels in the hypothalamus of both male and female mice and in the female aorta. Our findings indicate that repeated restraint in mice has an effect on TH and VEGF protein content at different brain and peripheral sites involved in the sympathetic and cardio-vascular response to stressful stimuli. NGF administration is able to counteract some of these stress-induced changes. Since NGF is known to be up-regulated during stress, a possible functional significance of our observations is that the circulating NGF released during and following stress may serve to prevent possible deficits and/or damage linked to stress-induced sympathetic and cardiovascular activation.
Katsuma, Ai; Yamamoto, Izumi; Komatsuzaki, Yo; Niikura, Takahito; Kawabe, Mayuko; Okabayashi, Yusuke; Yamakawa, Takafumi; Katsumata, Haruki; Nakada, Yasuyuki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi
A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection.
There is nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory-motor nerves, as well as in intracardiac neurons. Centers in the brain control heart activities and vagal cardiovascular reflexes involve purines. Adenine nucleotides and nucleosides act on purinoceptors on cardiomyocytes, AV and SA nodes, cardiac fibroblasts, and coronary blood vessels. Vascular tone is controlled by a dual mechanism. ATP, released from perivascular sympathetic nerves, causes vasoconstriction largely via P2X1 receptors. Endothelial cells release ATP in response to changes in blood flow (via shear stress) or hypoxia, to act on P2 receptors on endothelial cells to produce nitric oxide, endothelium-derived hyperpolarizing factor, or prostaglandins to cause vasodilation. ATP is also released from sensory-motor nerves during antidromic reflex activity, to produce relaxation of some blood vessels. Purinergic signaling is involved in the physiology of erythrocytes, platelets, and leukocytes. ATP is released from erythrocytes and platelets, and purinoceptors and ectonucleotidases are expressed by these cells. P1, P2Y1, P2Y12, and P2X1 receptors are expressed on platelets, which mediate platelet aggregation and shape change. Long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides promote migration and proliferation of vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis, vessel remodeling during restenosis after angioplasty and atherosclerosis. The involvement of purinergic signaling in cardiovascular pathophysiology and its therapeutic potential are discussed, including heart failure, infarction, arrhythmias, syncope, cardiomyopathy, angina, heart transplantation and coronary bypass grafts, coronary artery disease, diabetic cardiomyopathy, hypertension, ischemia, thrombosis, diabetes mellitus, and migraine. © 2017 American Heart Association, Inc.
Fatal immune-mediated pancytopenia and a TRALI-like syndrome associated with high titers of recipient-type antibodies against donor-derived peripheral blood cells after allogeneic bone marrow transplantation following dose reduced conditioning.
Knop, Stefan; Bux, Juergen; Kroeber, Stefan M; Bader, Peter; Hebart, Holger; Kanz, Lothar; Einsele, Hermann
Pancytopenia occurring after bone marrow transplantation is a rare complication. A 47 year old patient with progression of multiple myeloma after standard therapy received an allogeneic marrow graft from a matched unrelated donor. The non-myeloablative conditioning regimen consisted of fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and total body irradiation. GVHD prophylaxis consisted of cyclosporine. Neutrophil engraftment was as expected and the patient was discharged without signs of acute GvHD. On day +34 the patient presented with clinical and laboratory findings consistent with severe pancytopenia. Antibodies against red cells, platelets, lymphocytes and granulocytes were detected in extremely high titers. Immune-mediated pancytopenia was refractory on multiple immunosuppressive treatment strategies. Proliferation of polyclonal plasma cells of recipient-type that was documented postmortem, was most likely responsible for excessive antibody formation.
