Chih Hsin Hsu

Rosuvastatin improves vascular function of arteriovenous fistula in a diabetic rat model.

OBJECTIVE This study investigates the pathogenesis of arteriovenous (AV) fistula failure in patients with diabetes mellitus (DM) and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. METHODS DM was induced in rats by a single injection of streptozotocin. One week later, a fistula was created in the descending aorta and the adjacent inferior vena cava (aortocaval [AC] fistula). Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. Blood flow in the aortic segments of the fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined 2 weeks after creation of the AC fistulas using flow cytometry. Vascular function of the AC fistulas was assessed by isometric force testing. The expression of proinflammatory genes and generation of superoxide anions in the fistulas were examined. RESULTS The number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased the number of circulating EPCs. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated after treatment with rosuvastatin. Rosuvastatin also attenuated the expression of inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidase and generation of superoxide anions in the fistula tissues isolated from diabetic rats. CONCLUSIONS We provide the first evidence demonstrating that rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with DM by attenuating the activity of proinflammatory genes and generation of superoxide anions in the remodeled vasculature. CLINICAL RELEVANCE Arteriovenous (AV) fistula is the most common vascular access for hemodialysis in patients with end-stage renal disease. Studies have shown that blood flow in the AV fistula is significantly reduced in patients with diabetes and the period for maturation of an AV fistula is longer in these patients. The underlying mechanisms of AV fistula failure in diabetes are still poorly understood and there are limited therapeutic approaches that can increase the lifespan of these fistulas. The present study demonstrates that oral administration rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with diabetes, which results from attenuating the activity of proinflammatory genes in the remodeled vasculature, thereby reducing the generation of tissue superoxide anions. Our results may thus enhance our ability to prevent and manage vascular access failure in patients with diabetes with chronic renal disease.

Pulmonary nodules caused by Schizophyllum commune after cardiac transplantation

The incidence of pulmonary nodules after cardiac transplantation is not uncommon, and prompt diagnostic procedures are necessary to minimize disease-related morbidity and mortality. We report a 56-year-old woman who was found to have bilateral pulmonary nodules four months after cardiac transplantation. The microorganism was identified with a molecular diagnostic method as Schizophyllum commune, which had not been reported in English literature as a pathogen inducing pulmonary nodules after transplantation. She remained asymptomatic during the therapeutic period and the pulmonary nodules resolved six months later.

Bridge-to-recovery strategy using extracorporeal membrane oxygenation for critical pulmonary hypertension complicated with cardiogenic shock

OBJECTIVES Studies on mechanical-medical bridging for decompensated pulmonary hypertension (PH) are limited. We analysed the outcomes for critical PH patients who underwent extracorporeal membrane oxygenation (ECMO) support using a bridge-to-recovery (BTR) strategy. This study aimed to identify prognostic factors of BTR and evaluate the outcomes of survivors. METHODS Between 2009 and 2012, 6 patients who received veno-arterial ECMO due to decompensated PH with cardiogenic shock were retrospectively reviewed. All of the patients were managed with an aggressive titration of PH therapies and the optimization of right ventricular (RV) function to wean them off of ECMO. Three of the patients survived to discharge, and the others suffered in-hospital mortality. The differences between their baseline characteristics, ECMO set-up, haemodynamic change and complications were analysed. RESULTS The average age was 46.67 ± 14.07 years, with a male-to-female ratio of 1:2. The non-survival group exhibited a higher baseline systolic pulmonary artery pressure (127.67 ± 25.81 vs 67.67 ± 24.83 mmHg, P = 0.044) than the survival group before ECMO. All of the non-survivors underwent cardiopulmonary-cerebral resuscitation prior to ECMO implantation (100 vs 0%, P = 0.100). The survivors tended to have received suboptimal PH therapies before ECMO and had more readily correctable predisposing factors of right ventricular failure. The non-survivors required a longer duration of ECMO and suffered more end-organ failure or sepsis, although those differences were not statistically significant. Pneumonia developed in 3 of the survivors and caused late mortality in 2 after discharge. CONCLUSIONS ECMO provides a therapeutic window for the medical stabilization of critically decompensated PH patients. Prompt ECMO intervention before haemodynamic collapse and careful patient selection are critical for successful BTR outcomes.

