AT2R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression

Angiotensin II type 2 receptor (AT₂R) deficiency in AT₂R knockout (KO) mice has been linked to congenital abnormalities of the kidney and urinary tract; however, the mechanisms by which this occurs are poorly understood. In this study, we examined whether AT₂R deficiency impaired glomerulogenesis and mediated podocyte loss/dysfunction in vivo and in vitro. Nephrin‐cyan fluorescent protein (CFP)‐transgenic (Tg) and Nephrin/AT₂RKO mice were used to assess glomerulogenesis, while wild‐type and AT₂RKO mice were used to evaluate maturation of podocyte morphology/function. Immortalized mouse podocytes (mPODs) were employed for in vitro studies. AT₂R deficiency resulted in diminished glomerulogenesis in E15 embryos, but had no impact on actual nephron number in neonates. Pups lacking AT₂R displayed features of renal dysplasia with lower glomerular tuft volume and podocyte numbers. In vivo and in vitro studies demonstrated that loss of AT₂R was associated with elevated NADPH oxidase 4 levels, which in turn stimulated ectopic hedgehog interacting protein (Hhip) gene expression in podocytes. Consequently, ectopic Hhip expression activation either triggers caspase‐3 and p53‐related apoptotic processes resulting in podocyte loss, or activates TGFβ1–Smad2/3 cascades and α‐SMA expression to transform differentiated podocytes to undifferentiated podocyte‐derived fibrotic cells. We analyzed HHIP expression in the kidney disease database (Nephroseq) and then validated this using HHIP immunohistochemistry staining of human kidney biopsies (controls versus focal segmental glomerulosclerosis). In conclusion, loss of AT₂R is associated with podocyte loss/dysfunction and is mediated, at least in part, via augmented ectopic Hhip expression in podocytes. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Design,Analysis and Testing of a Novel Mitral Valve for Transcatheter Implantation

Mitral regurgitation is a common mitral valve dysfunction which may lead to heart failure. Because of the rapid aging of the population, conventional surgical repair and replacement of the pathological valve are often unsuitable for about half of symptomatic patients, who are judged high-risk. Transcatheter valve implantation could represent an effective solution. However, currently available aortic valve devices are inapt for the mitral position. This paper presents the design, development and hydrodynamic assessment of a novel bi-leaflet mitral valve suitable for transcatheter implantation. The device consists of two leaflets and a sealing component made from bovine pericardium, supported by a self-expanding wireframe made from superelastic NiTi alloy. A parametric design procedure based on numerical simulations was implemented to identify design parameters providing acceptable stress levels and maximum coaptation area for the leaflets. The wireframe was designed to host the leaflets and was optimised numerically to minimise the stresses for crimping in an 8 mm sheath for percutaneous delivery. Prototypes were built and their hydrodynamic performances were tested on a cardiac pulse duplicator, in compliance with the ISO5840-3:2013 standard. The numerical results and hydrodynamic tests show the feasibility of the device to be adopted as a transcatheter valve implant for treating mitral regurgitation.     

Long-term durability test of axial-flow ventricular assist device under pulsatile flow

A long-term durability test was conducted on a newly developed axial-flow ventricular assist device (VAD) with hydrodynamic bearings. The mock circulatory loop consisted of a diaphragm pump with a mechanical heart valve, a reservoir, a compliance tank, a resistance valve, and flow paths made of polymer or titanium. The VAD was installed behind the diaphragm pump. The blood analog fluid was a saline solution with added glycerin at a temperature of 37 °C. A pulsatile flow was introduced into the VAD over a range of flow rates to realize a positive flow rate and a positive pressure head at a given impeller rotational speed, yielding a flow rate of 5 L/min and a pressure of 100 mmHg. Pulsatile flow conditions were achieved with the diastolic and systolic flow rates of ~0 and 9.5 L/min, respectively, and an average flow rate of ~5 L/min at a pulse rate of 72 bpm. The VAD operation was judged by not only the rotational speed of the impeller, but also the diastolic, systolic, and average flow rates and the average pressure head of the VAD. The conditions of the mock circulatory loop, including the pulse rate of the diaphragm pump, the fluid temperature, and the fluid viscosity were maintained. Eight VADs were tested with testing periods of 2 years, during which they were continuously in operation. The VAD performance factors, including the power consumption and the vibration characteristics, were kept almost constant. The long-term durability of the developed VAD was successfully demonstrated.     

Biventricular support using a centrifugal pump in a 6 year old with fulminant myocarditis

We experienced a case of ventricular assist with both a pulsatile-flow and a continuous-flow pump in a pediatric patient, and herein report the clinical course and characteristics of the pumps. A 6-year-old female was diagnosed with fulminant myocarditis and transferred to our hospital for mechanical support. After 12 days of extracorporeal membrane oxygenation, we implanted a left ventricular assist device (LVAD) and a right ventricular assist device (RVAD) using centrifugal Gyro pumps with a membrane oxygenator in a paracorporeal fashion. The membrane oxygenator was removed on postoperative day (POD) 4, and the patient was weaned from the respirator on POD 6. The LVAD was exchanged on POD 13 and 17, and the RVAD was exchanged on POD 14 because of thrombus formation inside the pumps. The RVAD was removed on POD 25. On POD 32, the patient experienced cerebral infarction and the centrifugal Gyro pump was switched to an extracorporeal pulsatile pump. No thromboembolic event occurred after pump conversion, although continuous administration of vasodilators was required to avoid hypertension. She underwent successfully heart transplantation in the USA after 8 months of ventricular support. A centrifugal pump is considered useful for pediatric patients, as pump flow and blood pressure can be relatively easily controlled in the postoperative acute phase compared with the pulsatile pump. However, special care should be taken to monitor for thrombus formation when support length becomes longer than 13 days, and a switch to a pulsatile pump should be considered once the hemodynamic status stabilizes.