Iwasaki, Kenta; Yamamoto, Takayuki; Inanaga, Yukiko; Hiramitsu, Takahisa; Miwa, Yuko; Murotani, Kenta; Narumi, Shuji; Watarai, Yoshihiko; Katayama, Akio; Uchida, Kazuharu; Kobayashi, Takaaki
De novo donor-specific HLA antibody (DSA) would not necessarily contribute to chronic antibody-mediated rejection (CAMR) in kidney transplantation. Here, we investigated whether PBMC miRNAs could be predictable biomarkers for CAMR. Microarray profiling of 435 mature miRNAs in pooled samples was conducted. Individual analysis revealed that miR-142-5p was significantly (p < 0.01) underexpressed in patients with DSA. After DSA production, miR-486-5p and its target PTEN/foxO3 mRNA were significantly overexpressed (p < 0.01) and underexpressed (p < 0.01), respectively, in patients with biopsy-proven CAMR, compared with non-CAMR. Our studies suggest that miRNA expression patterns may serve as noninvasive diagnostic biomarkers to evaluate immune response and kidney allograft status.
Myburgh, Renier; Hochfeld, Warren E; Dodgen, Tyren M; Ker, James; Pepper, Michael S
Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.
Di Pasquale, E; Latronico, M V G; Jotti, G S; Condorelli, G
Engineered recombinant viral vectors are a powerful tool for vehiculating genetic information into mammalian cells. Because of their ability to infect both dividing and non-dividing cells with high efficiency, lentiviral vectors have gained particular interest for basic research and preclinical studies in the cardiovascular field. We review here the major applications for lentiviral-vector technology in the cardiovascular field: we will discuss their use in trailing gene expression during the induction of differentiation, in protocols for the isolation of cardiac cells and in the tracking of cardiac cells after transplantation in vivo; we will also describe lentivirally-mediated gene delivery uses, such as the induction of a phenotype of interest in a target cell or the treatment of cardiovascular diseases. In addition, a section of the review will be dedicated to reprogramming approaches, focusing attention on the generation of pluripotent stem cells and on transdifferentiation, two emerging strategies for the production of cardiac myocytes from human cells and for the investigation of human diseases. Finally, in order to give a perspective on their future clinical use we will critically discuss advantages and disadvantages of lentivirus-based strategies for the treatment of cardiovascular diseases.
Muscheites, Jutta; Meyer, Andreas Alexander; Drueckler, Erdmute; Wigger, Marianne; Fischer, Dagmar-Christiane; Kundt, Guenther; Kienast, Wolfgang; Haffner, Dieter
Long-term survival of children and adolescents with chronic kidney disease (CKD) is mainly limited by cardiovascular disease. Pediatric CKD patients (n = 26) on conservative treatment, dialysis and after renal transplantation were compared with healthy controls (n = 24) with respect to cardiovascular status. Mean baseline diameter of the brachial artery was significantly higher, and mean flow-mediated vasodilation (FMD) was significantly reduced, in CKD patients. CKD patients showed significantly increased left ventricular mass index, blood pressure (BP) values and age-related values of mean carotid intima-media thickness [intima-media thickness-standard deviation score (IMT-SDS)] compared with those of controls. Approximately 60% of patients presented with impaired FMD (< or = 5.79%), which was significantly associated with intima-media thickening, although only three patients (12%) presented with both, impaired FMD and increased age-related IMT. The latter was significantly associated with higher values for day-time BP. In contrast, duration and degree of CKD, mode of renal replacement therapy, homocysteine levels and concomitant medication showed no association with cardiovascular status. The majority of our pediatric CKD patients showed reduced endothelial function, which may have preceded the development of carotid arteriopathy. Therefore, routine assessment of FMD may be a useful tool to identify CKD patients at risk of progressive cardiovascular morbidity.
Adam, Benjamin; Mengel, Michael
Despite its long-standing status as the diagnostic "gold standard", the renal transplant biopsy is limited by a fundamental dependence on descriptive, empirically-derived consensus classification. The recent shift towards personalized medicine has resulted in an increased demand for precise, mechanism-based diagnoses, which is not fully met by the contemporary transplantation pathology standard of care. The expectation is that molecular techniques will provide novel pathogenetic insights that will allow for the identification of more accurate diagnostic, prognostic, and therapeutic targets. Here we review the current state of molecular renal transplantation pathology. Despite significant research activity and progress within the field, routine adoption of clinical molecular testing has not yet been achieved. The recent development of novel molecular platforms suitable for use with formalin-fixed paraffin-embedded tissue will offer potential solution for the major barriers to implementation. The recent incorporation of molecular diagnostic criteria into the 2013 Banff classification is a reflection of progress made and future directions in the area of molecular transplantation pathology. Transcripts related to endothelial injury and NK cell activation have consistently been shown to be associated with antibody-mediated rejection. Prospective multicenter validation and implementation of molecular diagnostics for major entities remains an unmet clinical need in transplantation. It is expected that an integrated system of transplantation pathology diagnosis comprising molecular, morphological, serological, and clinical variables will ultimately provide the greatest diagnostic precision.