Rosuvastatin Suppresses the Oxidative Response in the Venous Limb of an Arteriovenous Fistula and Enhances the Fistula Blood Flow in Diabetic Rats

Objective: The blood flow in the arteriovenous (AV) fistula is significantly reduced in diabetic patients. Statins are known to mediate pleiotropic effects in the vascular endothelium and attenuate inflammatory responses. This study tested the vascular protective effect of rosuvastatin in an experimental model of AV fistula. Methods: One week after the induction of diabetes mellitus (DM) in rats, a fistula was created in the abdominal aorta and inferior vena cava. Rats received placebo or rosuvastatin (15 mg/kg/day) in chow for 2 weeks. The blood flow in the venous segments of the fistula was measured. The expression of proinflammatory genes and the generation of superoxide in the venous fistula were examined. Results: The blood flow and luminal diameter of the AV fistula was significantly enhanced in animals treated with rosuvastatin. Rosuvastatin attenuated the expression of inducible nitric oxide synthase, NADPH oxidase, and monocyte chemotactic protein-1 in the fistula. The levels of superoxide anions and proinflammatory cytokines were also suppressed in rosuvastatin-treated animals. Neointimal formation in the AV fistula was not affected following treatment with rosuvastatin. Conclusions: We demonstrated that rosuvastatin improves luminal dilatation and blood flow in the AV fistula of subjects with DM. These vascular protective effects of rosuvastatin are most likely mediated by the attenuation of proinflammatory activities in the remodeled vasculature.

Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension

Objectives: Systemic left‐to‐right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon‐like peptide, exendin‐4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin‐4 (1 &mgr;g/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. Results: Exendin‐4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin‐1&bgr; levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin‐4. Smooth muscle‐myosin heavy chain‐II and &agr;‐smooth muscle actin protein levels increased in the pulmonary arteries of exendin‐4‐treated rats. Histology showed that exendin‐4 decreased the main and intra‐acinar pulmonary artery medial thickness. Conclusions: Exendin‐4 treatment improved pulmonary artery function in flow‐induced PH via its direct vasoactive properties, anti‐inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin‐1&bgr; and its downstream signaling molecules. Glucagon‐like peptide analogs may possess pleiotropic therapeutic potential in flow‐induced PH.

Hemodynamic, biological, and right ventricular functional changes following intraatrial shunt repair in patients with flow‐induced pulmonary hypertension

OBJECTIVES Atrial septal defects may result in pulmonary hypertension and right heart remodeling. We analyzed improvements in patients with flow-induced pulmonary hypertension and the activation of endothelial progenitor cells after flow reduction. DESIGN This prospective cohort study included 37 patients who were admitted for an occluder implantation. Blood samples were collected before and after the procedure. We determined the number of endothelial progenitor cells in outgrowth colonies and serum Hsp27 concentrations. Daily performance and cardiothoracic ratio were reevaluated later. RESULTS Closure of the defect significantly reduced the pulmonary pressure and B-type natriuretic peptide levels. The cardiothoracic ratio and daily performance status also improved. The number of endothelial progenitor cell outgrowth colony-forming units significantly increased and was positively correlated with daily performance. In patients with enhanced colony formation, Hsp27 levels were significantly increased. CONCLUSIONS The implantation of an occluder successfully improved hemodynamic, right ventricular, and daily performance. Qualitative enhancement of colony formation for endothelial progenitor cells was also noted and positively correlated with daily performance. Closure of defects may serve as a valid, reliable model to obtain a deeper understanding of the modulation of endothelial progenitor cell activity and its relationship with pulmonary hypertension prognosis.

Dose-normalization for exposure to mycophenolic acid and the early clinical outcome in patients taking tacrolimus after heart transplantation.

BACKGROUND The early phase of MPA exposure has rarely been investigated after solid organ transplantation, especially in heart transplantation patients. We evaluated the association between exposure to mycophenolic acid (MPA), a main metabolite of mycophenolate mofetil (MMF), and clinical events within 3 months after heart transplantation. MATERIAL AND METHODS Trough (C0) and area under the curve (AUC)0-12h levels of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were determined using high-performance liquid chromatography. Corresponding clinical endpoints included acute rejection or MMF-related adverse events (gastrointestinal symptoms, leucopenia, and anemia). AUC measurements (n=77) were collected from 21 patients. Dose-normalized C0 and AUC0-12h levels were used to evaluate the association between MPA or MPAG exposure and MMF-related adverse events. RESULTS No acute rejection or mortality occurred during the follow-up period. Twelve patients (57%) developed 13 MMF-related adverse events. The MMF dose was tapered from 2.50 g/day on D1 to 1.55±0.54 g/day on D90. Significantly higher levels of dose-normalized MPA C0 and AUC0-12h were associated with the events than with the absence of the events (C0: 1.04±0.42 vs. 0.84±0.85 µg/mL/g [p=0.047]; AUC0-12h: 20.37±3.21 vs. 14.97±1.13 µg × h/mL/g; [p=0.038]). Conclusions Dose-normalized MPA exposure may protect against MMF toxicity in the early stage after heart transplantation. The MMF dose can be decreased to near 1.5 g/day 3 months post-transplantation without jeopardizing patient safety; a well-planned, tapered MMF regimen should also be considered.