Kumar, Vijay; Kumar, Asha
Corneal transplant is the most common solid tissue transplant in humans. Advances in microsurgical techniques, eye banking and the use of corticosteroids have improved the success of corneal transplants. Over 65,000 corneal transplants are being performed worldwide annually. Most of these transplants are performed in developed countries. Cornea is considered an immune privileged site. Despite this, immune mediated graft rejection is the most single cause of cornea graft failure and is one of the major postoperative complications. Incidences from as low as 2% to as high as 50% have been reported depending upon the degree of vascularization. Rejection involves donor tissue recognition and various factors may influence this rejection. Major factors include the antigenic load of the donor tissue; other factors include death to enucleation time, methods and temperature of preserving the tissue. Host factors that may impact the graft include ocular surface diseases such as dry eye, chemical burns and autoimmune diseases such as mucous membrane pemphigoid. Following infection, surgery or trauma, cells of the innate immune system invade the cornea as a result of up-regulation of cytokines, cellular adhesion molecules and growth and angiogenic factors. These factors results in neoangiogenesis and lymphoangiogenesis, leading to immune activation and graft rejection. The various immunological mechanisms that may play a role in the corneal transplant are discussed.
Payne, Rupert A
Cardiovascular disease is a major, growing, worldwide problem. It is important that individuals at risk of developing cardiovascular disease can be effectively identified and appropriately stratified according to risk. This review examines what we understand by the term risk, traditional and novel risk factors, clinical scoring systems, and the use of risk for informing prescribing decisions. Many different cardiovascular risk factors have been identified. Established, traditional factors such as ageing are powerful predictors of adverse outcome, and in the case of hypertension and dyslipidaemia are the major targets for therapeutic intervention. Numerous novel biomarkers have also been described, such as inflammatory and genetic markers. These have yet to be shown to be of value in improving risk prediction, but may represent potential therapeutic targets and facilitate more targeted use of existing therapies. Risk factors have been incorporated into several cardiovascular disease prediction algorithms, such as the Framingham equation, SCORE and QRISK. These have relatively poor predictive power, and uncertainties remain with regards to aspects such as choice of equation, different risk thresholds and the roles of relative risk, lifetime risk and reversible factors in identifying and treating at-risk individuals. Nonetheless, such scores provide objective and transparent means of quantifying risk and their integration into therapeutic guidelines enables equitable and cost-effective distribution of health service resources and improves the consistency and quality of clinical decision making. PMID:22348281
Cardiovascular disease (CVD), particularly CHD (coronary heart disease) and stroke, remain the leading causes of death of women in America and most developed countries. In recent years the rate of CVD has declined in men but not in women. This is contributed to by an under-recognition of women’s C...
Achour, Abla; Baychelier, Florence; Besson, Caroline; Arnoux, Armelle; Marty, Michel; Hannoun, Laurent; Samuel, Didier; Debré, Patrice; Vieillard, Vincent
Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV(+) patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.
Cavka, Ana; Stupin, Marko; Panduric, Ana; Plazibat, Ana; Cosic, Anita; Rasic, Lidija; Debeljak, Zeljko; Martinovic, Goran; Drenjancevic, Ines
Objectives. To assess the effect of Red Bull© on (1) blood glucose and catecholamine levels, (2) cardiovascular and respiratory function changes before, during, and after exercise, (3) reaction time, (4) cognitive functions, and (5) response to mental stress test and emotions in young healthy individuals (N=38). Methods. Heart rate (HR) and arterial blood pressure (ABP), blood glucose, adrenaline, and noradrenalin plasma levels were measured before and after Red Bull© intake. Participants were subjected to 4 different study protocols by randomized order, before and 30 minutes after consumption of 500 mL of Red Bull©. Results. Mean ABP and HR were significantly increased at rest after Red Bull© intake. Blood glucose level and plasma catecholamine levels significantly increased after Red Bull© consumption. Heart rate, respiration rate, and respiratory flow rate were significantly increased during exercise after Red Bull© consumption compared to control condition. Intake of Red Bull© significantly improved reaction time, performance in immediate memory test, verbal fluency, and subject's attention as well as performance in mental stress test. Conclusion. This study demonstrated that Red Bull© has beneficial effect on some cognitive functions and effect on cardiovascular and respiratory system at rest and during exercise by increasing activity of the sympathetic nervous system. PMID:26124829
Davidsson, Pia; Söderling, Ann-Sofi; Svensson, Lena; Ahnmark, Andrea; Flodin, Christine; Wanag, Ewa; Screpanti-Sundqvist, Valentina; Gennemark, Peter
Tissue distribution and pharmacokinetics (PK) of full-length nontargeted antibody and its antigen-binding fragment (FAb) were evaluated for a range of tissues primarily of interest for cardiovascular and metabolic diseases. Mice were intravenously injected with a dose of 10 mg/kg of either human IgG1or its FAb fragment; perfused tissues were collected at a range of time points over 3 weeks for the human IgG1 antibody and 1 week for the human FAb antibody. Tissues were homogenized and antibody concentrations were measured by specific immunoassays on the Gyros system. Exposure in terms of maximum concentration (Cmax ) and area under the curve was assessed for all nine tissues. Tissue exposure of full-length antibody relative to plasma exposure was found to be between 1% and 10%, except for brain (0.2%). Relative concentrations of FAb antibody were the same, except for kidney tissue, where the antibody concentration was found to be ten times higher than in plasma. However, the absolute tissue uptake of full-length IgG was significantly higher than the absolute tissue uptake of the FAb antibody. This study provides a reference PK state for full-length whole and FAb antibodies in tissues related to cardiovascular and metabolic diseases that do not include antigen or antibody binding.
Bassareo, P P; Fanos, V; Puddu, M; Demuru, P; Cadeddu, F; Balzarini, M; Mercuro, G
Sporadic data present in literature report how preterm birth and low birth weight constitute the risk factors for the development of cardiovascular diseases in later life. To assess the presence of potential alterations to endothelial function in young adults born preterm at extremely low birth weight (<1000 g; ex ELBW). Thirty-two ex-ELBW subjects (10 males [M] and 22 females [F], aged 17-28 years, mean [+/- DS] 20.1 +/- 2.5 years) were compared with 32 healthy, age-matched subjects born at term (C, 9 M and 23 F). 1) pathological conditions known to affect endothelial function; 2) administration of drugs known to affect endothelial function. Endothelial function was assessed by non-invasive finger plethysmography, previously validated by the US Food and Drug Administration (Endopath; Itamar Medical Ltd., Cesarea, Israel). Endothelial function was significantly reduced in ex-ELBW subjects compared to C (1.94 +/- 0.37 vs. 2.68 +/- 0.41, p < 0.0001). Moreover, this function correlated significantly with gestational age (r = 0.56, p < 0.0009) and birth weight (r = 0.63, p < 0.0001). The results obtained reveal a significant decrease in endothelial function of ex-ELBW subjects compared to controls, underlining a probable correlation with preterm birth and low birth weight. Taken together, these results suggest that an ELBW may underlie the onset of early circulatory dysfunction predictive of increased cardiovascular risk.
For field pepper (Capsicum spp.) production, plants can be established from direct seed or transplants depending on the location and cultural practices for the specific pepper type grown. Direct seeding can result in slow, variable, and reduced plant stands due to variations in soil temperature, wat...
A heart transplant removes a damaged or diseased heart and replaces it with a healthy one. The healthy heart comes from a donor who has died. It is the last resort for people with heart failure when all other treatments have failed. The ...
Sweeney, Colin L; Choi, Uimook; Liu, Chengyu; Koontz, Sherry M; Ha, Seung-Kwon; Malech, Harry L
Chronic granulomatous disease (CGD) is characterized by defects in production of microbicidal reactive oxygen species (ROS) by phagocytes. Testing of gene and cell therapies for treatment of CGD in human hematopoietic cells requires pre-clinical transplant models. The use of the lymphocyte-deficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse strain for human hematopoietic cell xenografts to test CGD therapies is complicated by the presence of functional mouse granulocytes capable of producing ROS for subsequent bacterial and fungal killing. To establish a phagocyte-defective mouse model of X-linked CGD (X-CGD) in NSG mice, we utilized clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 for targeted knock-out of mouse Cybb on the X-chromosome by microinjection of NSG mouse zygotes with Cas9 mRNA and CRISPR single-guide RNA targeting Cybb exon 1 or exon 3. This resulted in a high incidence of indel formation at the CRISPR target site, with all mice exhibiting deletions in at least one Cybb allele based on sequence analysis of tail snip DNA. A female mouse heterozygous for a 235-bp deletion in Cybb exon 1 was bred to an NSG male to establish the X-CGD NSG mouse strain, NSG.Cybb[KO]. Resulting male offspring with the 235-bp deletion were found to be defective for production of ROS by neutrophils and other phagocytes, and demonstrated increased susceptibility to spontaneous bacterial and fungal infections with granulomatous inflammation. The establishment of the phagocyte-defective NSG.Cybb[KO] mouse model enables the in vivo assessment of gene and cell therapy strategies for treating CGD in human hematopoietic cell transplants without obfuscation by functional mouse phagocytes, and may also be useful for modeling of other phagocyte disorders in humanized NSG mouse xenografts.
Zhang, Hongyu; Siegel, Christopher T.; Shuai, Ling; Lai, Jiejuan; Zeng, Linli; Zhang, Yujun; Lai, Xiangdong; Bie, Ping; Bai, Lianhua
NG2-expressing cells are a population of periportal vascular stem/progenitors (MLpvNG2+ cells) that were isolated from healthy adult mouse liver by using a “Percoll-Plate-Wait” procedure. We demonstrated that isolated cells are able to restore liver function after transplantation into a cirrhotic liver, and co-localized with the pericyte marker (immunohistochemistry: PDGFR-β) and CK19. Cells were positive for: stem cell (Sca-1, CD133, Dlk) and liver stem cell markers (EpCAM, CD14, CD24, CD49f); and negative for: hematopoietic (CD34, CD45) and endothelial markers (CD31, vWf, von Willebrand factor). Cells were transplanted (1 × 106 cells) in mice with diethylnitrosamine-induced cirrhosis at week 6. Cells showed increased hepatic associated gene expression of alpha-fetoprotein (AFP), Albumin (Alb), Glucose-6-phosphatase (G6Pc), SRY (sex determining region Y)-box 9 (Sox9), hepatic nuclear factors (HNF1a, HNF1β, HNF3β, HNF4α, HNF6, Epithelial cell adhesion molecule (EpCAM), Leucine-rich repeated-containing G-protein coupled receptor 5-positive (Lgr5) and Tyrosine aminotransferase (TAT). Cells showed decreased fibrogenesis, hepatic stellate cell infiltration, Kupffer cells and inflammatory cytokines. Liver function markers improved. In a cirrhotic liver environment, cells could differentiate into hepatic lineages. In addition, grafted MLpvNG2+ cells could mobilize endogenous stem/progenitors to participate in liver repair. These results suggest that MLpvNG2+ cells may be novel adult liver progenitors that participate in liver regeneration. PMID:26905303
Min, Ji Won; Kim, Kyoung Woon; Kim, Bo-Mi; Doh, Kyoung Chan; Choi, Min Seok; Choi, Bum Soon; Park, Cheol Whee; Yang, Chul Woo; Kim, Yong-Soo
It is well known that pre-transplant B cell activating factor (BAFF) levels are associated with the development of de novo anti-HLA antibodies and antibody mediated rejection post-transplant. However, the clinical significance of BAFF values at allograft rejection has not been determined. In this study, we investigated the clinical significance of pre-transplant BAFF level as well as post-